類器官：修订间差异
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[[File:Intestinal_organoid.PNG|thumb|由 Lgr5+ 细胞株培養生成的腸道類器官]] |
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'''類器官'''（{{lang-en|Organoid}}）是原生動物所具有的一種特殊結構，負責執行類似高等動物器官的功能，也有人將其歸入細胞器。 |
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'''類器官'''是[[In vitro|體外]]培養生成的立體細胞團，是特定[[器官]]的迷你簡化版本，模仿該器官的關鍵功能、結構和生物複雜性。<ref>Zhao Z, Chen X, Dowbaj AM, Sljukic A, Bratlie K, Lin L, Fong ELS, Balachander GM, Chen Z, Soragni A, Huch M, Zeng YA, Wang Q, Yu H. Organoids. Nature Reviews Methods Primers 2, 94 (2022). https://doi.org/10.1038/s43586-022-00174-y</ref> 類器官的培養可以起源於[[胚胎幹細胞]]或者[[成体干细胞|成體幹細胞]]等[[細胞潛能|多能性]]幹細胞、[[诱导性多能干细胞|人工誘導性多能幹細胞]]以及[[腫瘤幹細胞|癌症幹細胞]]，這些細胞的自我更新以及[[细胞分化|分化]]潛能賦予其在立體培養條件下中自組裝的能力。類器官的發展提供科學家與工程師在實驗室中研究疾病與藥物開發的簡化模型。<ref>Hans Clevers, Asher Mullard. Mini-organs attract big pharma. Nature Reviews Drug Discovery (16 February 2023). https://doi.org/10.1038/d41573-023-00030-y</ref>協助個人化醫療、基因和細胞療法、組織工程和再生醫學等領域的發展。<ref>{{Cite journal |last=Zhao |first=Zixuan |last2=Chen |first2=Xinyi |last3=Dowbaj |first3=Anna M. |last4=Sljukic |first4=Aleksandra |last5=Bratlie |first5=Kaitlin |last6=Lin |first6=Luda |last7=Fong |first7=Eliza Li Shan |last8=Balachander |first8=Gowri Manohari |last9=Chen |first9=Zhaowei |last10=Soragni |first10=Alice |last11=Huch |first11=Meritxell |date=2022-12-01 |title=Organoids |url=https://www.nature.com/articles/s43586-022-00174-y |journal=Nature Reviews Methods Primers |language=en |volume=2 |issue=1 |doi=10.1038/s43586-022-00174-y |issn=2662-8449}}</ref> |
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== 歷史 == |
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'''類器官'''也可是一種科學研究技術，指一些细胞的培养物，能夠包含其代表器官的一些关键特性，以便進行檢測或科學研究。<ref>{{Cite web |url=http://tech.sina.com.cn/roll/2018-04-30/doc-ifzvpatr4248245.shtml |title=什么是类器官？解读近年来类器官领域重要研究进展！|publisher=新浪科技|access-date=2018-04-30 |archive-url=https://web.archive.org/web/20181027113320/http://tech.sina.com.cn/roll/2018-04-30/doc-ifzvpatr4248245.shtml |archive-date=2018-10-27 |dead-url=no }}</ref> |
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體外培養器官的始於一個解離再聚集實驗<ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}</ref> ，科學家[[亨利·范·彼特斯·威森|亨利·範·彼特斯·威森]]發現透過機械方式打散的[[海綿]]細胞可以自發性地重新聚集並組裝成完整個體<ref>{{Cite journal |vauthors=Wilson HV |date=June 1907 |title=A new method by which sponges may be artificially reared |url=https://zenodo.org/record/1447988 |journal=Science |volume=25 |issue=649 |page=912–5 |bibcode=1907Sci....25..912W |doi=10.1126/science.25.649.912 |pmid=17842577}}</ref>。在隨後的幾十年中，多個實驗室成功於兩棲動物<ref>{{Cite journal |vauthors=Holtfreter J |date=1944 |title=Experimental studies on the development of the pronephros. |journal=Rev. Can. Biol. |volume=3 |page=220–250}}</ref>和雞胚胎<ref>{{Cite journal |vauthors=Weiss P, Taylor AC |date=September 1960 |title=Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=46 |issue=9 |page=1177–85 |bibcode=1960PNAS...46.1177W |doi=10.1073/pnas.46.9.1177 |pmc=223021 |pmid=16590731 |doi-access=free}}</ref>身上取得的器官組織重現解離後自組裝的實驗，在體外生成各類型的器官<ref name="Lancaster, M. A. 2014" />。1975年，科學家透過共培養角質形成細胞和3T3纖維母細胞，首次在體外觀察到第一個組織樣細胞群的形成<ref>{{Cite journal |last=Rheinwald |first=James G. |last2=Green |first2=Howard |date=November 1975 |title=Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma |url=http://dx.doi.org/10.1016/0092-8674(75)90183-x |journal=Cell |volume=6 |issue=3 |page=317–330 |doi=10.1016/0092-8674(75)90183-x |issn=0092-8674 |pmid=1052770 |s2cid=28185779}}</ref>。這些透過機械外力打散器官後的細胞再聚集與自組裝的現象促致[[馬爾科姆·斯坦伯格]]提出了[[差異黏附假說]]（Differential adhesion hypothesis，DAH）<ref name="Lancaster, M. A. 2014" />。 隨著[[幹細胞]]生物學的出現，科學家開始認識到幹細胞在體外形成器官的潛力，因為觀察到當其形成畸胎瘤或擬胚體時，分化的細胞可以組織成類似於在體內發現的各種組織類型<ref name="Lancaster, M. A. 2014" />。類器官的出現始於細胞培養從二維平面基質轉為三維立體基質的階段，隨著細胞外基質的發展，3D培養基方法的方法成為可能<ref name=":5">{{Cite journal |last=Yi |first=Sang Ah |last2=Zhang |first2=Yixiao |last3=Rathnam |first3=Christopher |last4=Pongkulapa |first4=Thanapat |last5=Lee |first5=Ki-Bum |date=November 2021 |title=Bioengineering Approaches for the Advanced Organoid Research |journal=Advanced Materials |language=en |volume=33 |issue=45 |page=e2007949 |bibcode=2021AdM....3307949Y |doi=10.1002/adma.202007949 |issn=0935-9648 |pmc=8682947 |pmid=34561899}}</ref>，以允許器官立體結構的發育。<ref name="Lancaster, M. A. 2014" />20 世纪 80 年代末， [[米娜·贝塞尔|米娜·貝塞爾]]及其同事證明，富含[[层粘连蛋白|層粘連蛋白]]的凝膠可用作[[乳腺]][[上皮細胞]]培養分化的基底膜<ref>{{Cite journal |last=Li |first=M L |last2=Aggeler |first2=J |last3=Farson |first3=D A |last4=Hatier |first4=C |last5=Hassell |first5=J |last6=Bissell |first6=M J |date=January 1987 |title=Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. |journal=Proceedings of the National Academy of Sciences |volume=84 |issue=1 |page=136–140 |bibcode=1987PNAS...84..136L |doi=10.1073/pnas.84.1.136 |issn=0027-8424 |pmc=304157 |pmid=3467345 |doi-access=free}}</ref><ref>{{Cite journal |last=Barcellos-Hoff |first=M. H. |last2=Aggeler |first2=J. |last3=Ram |first3=T. G. |last4=Bissell |first4=M. J. |date=1989-02-01 |title=Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane |url=http://dx.doi.org/10.1242/dev.105.2.223 |journal=Development |volume=105 |issue=2 |page=223–235 |doi=10.1242/dev.105.2.223 |issn=0950-1991 |pmc=2948482 |pmid=2806122}}</ref>。如今，各類器官的培養方法已被提出並逐漸成熟<ref>{{Cite journal |last=Hofer |first=Moritz |last2=Lutolf |first2=Matthias P. |date=2021-05 |title=Engineering organoids |url=https://www.nature.com/articles/s41578-021-00279-y |journal=Nature Reviews Materials |language=en |volume=6 |issue=5 |doi=10.1038/s41578-021-00279-y |issn=2058-8437}}</ref>。在20世紀90年代，除了ECM提供細胞生長物理性質上的支持被提出外，還報導了ECM內的成分透過與基於整合素的黏著蛋白通路相互作用而影響基因表現<ref>{{Cite journal |last=Streuli |first=C H |last2=Schmidhauser |first2=C |last3=Bailey |first3=N |last4=Yurchenco |first4=P |last5=Skubitz |first5=A P |last6=Roskelley |first6=C |last7=Bissell |first7=M J |date=1995-05-01 |title=Laminin mediates tissue-specific gene expression in mammary epithelia. |url=http://dx.doi.org/10.1083/jcb.129.3.591 |journal=The Journal of Cell Biology |volume=129 |issue=3 |page=591–603 |doi=10.1083/jcb.129.3.591 |issn=0021-9525 |pmc=2120432 |pmid=7730398}}</ref>。2006年， Yaakov Nahmias和David Odde展示了血管[[肝臟|肝]]类器官的自组裝在體外環境维持了50多天<ref name="pmid 16846358">{{Cite journal |vauthors=Nahmias Y, Schwartz RE, Hu WS, Verfaillie CM, Odde DJ |date=June 2006 |title=Endothelium-mediated hepatocyte recruitment in the establishment of liver-like tissue in vitro |journal=Tissue Engineering |volume=12 |issue=6 |page=1627–38 |doi=10.1089/ten.2006.12.1627 |pmid=16846358}}</ref>。2008年，[[理化学研究所|日本理化学]]研究所的[[笹井芳樹|Yoshiki Sasai]]和他的团队证明，[[幹細胞|干细胞]]可以被诱导成[[神經元|神经]]细胞球並且自组织成独特的层狀構造<ref>{{Cite web|title=Lab-Grown Model Brains|url=http://www.the-scientist.com/?articles.view/articleNo/37262/title/Lab-Grown-Model-Brains/|website=[[The Scientist (magazine)|The Scientist]]|date=August 28, 2013|author-link=Ed Yong|last=Yong|first=Ed|name-list-style=vanc|access-date=26 December 2013}}</ref>。2009年，[[荷蘭皇家藝術與科學學院|荷蘭皇家藝術與科學研究所]]和[[乌特勒支大学|烏特勒支大學]]的Hans Clevers实验室表明，单个表达LGR5的肠干细胞可以在體外自组织成隐窝绒毛结构並且無須提供[[间充质|间质]]區位，这使它们成为第一个类器官<ref name="pmid19329995">{{Cite journal |author-link10=Peter J. Peters |display-authors=6 |vauthors=Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H |date=May 2009 |title=Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche |journal=Nature |volume=459 |issue=7244 |page=262–5 |bibcode=2009Natur.459..262S |doi=10.1038/nature07935 |pmid=19329995 |s2cid=4373784}}</ref>。2010 年，Mathieu Unbekandt 和Jamie A. Davies证明了利用鼠胚衍生的肾干细胞可产生肾类器官<ref name="sciencedirect.com">{{Cite journal |vauthors=Unbekandt M, Davies JA |date=March 2010 |title=Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues |journal=Kidney International |volume=77 |issue=5 |page=407–16 |doi=10.1038/ki.2009.482 |pmid=20016472 |doi-access=free}}</ref>。2014年，王峮及其同事设计了基于I型胶原和层粘连蛋白的凝胶和合成泡沫生物材料，用于培养和運輸肠道类器官<ref>Peng H, Poovaiah N, Forrester M, Cochran E, Wang Q. Ex Vivo Culture of Primary Intestinal Stem Cells in Collagen Gels and Foams. ACS Biomaterials Science & Engineering. 2014 Dec 2;1(1):37–42. https://doi.org/10.1021/ab500041d. PMID: 33435081.</ref> ，并将DNA功能化的金纳米颗粒封装到肠道类器官中，成為可供药物運送與基因治療的肠道特洛伊木马（intestinal Trojan horse）<ref>Peng H, Wang C, Xu X, Yu C, Wang Q. An intestinal Trojan horse for gene delivery. Nanoscale. 2015 Jan 6;7(10):4354–4360. https://doi.org/10.1039/C4NR06377E. PMID: 25619169.</ref>。後續的研究显示这些类器官在體外<ref>{{Cite journal |vauthors=Lawrence ML, Chang CH, Davies JA |date=March 2015 |title=Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys |journal=Scientific Reports |volume=5 |page=9092 |bibcode=2015NatSR...5E9092L |doi=10.1038/srep09092 |pmc=4357899 |pmid=25766625}}</ref>和''[[In vivo|体内]]''同樣具有显着的生理功能<ref>{{Cite journal |display-authors=6 |vauthors=Xinaris C, Benedetti V, Rizzo P, Abbate M, Corna D, Azzollini N, Conti S, Unbekandt M, Davies JA, Morigi M, Benigni A, Remuzzi G |date=November 2012 |title=In vivo maturation of functional renal organoids formed from embryonic cell suspensions |journal=Journal of the American Society of Nephrology |volume=23 |issue=11 |page=1857–68 |doi=10.1681/ASN.2012050505 |pmc=3482737 |pmid=23085631}}</ref> <ref>Yui, S., Nakamura, T., Sato, T. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nature Medicine 18, 618–623 (2012). https://doi.org/10.1038/nm.2695</ref>。 |
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其他重大的早期进展包括 2013 年，[[奧地利科學院|奥地利科学院]]分子生物技术研究所的Madeline Lancaster制定了一项流程，可以从多能干细胞开始生成模仿人类大脑细胞组织发育的[[類人腦|大脑类器官]]<ref name="lancaster">{{Cite journal |display-authors=6 |vauthors=Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA |date=September 2013 |title=Cerebral organoids model human brain development and microcephaly |journal=Nature |volume=501 |issue=7467 |page=373–9 |bibcode=2013Natur.501..373L |doi=10.1038/nature12517 |pmc=3817409 |pmid=23995685}}</ref>。[[荷蘭皇家藝術與科學學院|荷蘭皇家藝術與科學研究所]]和[[乌特勒支大学|烏特勒支大學]]医学中心的Meritxell Huch與Craig Dorrell证明，来自受损小鼠肝脏的单个Lgr5+细胞可以在基于Rspo1的培养基中複製並扩增數個月並最終形成肝类器官<ref>Huch, M., Dorrell, C., Boj, S. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013). https://doi.org/10.1038/nature11826</ref>。2014 年，[[伊利諾大學厄巴納-香檳分校]]的Artem Shkumatov等人证明，通过調控[[胚胎幹細胞|胚胎干细胞]]粘附的基质硬度，可以形成心血管类器官。生理上的硬度特性促进了EB的立體性質與心肌分化<ref name="pmid24732893">{{Cite journal |vauthors=Shkumatov A, Baek K, Kong H |year=2014 |title=Matrix rigidity-modulated cardiovascular organoid formation from embryoid bodies |journal=PLOS ONE |volume=9 |issue=4 |page=e94764 |bibcode=2014PLoSO...994764S |doi=10.1371/journal.pone.0094764 |pmc=3986240 |pmid=24732893 |doi-access=free}}</ref>。2015 年，Takebe 等人通过将多能干细胞衍生的组织特异性祖细胞或相关组织样本与内皮细胞和间质干细胞相结合，展示了一种从不同组织形成器官芽的通用方法。他们认为，通过自组织凝聚原理产生的不太成熟的组织或器官芽可能是移植后重建成熟器官功能的最有效方法，而不是由發育上更加成熟阶段的细胞凝聚物<ref>{{Cite journal |display-authors=6 |vauthors=Takebe T, Enomura M, Yoshizawa E, Kimura M, Koike H, Ueno Y, Matsuzaki T, Yamazaki T, Toyohara T, Osafune K, Nakauchi H, Yoshikawa HY, Taniguchi H |date=May 2015 |title=Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation |journal=Cell Stem Cell |volume=16 |issue=5 |page=556–65 |doi=10.1016/j.stem.2015.03.004 |pmid=25891906 |doi-access=free}}</ref>。 |
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類器官的例子有<ref>{{Cite book|title=簡明動物學（第二版）|last=宋|first=憬愚|publisher=科學出版社|year=|isbn=978-7-03-052366-2|location=|pages=}}</ref>： |
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*運動類器官：[[鞭毛]]、[[纖毛]]、僞足等 |
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*攝食類器官：胞口、口溝等 |
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*調節滲透壓類器官：伸縮泡等 |
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== 特性 == |
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Lancaster 和 Knoblich <ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}</ref>將類器官定義為從幹細胞或器官前驅細胞發育而來的器官特異性細胞類型的集合，透過細胞分選和空間限制的譜系定型以類似於體內的方式進行自組織，並表現出以下特徵特性： |
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{{reflist}} |
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* 具備數種器官特異性的細胞類型。 |
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* 能夠概括器官的特定功能（例如[[肌肉收缩|收縮]]、神經活動、[[內分泌系統|內分泌]]、過濾、[[排泄]]）。 |
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* 細胞能夠聚集並且自組裝成為類似器官的功能性構造。 |
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== 培養過程 == |
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{{生物小作品}} |
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类器官的生長通常需要在立體培养基中培养[[幹細胞|干细胞]]或[[祖細胞|祖细胞]]<ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFLancasterKnoblich2014">Lancaster MA, Knoblich JA (July 2014). "Organogenesis in a dish: modeling development and disease using organoid technologies". ''Science''. '''345''' (6194): 1247125. [[DOI|doi]]:[[doi:10.1126/science.1247125|10.1126/science.1247125]]. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/25035496 25035496]. [[语义学者|S2CID]] [https://api.semanticscholar.org/CorpusID:16105729 16105729].</cite></ref>。干细胞具有自我更新和[[分化]]成各种细胞類型的能力，并且能够用於了解发育和疾病进展的过程<ref>{{Cite journal |last=Murry |first=Charles E. |last2=Keller |first2=Gordon |date=February 2008 |title=Differentiation of Embryonic Stem Cells to Clinically Relevant Populations: Lessons from Embryonic Development |url=http://dx.doi.org/10.1016/j.cell.2008.02.008 |journal=Cell |volume=132 |issue=4 |page=661–680 |doi=10.1016/j.cell.2008.02.008 |issn=0092-8674 |pmid=18295582 |doi-access=free}}</ref>。因此，源自干细胞的类器官能够在器官水平上研究生理学<ref>{{Cite journal |last=Choudhury |first=Deepak |last2=Ashok |first2=Aswathi |last3=Naing |first3=May Win |date=March 2020 |title=Commercialization of Organoids |url=http://dx.doi.org/10.1016/j.molmed.2019.12.002 |journal=Trends in Molecular Medicine |volume=26 |issue=3 |page=245–249 |doi=10.1016/j.molmed.2019.12.002 |issn=1471-4914 |pmid=31982341 |s2cid=210922708}}</ref>。立體培养基可以使用[[细胞外基质]][[水凝胶]]（例如[[康宁Matrigel基质|Matrigel]]或 Cultrex BME）制成，这是一种富含[[层粘连蛋白]]的细胞外基质，由 Engelbreth-Holm-Swarm肿瘤細胞株分泌<ref>{{Cite journal |vauthors=Li ML, Aggeler J, Farson DA, Hatier C, Hassell J, Bissell MJ |date=January 1987 |title=Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=84 |issue=1 |page=136–40 |bibcode=1987PNAS...84..136L |doi=10.1073/pnas.84.1.136 |pmc=304157 |pmid=3467345 |doi-access=free}}</ref>，可以通过将干细胞嵌入 基质中来制备类器官<ref name="Lancaster, M. A. 2014" />。当[[細胞潛能|多能性]]幹细胞用于创建类器官时，细胞通常（但并非总是）形成[[擬胚體]]<ref name="Lancaster, M. A. 2014" />。然后用模式因子对这些拟胚体进行处理，以驱动所需类器官特征的形成<ref name="Lancaster, M. A. 2014" />。此外，也可以使用目標器官中提取的成体干细胞創建类器官，并在立體培养基中培养<ref name="Pastuła, A. 2016">{{Cite journal |display-authors=6 |vauthors=Pastuła A, Middelhoff M, Brandtner A, Tobiasch M, Höhl B, Nuber AH, Demir IE, Neupert S, Kollmann P, Mazzuoli-Weber G, Quante M |year=2016 |title=Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche |journal=Stem Cells International |volume=2016 |page=3710836 |doi=10.1155/2016/3710836 |pmc=4677245 |pmid=26697073 |doi-access=free}}</ref>。 |
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生物化學的特性已被纳入类器官培养中，藉由添加形态发生素、形态发生抑制剂或生长因子，可以誘導胚胎干细胞或成体干细胞發育成為类器官。血管化技術可用於賦予微環境在生理上接近其相對應部位的特性。可以藉由[[微流控|微流体]]系统、血管内皮生长因子输送系统和内皮细胞涂层模块来達成可促进氧气或营养物质进入类器官内部的血管系统<ref name=":5">{{Cite journal |last=Yi |first=Sang Ah |last2=Zhang |first2=Yixiao |last3=Rathnam |first3=Christopher |last4=Pongkulapa |first4=Thanapat |last5=Lee |first5=Ki-Bum |date=November 2021 |title=Bioengineering Approaches for the Advanced Organoid Research |journal=Advanced Materials |language=en |volume=33 |issue=45 |page=e2007949 |bibcode=2021AdM....3307949Y |doi=10.1002/adma.202007949 |issn=0935-9648 |pmc=8682947 |pmid=34561899}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFYiZhangRathnamPongkulapa2021">Yi, Sang Ah; Zhang, Yixiao; Rathnam, Christopher; Pongkulapa, Thanapat; Lee, Ki-Bum (November 2021). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8682947 "Bioengineering Approaches for the Advanced Organoid Research"]. ''Advanced Materials''. '''33''' (45): e2007949. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2021AdM....3307949Y 2021AdM....3307949Y]. [[DOI|doi]]:[[doi:10.1002/adma.202007949|10.1002/adma.202007949]]. [[國際標準期刊號|ISSN]] [[issn:0935-9648|0935-9648]]. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8682947 8682947]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/34561899 34561899].</cite></ref>。利用源自患者的[[诱导性多能干细胞|诱导多能干细胞]](iPSC) <ref>{{Cite journal |last=Takahashi |first=Kazutoshi |last2=Yamanaka |first2=Shinya |date=August 2006 |title=Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors |url=http://dx.doi.org/10.1016/j.cell.2006.07.024 |journal=Cell |volume=126 |issue=4 |page=663–676 |doi=10.1016/j.cell.2006.07.024 |issn=0092-8674 |hdl=2433/159777 |pmid=16904174 |hdl-access=free}}</ref>和基于[[CRISPR|CRISPR/Cas9]]的基因编辑<ref>{{Cite journal |last=Ran |first=F Ann |last2=Hsu |first2=Patrick D |last3=Wright |first3=Jason |last4=Agarwala |first4=Vineeta |last5=Scott |first5=David A |last6=Zhang |first6=Feng |date=2013-10-24 |title=Genome engineering using the CRISPR-Cas9 system |url=http://dx.doi.org/10.1038/nprot.2013.143 |journal=Nature Protocols |volume=8 |issue=11 |page=2281–2308 |doi=10.1038/nprot.2013.143 |issn=1754-2189 |pmc=3969860 |pmid=24157548}}</ref>技术，可以生成基因組編輯或突變的多能幹細胞（PSCs），並改變信號傳遞特性，以控制器官模型內的內在性質。 |
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[[Category:細胞器]] |
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[[Category:细胞运动]] |
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== 類型 == |
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使用類器官可以概括多種器官結構<ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}</ref>。本節旨在透過提供一份精簡的器官模型清單，概述目前該領域的現狀，並根據最新文獻對每個器官模型進行簡要概述，並提供其在研究中的應用示例。 |
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=== 腦類器官 === |
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脑类器官是指體外培養的类似于[[脑|大脑]]的微型器官。大脑类器官於旋转[[生物反应器]]在三维環境下中培养人类[[幹細胞|多能干细胞]]产生，并需要数月的时间发育<ref name="lancaster">{{Cite journal |display-authors=6 |vauthors=Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA |date=September 2013 |title=Cerebral organoids model human brain development and microcephaly |journal=Nature |volume=501 |issue=7467 |page=373–9 |bibcode=2013Natur.501..373L |doi=10.1038/nature12517 |pmc=3817409 |pmid=23995685}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFLancasterRennerMartinWenzel2013">Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. (September 2013). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817409 "Cerebral organoids model human brain development and microcephaly"]. ''Nature''. '''501''' (7467): 373–9. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2013Natur.501..373L 2013Natur.501..373L]. [[DOI|doi]]:[[doi:10.1038/nature12517|10.1038/nature12517]]. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817409 3817409]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/23995685 23995685].</cite></ref>。這對脑部发育、生理学和功能的研究中具有潜在的应用。腦类器官可能会对外部刺激产生「简单的感觉」，神经科学家也对这些器官可能发展出[[感情|感知能力]]表示担忧。他们提出，该技术的进一步发展需要受到严格的监督<ref>{{Cite journal |vauthors=Lavazza A, Massimini M |date=September 2018 |title=Cerebral organoids: ethical issues and consciousness assessment |journal=Journal of Medical Ethics |volume=44 |issue=9 |page=606–610 |doi=10.1136/medethics-2017-104555 |pmid=29491041 |doi-access=free}}</ref> <ref>{{Cite news|author=Prosser Scully|first=Ruby|title=Miniature brains grown in the lab have human-like neural activity|url=https://www.newscientist.com/article/2207911-miniature-brains-grown-in-the-lab-have-human-like-neural-activity/|work=[[New Scientist]]|issue=3237|date=6 July 2019}}</ref> <ref>{{Cite news|author=Sample|first=Ian|title=Scientists 'may have crossed ethical line' in growing human brains|url=https://www.theguardian.com/science/2019/oct/21/scientists-may-have-crossed-ethical-line-in-growing-human-brains|work=[[The Guardian]]|date=21 October 2019|page=15}}</ref>。2023年，研究人员建造了一台混合生物计算机，将实验室培养的人脑类器官与传统电路相结合，可以完成语音识别等任务<ref>Cai, H., Ao, Z., Tian, C. et al. Brain organoid reservoir computing for artificial intelligence. Nat Electron (2023). https://doi.org/10.1038/s41928-023-01069-w.</ref>。脑类器官目前正用于研究和开发类器官智能（OI）技术。 <ref>Smirnova L, Caffo BS, Gracias DH, Huang Q, Morales Pantoja IE, Tang B, Zack DJ, Berlinicke CA, Boyd JL, Harris TD, Johnson EC, Kagan BJ, Kahn J, Muotri AR, Paulhamus BL, Schwamborn JC, Plotkin J, Szalay AS, Vogelstein JT, Worley PF and Hartung T. Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish. Front Sci (2023) 1:1017235. https://doi.org/10.3389/fsci.2023.1017235.</ref> |
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=== 胃腸道類器官 === |
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胃腸道類器官是指概括[[消化系统|胃腸道]]結構的類器官。胃腸道起源於[[内胚层|內胚層]]，在發育過程中形成一個管狀構造，可以分為三個不同的區域，與其他器官一起產生胃腸道的以下部分：<ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}</ref> |
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:# [[前腸]]發育形成[[口腔]]和[[胃]] |
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:# [[中腸]]發育形成[[小肠|小腸]]和[[升结肠|升結腸]] |
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:# [[後腸]]發育形成結腸的其餘部分和[[直肠|直腸]] |
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胃腸道類器官又可細分為以下數種： |
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==== 腸類器官 ==== |
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迄今为止，肠类器官<ref name="pmid19329995">{{Cite journal |author-link10=Peter J. Peters |display-authors=6 |vauthors=Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H |date=May 2009 |title=Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche |journal=Nature |volume=459 |issue=7244 |page=262–5 |bibcode=2009Natur.459..262S |doi=10.1038/nature07935 |pmid=19329995 |s2cid=4373784}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFSatoVriesSnippertvan_de_Wetering2009">Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. (May 2009). "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche". ''Nature''. '''459''' (7244): 262–5. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2009Natur.459..262S 2009Natur.459..262S]. [[DOI|doi]]:[[doi:10.1038/nature07935|10.1038/nature07935]]. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/19329995 19329995]. [[语义学者|S2CID]] [https://api.semanticscholar.org/CorpusID:4373784 4373784].</cite></ref>属于直接由肠组织或多能干细胞产生的肠道类器官<ref name="Lancaster, M. A. 2014">{{Cite journal |vauthors=Lancaster MA, Knoblich JA |date=July 2014 |title=Organogenesis in a dish: modeling development and disease using organoid technologies |journal=Science |volume=345 |issue=6194 |page=1247125 |doi=10.1126/science.1247125 |pmid=25035496 |s2cid=16105729}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFLancasterKnoblich2014">Lancaster MA, Knoblich JA (July 2014). "Organogenesis in a dish: modeling development and disease using organoid technologies". ''Science''. '''345''' (6194): 1247125. [[DOI|doi]]:[[doi:10.1126/science.1247125|10.1126/science.1247125]]. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/25035496 25035496]. [[语义学者|S2CID]] [https://api.semanticscholar.org/CorpusID:16105729 16105729].</cite></ref>。促使人类多能干细胞形成肠类器官的方法是，首先使用[[激活素与抑制素|激活素]]A 驱動细胞进入中内胚层状态，然后对Wnt3a和Fgf4信号通路进行上调，因为它们已被证明可以促进組織走向后肠道細胞命运<ref name="Lancaster, M. A. 2014" />。肠类器官也可以由肠干细胞产生，从成体组织中提取并在立體培养基中培养<ref name="Pastuła, A. 2016">{{Cite journal |display-authors=6 |vauthors=Pastuła A, Middelhoff M, Brandtner A, Tobiasch M, Höhl B, Nuber AH, Demir IE, Neupert S, Kollmann P, Mazzuoli-Weber G, Quante M |year=2016 |title=Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche |journal=Stem Cells International |volume=2016 |page=3710836 |doi=10.1155/2016/3710836 |pmc=4677245 |pmid=26697073 |doi-access=free}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFPastułaMiddelhoffBrandtnerTobiasch2016">Pastuła A, Middelhoff M, Brandtner A, Tobiasch M, Höhl B, Nuber AH, et al. (2016). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677245 "Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche"]. ''Stem Cells International''. '''2016''': 3710836. [[DOI|doi]]:<span class="cs1-lock-free" title="Freely accessible">[[doi:10.1155/2016/3710836|10.1155/2016/3710836]]</span>. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677245 4677245]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/26697073 26697073].</cite></ref>。这些成体干细胞衍生的类器官通常被称为肠类器官或类结肠类器官，具体取决于它们的起源部分，并且是从人类和小鼠肠道中建立的<ref name="pmid19329995" /> <ref>{{Cite journal |last=Sato |first=Toshiro |last2=Stange |first2=Daniel E. |last3=Ferrante |first3=Marc |last4=Vries |first4=Robert G.J. |last5=van Es |first5=Johan H. |last6=van den Brink |first6=Stieneke |last7=van Houdt |first7=Winan J. |last8=Pronk |first8=Apollo |last9=van Gorp |first9=Joost |last10=Siersema |first10=Peter D. |last11=Clevers |first11=Hans |date=November 2011 |title=Long-term Expansion of Epithelial Organoids From Human Colon, Adenoma, Adenocarcinoma, and Barrett's Epithelium |journal=Gastroenterology |volume=141 |issue=5 |page=1762–1772 |doi=10.1053/j.gastro.2011.07.050 |issn=0016-5085 |pmid=21889923 |doi-access=free}}</ref> <ref>{{Cite journal |last=Jung |first=Peter |last2=Sato |first2=Toshiro |last3=Merlos-Suárez |first3=Anna |last4=Barriga |first4=Francisco M |last5=Iglesias |first5=Mar |last6=Rossell |first6=David |last7=Auer |first7=Herbert |last8=Gallardo |first8=Mercedes |last9=Blasco |first9=Maria A |last10=Sancho |first10=Elena |last11=Clevers |first11=Hans |date=October 2011 |title=Isolation and in vitro expansion of human colonic stem cells |url=http://www.nature.com/articles/nm.2470 |journal=Nature Medicine |language=en |volume=17 |issue=10 |page=1225–1227 |doi=10.1038/nm.2470 |issn=1078-8956 |pmid=21892181 |s2cid=205388154}}</ref>。肠类器官由围绕中央管腔的单层极化肠[[上皮組織|上皮]]细胞组成。因此，通过概括肠道的功能、生理学和组织，并维持结构中正常存在的所有细胞类型（包括肠干细胞），概括肠道的隐窝绒毛结构<ref name="Lancaster, M. A. 2014" />。因此，肠类器官是研究肠道营养转运<ref>Cai T, Qi Y, Jergens A, Wannemuehler M, Barrett TA, Wang Q. Effects of six common dietary nutrients on murine intestinal organoid growth. PLoS One. 2018 Feb 1;13(2):e0191517. https://doi.org/10.1371/journal.pone.0191517. PMID: 29389993; PMCID: PMC5794098.</ref> <ref>Qi Y, Lohman J, Bratlie KM, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Yoon KJ, Barrett TA, Wang Q. Vitamin C and B3 as new biomaterials to alter intestinal stem cells. Journal of Biomedical Materials Research Part A. 2019 Sep;107(9):1886–1897. https://doi.org/10.1002/jbm.a.36715. Epub 2019 May 23. PMID: 31071241; PMCID: PMC6626554.</ref>、药物吸收和递送<ref>Davoudi Z, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Barrett TA, Narasimhan B, Wang Q. Intestinal organoids containing poly(lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases. Journal of Biomedical Materials Research Part A. 2018 Apr;106(4):876–886. https://doi.org/10.1002/jbm.a.36305. Epub 2017 Dec 21. PMID: 29226615; PMCID: PMC5826879.</ref> <ref>Davoudi Z, Peroutka-Bigus N, Bellaire B, Jergens A, Wannemuehler M, Wang Q. Gut Organoid as a New Platform to Study Alginate and Chitosan Mediated PLGA Nanoparticles for Drug Delivery. Marine Drugs. 2021 May 20;19(5):282. https://doi.org/10.3390/md19050282. PMID: 34065505; PMCID: PMC8161322.</ref>、纳米材料和纳米医学<ref>Qi Y, Shi E, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Jergens A, Barrett T, Wu Y, Wang Q. Ex Vivo Study of Telluride Nanowires in Minigut. Journal of Biomedical Nanotechnology. 2018 May 1;14(5):978–986. https://doi.org/10.1166/jbn.2018.2578. PMID: 29883567</ref> <ref>Reding B, Carter P, Qi Y, Li Z, Wu Y, Wannemuehler M, Bratlie KM, Wang Q. Manipulate intestinal organoids with niobium carbide nanosheets. Journal of Biomedical Materials Research Part A. 2021 Apr;109(4):479–487. https://doi.org/10.1002/jbm.a.37032. Epub 2020 Jun 17. PMID: 32506610.</ref>、肠泌素分泌<ref>{{Cite journal |vauthors=Zietek T, Rath E, Haller D, Daniel H |date=November 2015 |title=Intestinal organoids for assessing nutrient transport, sensing and incretin secretion |journal=Scientific Reports |volume=5 |issue=1 |page=16831 |bibcode=2015NatSR...516831Z |doi=10.1038/srep16831 |pmc=4652176 |pmid=26582215 |doi-access=free}}</ref> <ref>{{Cite journal |display-authors=6 |vauthors=Zietek T, Giesbertz P, Ewers M, Reichart F, Weinmüller M, Demir IE, Haller D, Ceyhan GO, Kessler H, Rath E |date=2020 |title=Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism – Update to the Human Model and Expansion of Applications |journal=Frontiers in Bioengineering and Biotechnology |volume=8 |page=577656 |doi=10.3389/fbioe.2020.577656 |pmc=7516017 |pmid=33015026 |doi-access=free}}</ref>和各种肠道病原体感染<ref>{{Cite journal |last=Rahmani |first=Sara |last2=Breyner |first2=Natalia M. |last3=Su |first3=Hsuan-Ming |last4=Verdu |first4=Elena F. |last5=Didar |first5=Tohid F. |date=2019-02-01 |title=Intestinal organoids: A new paradigm for engineering intestinal epithelium in vitro |url=https://www.sciencedirect.com/science/article/abs/pii/S0142961218308287 |journal=Biomaterials |language=en |volume=194 |page=195–214 |doi=10.1016/j.biomaterials.2018.12.006 |issn=0142-9612 |pmid=30612006 |s2cid=58603850}}</ref> <ref>Sun L, Rollins D, Qi Y, Fredericks J, Mansell TJ, Jergens A, Phillips GJ, Wannemuehler M, Wang Q. TNFα regulates intestinal organoids from mice with both defined and conventional microbiota. International Journal of Biological Macromolecules. 2020 Dec 1;164:548–556. https://doi.org/10.1016/j.ijbiomac.2020.07.176. Epub 2020 Jul 18. PMID: 32693143; PMCID: PMC7657954.</ref>等議題的有力模型。 |
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例如，王峮团队利用肠类器官衍生的粘膜模型设计了人工病毒纳米顆粒作为口服药物递送载体（ODDV）<ref>Tong T, Qi Y, Rollins D, Bussiere LD, Dhar D, Miller CL, Yu C, Wang Q. Rational design of oral drugs targeting mucosa delivery with gut organoid platforms. Bioactive Materials. 2023; 30: 116–128. https://doi.org/10.1016/j.bioactmat.2023.07.014. PMID: 37560199.</ref>，并展示了利用新建立的结肠类器官作为高通量药物筛选、毒性分析工具的新概念。测试和口服药物开发<ref>Davoudi Z, Atherly T, Borcherding DC, Jergens AE, Wannemuehler M, Barrett TA, Wang Q. Study Transportation of Drugs within Newly Established Murine Colon Organoid Systems. Advanced Biology. 2023; e2300103. https://doi.org/10.1002/adbi.202300103. PMID: 37607116.</ref>。肠类器官还以如此高的保真度再现了[[利貝昆氏腺|隐窝绒毛]]结构，以至于它们已成功移植到小鼠肠道中，因此被高度视为有价值的研究模型<ref name="Lancaster, M. A. 2014" />。肠类器官已被利用的研究领域之一是干细胞生态位。肠类器官被用来研究肠干细胞區位的性质，並证明了IL-22在维持肠干细胞中的重要作用<ref>{{Cite journal |display-authors=6 |vauthors=Lindemans C, Mertelsmann A, Dudakov JA, Velardi E, Hua G, O'Connor M, Kolesnick R, van den Brink MR, Hanash AM |year=2014 |title=IL-22 Administration Protects Intestinal Stem Cells from Gvhd |journal=Biology of Blood and Marrow Transplantation |volume=20 |issue=2 |page=S53–S54 |doi=10.1016/j.bbmt.2013.12.056 |doi-access=free}}</ref>以及其他細胞類型（如神經元和成纖維細胞）在維持腸道幹細胞的重要性<ref name="Pastuła, A. 2016" />。在感染生物学领域，人们已经探索各類基于肠道类器官的模型系统。一方面，只需将类器官与感兴趣的[[腸胃炎|肠道病原体]]混合即可大量感染<ref>{{Cite journal |last=Zhang |first=Yong-Guo |last2=Wu |first2=Shaoping |last3=Xia |first3=Yinglin |last4=Sun |first4=Jun |date=September 2014 |title=Salmonella -infected crypt-derived intestinal organoid culture system for host-bacterial interactions |journal=Physiological Reports |language=en |volume=2 |issue=9 |page=e12147 |doi=10.14814/phy2.12147 |pmc=4270227 |pmid=25214524}}</ref>。然而，为了模擬更接近自然情況下，由肠腔开始的感染途徑，需要使用[[病原体]]进行显微注射<ref>{{Cite journal |last=Geiser |first=Petra |last2=Di Martino |first2=Maria Letizia |last3=Samperio Ventayol |first3=Pilar |last4=Eriksson |first4=Jens |last5=Sima |first5=Eduardo |last6=Al-Saffar |first6=Anas Kh. |last7=Ahl |first7=David |last8=Phillipson |first8=Mia |last9=Webb |first9=Dominic-Luc |last10=Sundbom |first10=Magnus |last11=Hellström |first11=Per M. |date=2021-02-23 |editor-last=Sperandio |editor-first=Vanessa |title=Salmonella enterica Serovar Typhimurium Exploits Cycling through Epithelial Cells To Colonize Human and Murine Enteroids |journal=mBio |language=en |volume=12 |issue=1 |doi=10.1128/mBio.02684-20 |issn=2161-2129 |pmc=7844539 |pmid=33436434}}</ref> <ref>{{Cite journal |last=Dutta |first=Devanjali |last2=Heo |first2=Inha |last3=O'Connor |first3=Roberta |date=2019-09-14 |title=Studying Cryptosporidium Infection in 3D Tissue-derived Human Organoid Culture Systems by Microinjection |url=https://www.jove.com/video/59610/studying-cryptosporidium-infection-3d-tissue-derived-human-organoid |journal=Journal of Visualized Experiments |language=en |issue=151 |page=59610 |doi=10.3791/59610 |issn=1940-087X |pmid=31566619 |s2cid=203377662}}</ref>。此外，肠类器官的极性可以反转<ref>{{Cite journal |last=Co |first=Julia Y. |last2=Margalef-Català |first2=Mar |last3=Li |first3=Xingnan |last4=Mah |first4=Amanda T. |last5=Kuo |first5=Calvin J. |last6=Monack |first6=Denise M. |last7=Amieva |first7=Manuel R. |date=February 2019 |title=Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions |journal=Cell Reports |language=en |volume=26 |issue=9 |page=2509–2520.e4 |doi=10.1016/j.celrep.2019.01.108 |pmc=6391775 |pmid=30811997}}</ref>，甚至可以解离成单个[[细胞]]并以二维单层培养<ref>Tong T, Qi Y, Bussiere LD, Wannemuehler M, Miller CL, Wang Q, Yu C . Transport of artificial virus-like nanocarriers through intestinal monolayers via microfold cells. Nanoscale. 2020 Aug 14;12(30):16339-16347. https://doi.org/10.1039/D0NR03680C. Epub 2020 Jul 29. PMID: 32725029.</ref> <ref name=":1">{{Cite journal |last=Noel |first=Gaelle |last2=Baetz |first2=Nicholas W. |last3=Staab |first3=Janet F. |last4=Donowitz |first4=Mark |last5=Kovbasnjuk |first5=Olga |last6=Pasetti |first6=Marcela F. |last7=Zachos |first7=Nicholas C. |date=2017-05-31 |title=A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions |journal=Scientific Reports |language=en |volume=7 |issue=1 |page=45270 |bibcode=2017NatSR...745270N |doi=10.1038/srep45270 |issn=2045-2322 |pmc=5366908 |pmid=28345602}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFNoelBaetzStaabDonowitz2017">Noel, Gaelle; Baetz, Nicholas W.; Staab, Janet F.; Donowitz, Mark; Kovbasnjuk, Olga; Pasetti, Marcela F.; Zachos, Nicholas C. (2017-05-31). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366908 "A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions"]. ''Scientific Reports''. '''7''' (1): 45270. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2017NatSR...745270N 2017NatSR...745270N]. [[DOI|doi]]:[[doi:10.1038/srep45270|10.1038/srep45270]]. [[國際標準期刊號|ISSN]] [[issn:2045-2322|2045-2322]]. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366908 5366908]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/28345602 28345602].</cite></ref> ，以便使上皮的顶端和基底外侧更容易接近。最後，肠类器官也显示出用於治疗的潜力<ref name="Bouchi_2914">{{Cite journal |vauthors=Bouchi R, Foo KS, Hua H, Tsuchiya K, Ohmura Y, Sandoval PR, Ratner LE, Egli D, Leibel RL, Accili D |date=June 2014 |title=FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures |journal=Nature Communications |volume=5 |page=4242 |bibcode=2014NatCo...5.4242B |doi=10.1038/ncomms5242 |pmc=4083475 |pmid=24979718}}</ref>。 |
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[[File:Intestinal_Organoid.gif|thumb|顯微鏡下腸類器官Mini-Gut生長的代表圖。比例尺為200微米。]] |
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為了更準確地再現體內腸道，開發了腸道類器官和[[免疫細胞]]的共培養方式<ref name=":1">{{Cite journal |last=Noel |first=Gaelle |last2=Baetz |first2=Nicholas W. |last3=Staab |first3=Janet F. |last4=Donowitz |first4=Mark |last5=Kovbasnjuk |first5=Olga |last6=Pasetti |first6=Marcela F. |last7=Zachos |first7=Nicholas C. |date=2017-05-31 |title=A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions |journal=Scientific Reports |language=en |volume=7 |issue=1 |page=45270 |bibcode=2017NatSR...745270N |doi=10.1038/srep45270 |issn=2045-2322 |pmc=5366908 |pmid=28345602}}</ref>。此外，[[器官晶片]]模型将肠道类器官与其他細胞或體內環境（例如[[內皮|内皮]]细胞、[[白血球|免疫细胞]]以及[[蠕动]]）结合起来<ref>{{Cite journal |last=Sontheimer-Phelps |first=Alexandra |last2=Chou |first2=David B. |last3=Tovaglieri |first3=Alessio |last4=Ferrante |first4=Thomas C. |last5=Duckworth |first5=Taylor |last6=Fadel |first6=Cicely |last7=Frismantas |first7=Viktoras |last8=Sutherland |first8=Arlene D. |last9=Jalili-Firoozinezhad |first9=Sasan |last10=Kasendra |first10=Magdalena |last11=Stas |first11=Eric |date=2020 |title=Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology |journal=Cellular and Molecular Gastroenterology and Hepatology |language=en |volume=9 |issue=3 |page=507–526 |doi=10.1016/j.jcmgh.2019.11.008 |pmc=7036549 |pmid=31778828}}</ref> <ref>{{Cite journal |last=Grassart |first=Alexandre |last2=Malardé |first2=Valérie |last3=Gobaa |first3=Samy |last4=Sartori-Rupp |first4=Anna |last5=Kerns |first5=Jordan |last6=Karalis |first6=Katia |last7=Marteyn |first7=Benoit |last8=Sansonetti |first8=Philippe |last9=Sauvonnet |first9=Nathalie |date=September 2019 |title=Bioengineered Human Organ-on-Chip Reveals Intestinal Microenvironment and Mechanical Forces Impacting Shigella Infection |journal=Cell Host & Microbe |language=en |volume=26 |issue=3 |page=435–444.e4 |doi=10.1016/j.chom.2019.08.007 |pmid=31492657 |s2cid=201868491 |doi-access=free}}</ref>。 |
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==== 胃類器官 ==== |
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胃类器官部分地概括了[[胃]]的生理性質。通过在三维培养条件下对[[成纤维细胞生长因子|FGF]] 、 [[Wnt信号通路|WNT]] 、 [[骨塑型蛋白|BMP]] 、视黄酸和[[表皮生长因子|EGF]]信号通路进行时间尺度上的調控，可以從多能干细胞直接生成胃類器官<ref name="Mccracken, K. W. 2014">{{Cite journal |display-authors=6 |vauthors=McCracken KW, Catá EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE, Tsai YH, Mayhew CN, Spence JR, Zavros Y, Wells JM |date=December 2014 |title=Modelling human development and disease in pluripotent stem-cell-derived gastric organoids |journal=Nature |volume=516 |issue=7531 |page=400–4 |bibcode=2014Natur.516..400M |doi=10.1038/nature13863 |pmc=4270898 |pmid=25363776}}</ref>。胃类器官也可以由LGR5<sup>+</sup>的胃[[成体干细胞]]产生<ref>{{Cite journal |display-authors=6 |vauthors=Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H |date=January 2010 |title=Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro |journal=Cell Stem Cell |volume=6 |issue=1 |page=25–36 |doi=10.1016/j.stem.2009.11.013 |pmid=20085740 |doi-access=free}}</ref>。胃类器官已被用作研究[[癌症]]<ref>{{Cite journal |display-authors=6 |vauthors=Li X, Nadauld L, Ootani A, Corney DC, Pai RK, Gevaert O, Cantrell MA, Rack PG, Neal JT, Chan CW, Yeung T, Gong X, Yuan J, Wilhelmy J, Robine S, Attardi LD, Plevritis SK, Hung KE, Chen CZ, Ji HP, Kuo CJ |date=July 2014 |title=Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture |journal=Nature Medicine |volume=20 |issue=7 |page=769–77 |doi=10.1038/nm.3585 |pmc=4087144 |pmid=24859528}}</ref> <ref name="Nadauld, L. D. 2014">{{Cite journal |display-authors=6 |vauthors=Nadauld LD, Garcia S, Natsoulis G, Bell JM, Miotke L, Hopmans ES, Xu H, Pai RK, Palm C, Regan JF, Chen H, Flaherty P, Ootani A, Zhang NR, Ford JM, Kuo CJ, Ji HP |date=August 2014 |title=Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer |journal=Genome Biology |volume=15 |issue=8 |page=428 |doi=10.1186/s13059-014-0428-9 |pmc=4145231 |pmid=25315765 |doi-access=free}}</ref>以及其他人类疾病发育的模型<ref name="Mccracken, K. W. 2014" />。例如，一项研究<ref name="Nadauld, L. D. 2014" />调查了患者[[遠端轉移|转移性肿瘤]]背后的潜在遗传變化，发现相較於同一患者身上的原发性肿瘤，转移性肿瘤的[[转化生长因子BR2|TGFBR2]]基因的两个[[等位基因]]均发生突变。为了进一步评估TGFBR2在转移中的作用，研究人员创建了TGFBR2[[基因敲落]]的类器官，透過这种类器官，他们证明TGFBR2活性降低会导致體內與體外環境下的惡性肿瘤侵袭與转移。 |
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=== 舌類器官 === |
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舌类器官是概括舌头生理学各方面的类器官。在立體培养条件下，透過[[表皮生长因子|EGF]] 、 [[Wnt信号通路|WNT]]和[[转化生长因子-β|TGF-β]]的調控，使用表达BMI1 的上皮幹细胞培養出上皮舌类器官<ref name="Hisha, H. 2013">{{Cite journal |display-authors=6 |vauthors=Hisha H, Tanaka T, Kanno S, Tokuyama Y, Komai Y, Ohe S, Yanai H, Omachi T, Ueno H |date=November 2013 |title=Establishment of a novel lingual organoid culture system: generation of organoids having mature keratinized epithelium from adult epithelial stem cells |journal=Scientific Reports |volume=3 |page=3224 |bibcode=2013NatSR...3E3224H |doi=10.1038/srep03224 |pmc=3828633 |pmid=24232854}}</ref>。然而，这种类器官培养物缺乏[[味觉感受器|味觉受体]]<ref name="Hisha, H. 2013" />。相較之下，含有味觉细胞的味蕾类器官則是使用LGR5<sup>+</sup>或[[CD44]]<sup>+</sup>的輪狀乳突幹細胞/前驅細胞<ref name="Aihara, E. 2015">{{Cite journal |display-authors=6 |vauthors=Aihara E, Mahe MM, Schumacher MA, Matthis AL, Feng R, Ren W, Noah TK, Matsu-ura T, Moore SR, Hong CI, Zavros Y, Herness S, Shroyer NF, Iwatsuki K, Jiang P, Helmrath MA, Montrose MH |date=November 2015 |title=Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid |journal=Scientific Reports |volume=5 |page=17185 |bibcode=2015NatSR...517185A |doi=10.1038/srep17185 |pmc=4665766 |pmid=26597788}}</ref>或者Lgr5<sup>+</sup>或LGR6<sup>+</sup>的味觉幹细胞创建的<ref>{{Cite journal |vauthors=Ren W, Lewandowski BC, Watson J, Aihara E, Iwatsuki K, Bachmanov AA, Margolskee RF, Jiang P |date=November 2014 |title=Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=111 |issue=46 |page=16401–6 |bibcode=2014PNAS..11116401R |doi=10.1073/pnas.1409064111 |pmc=4246268 |pmid=25368147 |doi-access=free}}</ref>。 |
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=== 其他 === |
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* [[甲狀腺]]類器官<ref name="pmid10614741">{{Cite journal |vauthors=Martin A, Barbesino G, Davies TF |year=1999 |title=T-cell receptors and autoimmune thyroid disease—signposts for T-cell-antigen driven diseases |journal=International Reviews of Immunology |volume=18 |issue=1–2 |page=111–40 |doi=10.3109/08830189909043021 |pmid=10614741}}</ref> |
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* [[胸腺]]類器官<ref>{{Cite journal |vauthors=Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC |date=September 2014 |title=An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts |journal=Nature Cell Biology |volume=16 |issue=9 |page=902–8 |doi=10.1038/ncb3023 |pmc=4153409 |pmid=25150981}}</ref> |
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:: [[胸腺]]是負責[[T細胞]]成熟的[[淋巴器官]]。胸腺類器官部分概括了胸腺的結構以及幹細胞區位的功能<ref name="Vianello_2007">{{Cite book|vauthors=Vianello F, Poznansky MC|title=Generation of a tissue-engineered thymic organoid|series=Methods in Molecular Biology|volume=380|pages=163–70|year=2007|pmid=17876092|doi=10.1385/1-59745-395-1:163|doi_brokendate=2024-01-24|isbn=978-1-59745-395-0}}</ref>。胸腺類器官的培養是藉由在立體培養環境中接種胸腺基質細胞而達成的<ref name="Vianello_2007" />。由於其成功再現胸腺的功能，因此可以藉由共培養人類[[造血干细胞|造血幹細胞]]/骨髓幹細胞與[[小鼠]]胸腺類器官產生T細胞<ref name="Vianello_2007" />。 |
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* 睪丸類器官<ref>{{Cite journal |last=Sakib |first=Sadman |display-authors=etal |date=1 June 2019 |title=Formation of organotypic testicular organoids in microwell culture |journal=Biology of Reproduction |volume=100 |issue=6 |page=1648–1660 |doi=10.1093/biolre/ioz053 |pmc=7302515 |pmid=30927418}}</ref> |
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* 前列腺類器官<ref>{{Cite journal |last=Drost |first=Jarno |last2=Karthaus |first2=Wouter R. |last3=Gao |first3=Dong |last4=Driehuis |first4=Else |last5=Sawyers |first5=Charles L. |last6=Chen |first6=Yu |last7=Clevers |first7=Hans |date=21 January 2016 |title=Organoid culture systems for prostate epithelial and cancer tissue |journal=Nature Protocols |language=en |volume=11 |issue=2 |page=347–358 |doi=10.1038/nprot.2016.006 |issn=1750-2799 |pmc=4793718 |pmid=26797458}}</ref> |
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* 肝臟類器官<ref name="pmid25533785">{{Cite journal |display-authors=6 |vauthors=Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H |date=January 2015 |title=Long-term culture of genome-stable bipotent stem cells from adult human liver |journal=Cell |volume=160 |issue=1–2 |page=299–312 |doi=10.1016/j.cell.2014.11.050 |pmc=4313365 |pmid=25533785}}</ref>。近期的研究表明，該技術在協助[[戊型肝炎]]的新藥開發上十分有效，因為它可以重現整個病毒生命週期<ref>{{Cite journal |last=Li P, Li Y, Wang Y, Liu J, Lavrijsen M, Li Y, Zhang R, Verstegen MMA, Wang Y, Li TC, Ma Z, Kainov DE, Bruno MJ, de Man RA, van der Laan LJW, Peppelenbosch MP, Pan Q |date=2022 |title=Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids |url=https://pure.eur.nl/en/publications/2a130980-ce88-4339-934b-df2aef36716c |journal=Science Advances |volume=8 |issue=3 |page=103–111 |bibcode=2022SciA....8.5908L |doi=10.1126/sciadv.abj5908 |hdl=11250/3047921 |pmid=5044825 |s2cid=246069868 |hdl-access=free}}</ref>。 |
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* 胰腺類器官<ref name="pmid24045232">{{Cite journal |display-authors=6 |vauthors=Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, Ringnalda F, Begthel H, Hamer K, Mulder J, van Es JH, de Koning E, Vries RG, Heimberg H, Clevers H |date=October 2013 |title=Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis |journal=The EMBO Journal |volume=32 |issue=20 |page=2708–21 |doi=10.1038/emboj.2013.204 |pmc=3801438 |pmid=24045232}}</ref> <ref name="pmid29673279">{{Cite journal |last=Hou S, Tiriac H, Sridharan BP, Scampavia L, Madoux F, Seldin J |display-authors=etal |year=2018 |title=Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening. |journal=SLAS Discov |volume=23 |issue=6 |page=574–584 |doi=10.1177/2472555218766842 |pmc=6013403 |pmid=29673279}}</ref> <ref name="pmid29599906">{{Cite journal |last=Wolff RA, Wang-Gillam A, Alvarez H, Tiriac H, Engle D, Hou S |display-authors=etal |year=2018 |title=Dynamic changes during the treatment of pancreatic cancer. |journal=Oncotarget |volume=9 |issue=19 |page=14764–14790 |doi=10.18632/oncotarget.24483 |pmc=5871077 |pmid=29599906}}</ref> <ref>{{Cite journal |last=Below |first=Christopher R. |last2=Kelly |first2=Joanna |last3=Brown |first3=Alexander |last4=Humphries |first4=Jonathan D. |last5=Hutton |first5=Colin |last6=Xu |first6=Jingshu |last7=Lee |first7=Brian Y. |last8=Cintas |first8=Celia |last9=Zhang |first9=Xiaohong |last10=Hernandez-Gordillo |first10=Victor |last11=Stockdale |first11=Linda |date=2021-09-13 |title=A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids |journal=Nature Materials |language=en |volume=21 |issue=1 |page=110–119 |doi=10.1038/s41563-021-01085-1 |issn=1476-4660 |pmc=7612137 |pmid=34518665}}</ref> |
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:: 细胞排斥性微量滴定板的最新进展使得能够快速、经济高效地筛选大分子药物（例如针对胰腺癌 3D 模型的库）。这些模型在表型和表达谱上与David Tuveson博士实验室发现的模型一致。 |
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* 上皮类器官<ref name="pmid19329995">{{Cite journal |author-link10=Peter J. Peters |display-authors=6 |vauthors=Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H |date=May 2009 |title=Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche |journal=Nature |volume=459 |issue=7244 |page=262–5 |bibcode=2009Natur.459..262S |doi=10.1038/nature07935 |pmid=19329995 |s2cid=4373784}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFSatoVriesSnippertvan_de_Wetering2009">Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. (May 2009). "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche". ''Nature''. '''459''' (7244): 262–5. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2009Natur.459..262S 2009Natur.459..262S]. [[DOI|doi]]:[[doi:10.1038/nature07935|10.1038/nature07935]]. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/19329995 19329995]. [[语义学者|S2CID]] [https://api.semanticscholar.org/CorpusID:4373784 4373784].</cite></ref> <ref name="pmid17934449">{{Cite journal |author-link10=Peter J. Peters |display-authors=6 |vauthors=Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H |date=October 2007 |title=Identification of stem cells in small intestine and colon by marker gene Lgr5 |journal=Nature |volume=449 |issue=7165 |page=1003–7 |bibcode=2007Natur.449.1003B |doi=10.1038/nature06196 |pmid=17934449 |s2cid=4349637}}</ref> |
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* 肺类器官<ref>{{Cite journal |display-authors=6 |vauthors=Lee JH, Bhang DH, Beede A, Huang TL, Stripp BR, Bloch KD, Wagers AJ, Tseng YH, Ryeom S, Kim CF |date=January 2014 |title=Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis |journal=Cell |volume=156 |issue=3 |page=440–55 |doi=10.1016/j.cell.2013.12.039 |pmc=3951122 |pmid=24485453}}</ref> |
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* 肾类器官<ref name="sciencedirect.com">{{Cite journal |vauthors=Unbekandt M, Davies JA |date=March 2010 |title=Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues |journal=Kidney International |volume=77 |issue=5 |page=407–16 |doi=10.1038/ki.2009.482 |pmid=20016472 |doi-access=free}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFUnbekandtDavies2010">Unbekandt M, Davies JA (March 2010). [[doi:10.1038/ki.2009.482|"Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues"]]. ''Kidney International''. '''77''' (5): 407–16. [[DOI|doi]]:<span class="cs1-lock-free" title="Freely accessible">[[doi:10.1038/ki.2009.482|10.1038/ki.2009.482]]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/20016472 20016472].</cite></ref> <ref>{{Cite journal |display-authors=6 |vauthors=Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH |date=October 2015 |title=Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis |journal=Nature |volume=526 |issue=7574 |page=564–8 |bibcode=2015Natur.526..564T |doi=10.1038/nature15695 |pmid=26444236 |s2cid=4443766}}</ref> <ref name="ReferenceA">{{Cite journal |display-authors=6 |vauthors=Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV |date=October 2015 |title=Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids |journal=Nature Communications |volume=6 |page=8715 |bibcode=2015NatCo...6.8715F |doi=10.1038/ncomms9715 |pmc=4620584 |pmid=26493500}}</ref> <ref>{{Cite journal |vauthors=Morizane R, Lam AQ, Freedman BS, Kishi S, Valerius MT, Bonventre JV |date=November 2015 |title=Nephron organoids derived from human pluripotent stem cells model kidney development and injury |journal=Nature Biotechnology |volume=33 |issue=11 |page=1193–200 |doi=10.1038/nbt.3392 |pmc=4747858 |pmid=26458176}}</ref> |
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* 原肠胚（胚胎类器官） <ref>{{Cite journal |display-authors=6 |vauthors=van den Brink SC, Baillie-Johnson P, Balayo T, Hadjantonakis AK, Nowotschin S, Turner DA, Martinez Arias A |date=November 2014 |title=Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells |journal=Development |volume=141 |issue=22 |page=4231–42 |doi=10.1242/dev.113001 |pmc=4302915 |pmid=25371360}}</ref> <ref>{{Cite journal |vauthors=Turner DA, Baillie-Johnson P, Martinez Arias A |date=February 2016 |title=Organoids and the genetically encoded self-assembly of embryonic stem cells |journal=BioEssays |volume=38 |issue=2 |page=181–91 |doi=10.1002/bies.201500111 |pmc=4737349 |pmid=26666846}}</ref> <ref>{{Cite journal |display-authors=6 |vauthors=Turner DA, Girgin M, Alonso-Crisostomo L, Trivedi V, Baillie-Johnson P, Glodowski CR, Hayward PC, Collignon J, Gustavsen C, Serup P, Steventon B, P Lutolf M, Arias AM |date=November 2017 |title=Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids |journal=Development |volume=144 |issue=21 |page=3894–3906 |doi=10.1242/dev.150391 |pmc=5702072 |pmid=28951435}}</ref> <ref name=":0">{{Cite journal |last=Beccari |first=Leonardo |last2=Moris |first2=Naomi |last3=Girgin |first3=Mehmet |last4=Turner |first4=David A. |last5=Baillie-Johnson |first5=Peter |last6=Cossy |first6=Anne-Catherine |last7=Lutolf |first7=Matthias P. |last8=Duboule |first8=Denis |last9=Arias |first9=Alfonso Martinez |date=2018-10 |title=Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids |url=https://www.nature.com/articles/s41586-018-0578-0 |journal=Nature |language=en |volume=562 |issue=7726 |doi=10.1038/s41586-018-0578-0 |issn=1476-4687}}</ref> —— 可以生成所有胚胎轴並且在前后轴的方向與''Hox''基因表达的形式共線。 <ref name=":0" /> |
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* 囊胚類器官 <ref>{{Cite web|title=Blastoid: The backstory of the formation of blastocyst-like structure solely from stem cells|url=https://thenode.biologists.com/blastoid-the-backstory-of-the-formation-of-blastocyst-like-structure-solely-from-stem-cells/highlights/|date=2018-06-27}}</ref> <ref>{{Cite web|title=Nicolas Rivron Lab | Blastoid | Netherlands|url=https://www.nicolasrivron.org/theblastoid}}</ref> <ref>{{Cite journal |display-authors=6 |vauthors=Rivron NC, Frias-Aldeguer J, Vrij EJ, Boisset JC, Korving J, Vivié J, Truckenmüller RK, van Oudenaarden A, van Blitterswijk CA, Geijsen N |date=May 2018 |title=Blastocyst-like structures generated solely from stem cells |url=https://cris.maastrichtuniversity.nl/ws/files/60703351/Blitterswijk_2018_Blastocyst_like_structures_generated_solely.pdf |journal=Nature |volume=557 |issue=7703 |page=106–111 |bibcode=2018Natur.557..106R |doi=10.1038/s41586-018-0051-0 |pmid=29720634 |s2cid=13749109}}</ref> |
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* 子宫内膜类器官<ref name="Rawlings">{{Cite journal |vauthors=Rawlings TM, Makwana K, Tryfonos M, Lucas ES |date=July 2021 |title=Organoids to model the endometrium: implantation and beyond |url= |journal=Reprod Fertil |volume=2 |issue=3 |page=R85–R101 |doi=10.1530/RAF-21-0023 |pmc=8801025 |pmid=35118399}}</ref> |
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* 心脏类器官<ref>{{Cite journal |vauthors=Lee EJ, Kim DE, Azeloglu EU, Costa KD |date=February 2008 |title=Engineered cardiac organoid chambers: toward a functional biological model ventricle |journal=Tissue Engineering. Part A |volume=14 |issue=2 |page=215–25 |doi=10.1089/tea.2007.0351 |pmid=18333774}}</ref> —— 2018 年，中空心脏类器官被提出，並表現心搏且可以對刺激產生反應而改變跳動速度<ref>{{Cite magazine|last=Molteni|first=Megan|date=2018-06-27|title=These Beating Mini-Hearts Could Save Big Bucks—And Maybe Lives|url=https://www.wired.com/story/these-beating-mini-hearts-could-save-big-bucksand-maybe-lives/|magazine=WIRED|access-date=2018-06-30}}</ref>。 |
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* 视网膜类器官<ref>{{Cite journal |display-authors=6 |vauthors=Wiley LA, Burnight ER, DeLuca AP, Anfinson KR, Cranston CM, Kaalberg EE, Penticoff JA, Affatigato LM, Mullins RF, Stone EM, Tucker BA |date=July 2016 |title=cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness |journal=Scientific Reports |volume=6 |page=30742 |bibcode=2016NatSR...630742W |doi=10.1038/srep30742 |pmc=4965859 |pmid=27471043}}</ref> <ref>{{Cite journal |last=Zilova |first=Lucie |last2=Weinhardt |first2=Venera |last3=Tavhelidse |first3=Tinatini |last4=Schlagheck |first4=Christina |last5=Thumberger |first5=Thomas |last6=Wittbrodt |first6=Joachim |date=2021-07-12 |editor-last=Martínez Arias |editor-first=Alfonso |editor2-last=Stainier |editor2-first=Didier YR |editor3-last=Martínez Arias |editor3-first=Alfonso |title=Fish primary embryonic pluripotent cells assemble into retinal tissue mirroring in vivo early eye development |journal=eLife |volume=10 |page=e66998 |doi=10.7554/eLife.66998 |issn=2050-084X |pmc=8275126 |pmid=34252023 |doi-access=free}}</ref> |
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* [[乳癌|乳腺癌]]类器官<ref>{{Cite journal |last=Sachs |first=Norman |last2=de Ligt |first2=Joep |last3=Kopper |first3=Oded |last4=Gogola |first4=Ewa |last5=Bounova |first5=Gergana |last6=Weeber |first6=Fleur |last7=Balgobind |first7=Anjali Vanita |last8=Wind |first8=Karin |last9=Gracanin |first9=Ana |last10=Begthel |first10=Harry |last11=Korving |first11=Jeroen |display-authors=14 |date=2018 |title=A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity |journal=Cell |volume=172 |issue=1–2 |page=373–386.e10 |doi=10.1016/j.cell.2017.11.010 |issn=0092-8674 |pmid=29224780 |doi-access=free}}</ref> |
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* [[大腸癌|结直肠癌]]类器官<ref>{{Cite journal |last=van de Wetering |first=Marc |last2=Francies |first2=Hayley |last3=Francis |first3=Joshua |last4=Bounova |first4=Gergana |last5=Iorio |first5=Francesco |last6=Pronk |first6=Apollo |last7=van Houdt |first7=Winan |last8=van Gorp |first8=Joost |last9=Taylor-Weiner |first9=Amaro |last10=Kester |first10=Lennart |last11=McLaren-Douglas |first11=Anne |display-authors=14 |date=2015 |title=Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients |url=https://doi.org/10.1016/j.cell.2015.03.053 |journal=Cell |volume=161 |issue=4 |page=933–945 |doi=10.1016/j.cell.2015.03.053 |issn=0092-8674 |pmc=6428276 |pmid=25957691}}</ref> |
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* [[胶质母细胞瘤]]类器官<ref name="pmid29750582">{{Cite journal |last=Quereda V, Hou S, Madoux F, Scampavia L, Spicer TP, Duckett D |year=2018 |title=A Cytotoxic Three-Dimensional-Spheroid, High-Throughput Assay Using Patient-Derived Glioma Stem Cells. |journal=SLAS Discov |volume=23 |issue=8 |page=842–849 |doi=10.1177/2472555218775055 |pmc=6102052 |pmid=29750582}}</ref> |
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<blockquote>現今，來自患者的外植體（patient derived explants，PDX）或直接來自癌症組織的三維器官模型已經可以輕易製備，並且可將其用於現有核准藥物的高通量篩選。</blockquote> |
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* [[神經內分泌腫瘤|神经内分泌肿瘤]]类器官<ref>{{Cite journal |last=Dayton |first=Talya L. |last2=Alcala |first2=Nicolas |last3=Moonen |first3=Laura |last4=den Hartigh |first4=Lisanne |last5=Geurts |first5=Veerle |last6=Mangiante |first6=Lise |last7=Lap |first7=Lisa |last8=Dost |first8=Antonella F.M. |last9=Beumer |first9=Joep |last10=Levy |first10=Sonja |last11=van Leeuwaarde |first11=Rachel S. |display-authors=14 |date=2023 |title=Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites |journal=Cancer Cell |volume=41 |issue=12 |page=2083–2099 |doi=10.1016/j.ccell.2023.11.007 |issn=1535-6108 |pmid=38086335 |doi-access=free}}</ref> |
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* 髓鞘類器官<ref>{{Cite journal |last=James |first=Owen G. |last2=Selvaraj |first2=Bhuvaneish T. |last3=Magnani |first3=Dario |last4=Burr |first4=Karen |last5=Connick |first5=Peter |last6=Barton |first6=Samantha K. |last7=Vasistha |first7=Navneet A. |last8=Hampton |first8=David W. |last9=Story |first9=David |last10=Smigiel |first10=Robert |last11=Ploski |first11=Rafal |date=2021-05-03 |title=iPSC-derived myelinoids to study myelin biology of humans |url=https://www.sciencedirect.com/science/article/pii/S1534580721003154 |journal=Developmental Cell |volume=56 |issue=9 |doi=10.1016/j.devcel.2021.04.006 |issn=1534-5807}}</ref> |
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* 血脑屏障类器官<ref>{{Cite journal |last=Zidarič |first=Tanja |last2=Gradišnik |first2=Lidija |last3=Velnar |first3=Tomaž |date=2022-04-01 |title=Astrocytes and human artificial blood-brain barrier models |url=https://www.bjbms.org/ojs/index.php/bjbms/article/view/6943 |journal=Bosnian Journal of Basic Medical Sciences |language=en |volume=22 |issue=5 |page=651–672 |doi=10.17305/bjbms.2021.6943 |issn=1840-4812 |pmc=9519155 |pmid=35366791}}</ref> |
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<blockquote>由腦微血管內皮細胞（BMECs）、星形細胞和周細胞組成的自組裝細胞聚集體正逐漸成為物質穿膜和微流體模型的潛在替代方案。這些器官模型能夠生成血腦屏障（BBB）的許多特徵，如[[紧密连接|緊密連接]]的表達、分子運輸蛋白和藥物排出泵，因此可以用來模擬藥物穿越BBB的過程。此外，它們可以作為評估BBB與相鄰腦組織之間相互作用的模型，並提供了一個了解新藥物克服BBB的綜合能力以及其對腦組織的影響的平台。此類模型具有高度可擴展性，且比微流體裝置更容易製造和操作。然而，它們對於重建BBB的形態和生理學以及模擬生理流動和[[剪應力]]的能力有限。<ref>{{Cite journal |last=Zidarič |first=Tanja |last2=Gradišnik |first2=Lidija |last3=Velnar |first3=Tomaž |date=2022-04-01 |title=Astrocytes and human artificial blood-brain barrier models |url=https://www.bjbms.org/ojs/index.php/bjbms/article/view/6943 |journal=Bosnian Journal of Basic Medical Sciences |language=en |volume=22 |issue=5 |page=651–672 |doi=10.17305/bjbms.2021.6943 |issn=1840-4812 |pmc=9519155 |pmid=35366791}}</ref></blockquote> |
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== 基礎研究 == |
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类器官能够協助研究细胞與細胞間、細胞與环境之間的相互作用以及疾病和藥物如何影響他們的作用。[[體外]]培养使该系统易于操作及监测。器官的實際體積過大使得物質滲透受到限制而不易培養，但类器官的小尺寸可以規避此问题。另一方面，類器官并不表现出所有器官特征，并且与其他器官的相互作用''在''体外也无法重现。虽然腸道類器官的第一個研究方向是用於探討[[幹細胞|幹细胞]]特性的调控<ref name="pmid19329995">{{Cite journal |author-link10=Peter J. Peters |display-authors=6 |vauthors=Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H |date=May 2009 |title=Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche |journal=Nature |volume=459 |issue=7244 |page=262–5 |bibcode=2009Natur.459..262S |doi=10.1038/nature07935 |pmid=19329995 |s2cid=4373784}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFSatoVriesSnippertvan_de_Wetering2009">Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. (May 2009). "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche". ''Nature''. '''459''' (7244): 262–5. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2009Natur.459..262S 2009Natur.459..262S]. [[DOI|doi]]:[[doi:10.1038/nature07935|10.1038/nature07935]]. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/19329995 19329995]. [[语义学者|S2CID]] [https://api.semanticscholar.org/CorpusID:4373784 4373784].</cite></ref>，但如今也用于研究营养物质的摄取、药物转运和肠泌素的分泌等議題<ref>{{Cite journal |vauthors=Zietek T, Rath E, Haller D, Daniel H |date=November 2015 |title=Intestinal organoids for assessing nutrient transport, sensing and incretin secretion |journal=Scientific Reports |volume=5 |page=16831 |bibcode=2015NatSR...516831Z |doi=10.1038/srep16831 |pmc=4652176 |pmid=26582215}}</ref>。这对于[[吸收不良]]疾病以及[[肥胖症|肥胖]]、[[胰岛素抵抗]]和[[糖尿病]]等代谢疾病具有重要意义。 |
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== 疾病模型 == |
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类器官提供建立人类疾病细胞模型的机会，可以在实验室中进行研究以更好地了解疾病的原因并确定可能的治疗方法。类器官在这方面的潛力首次在[[小頭畸形|小头畸形]]的遗传研究中顯現，其中患者细胞被用来制造[[類人腦|脑类器官]]，这种类器官较小并且在早期神经元生成中表现出异常<ref name="lancaster">{{Cite journal |display-authors=6 |vauthors=Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA |date=September 2013 |title=Cerebral organoids model human brain development and microcephaly |journal=Nature |volume=501 |issue=7467 |page=373–9 |bibcode=2013Natur.501..373L |doi=10.1038/nature12517 |pmc=3817409 |pmid=23995685}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFLancasterRennerMartinWenzel2013">Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. (September 2013). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817409 "Cerebral organoids model human brain development and microcephaly"]. ''Nature''. '''501''' (7467): 373–9. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2013Natur.501..373L 2013Natur.501..373L]. [[DOI|doi]]:[[doi:10.1038/nature12517|10.1038/nature12517]]. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817409 3817409]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/23995685 23995685].</cite></ref>。另一个案例是将CRISPR应用于人类多能干细胞，在与两种不同肾脏疾病（[[多囊性腎病變|多囊肾病]]和[[局灶節段性腎小球硬化症|局灶节段性肾小球硬化症）]]相关的基因中引入靶向突变<ref name="ReferenceA">{{Cite journal |display-authors=6 |vauthors=Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV |date=October 2015 |title=Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids |journal=Nature Communications |volume=6 |page=8715 |bibcode=2015NatCo...6.8715F |doi=10.1038/ncomms9715 |pmc=4620584 |pmid=26493500}}<cite class="citation journal cs1" data-ve-ignore="true" id="CITEREFFreedmanBrooksLamFu2015">Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, et al. (October 2015). [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620584 "Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids"]. ''Nature Communications''. '''6''': 8715. [[Bibcode]]:[https://ui.adsabs.harvard.edu/abs/2015NatCo...6.8715F 2015NatCo...6.8715F]. [[DOI|doi]]:[[doi:10.1038/ncomms9715|10.1038/ncomms9715]]. [[PubMed Central|PMC]] <span class="cs1-lock-free" title="Freely accessible">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620584 4620584]</span>. [[PubMed|PMID]] [https://pubmed.ncbi.nlm.nih.gov/26493500 26493500].</cite></ref>。这些经过 CRISPR修饰的多能干细胞随后被培养成人类肾类器官，表现出疾病特异性表型。来自患有多囊肾病突变的干细胞的肾脏类器官由肾小管形成了巨大的半透明囊肿结构。当在悬浮的情况下培养时，这些包囊的大小在數個月內达到直径1厘米<ref name="ReferenceD">{{Cite journal |display-authors=6 |vauthors=Cruz NM, Song X, Czerniecki SM, Gulieva RE, Churchill AJ, Kim YK, Winston K, Tran LM, Diaz MA, Fu H, Finn LS, Pei Y, Himmelfarb J, Freedman BS |date=November 2017 |title=Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease |journal=Nature Materials |volume=16 |issue=11 |page=1112–1119 |bibcode=2017NatMa..16.1112C |doi=10.1038/nmat4994 |pmc=5936694 |pmid=28967916}}</ref>。与局灶节段性肾小球硬化症相关的基因发生突变的肾类器官，其足细胞（该疾病中受影响的过滤细胞）之间出现了細胞连接的缺陷<ref name="ReferenceE">{{Cite journal |display-authors=6 |vauthors=Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE, Hughes MR, Cruz NM, Liu Y, Churchill AJ, Wang Y, Fu H, Pippin JW, Lin LY, Shankland SJ, Vogl AW, McNagny KM, Freedman BS |date=December 2017 |title=Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development |journal=Stem Cells |volume=35 |issue=12 |page=2366–2378 |doi=10.1002/stem.2707 |pmc=5742857 |pmid=28905451}}</ref>。重要的是，这些疾病表型在具有相同遗传背景但缺乏CRISPR突变的对照类器官中不存在<ref name="ReferenceA" /> <ref name="ReferenceD" /> <ref name="ReferenceE" />。将这些类器官表型与小鼠和人类的患病组织进行比较，发现它们与早期发育缺陷有相似之处<ref name="ReferenceD" /> <ref name="ReferenceE" />。 |
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正如Takahashi和Yamanaka于 2007 年首次發表的那样，[[诱导性多能干细胞|诱导多能干细胞]]（iPSC）也可以从患者皮肤纖維母细胞中重编程<ref>{{Cite journal |display-authors=6 |vauthors=Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S |date=November 2007 |title=Induction of pluripotent stem cells from adult human fibroblasts by defined factors |url=https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf |journal=Cell |volume=131 |issue=5 |page=861–72 |doi=10.1016/j.cell.2007.11.019 |hdl=2433/49782 |pmid=18035408 |s2cid=8531539 |hdl-access=free}}</ref>。这些干细胞携带患者的确切遗传背景，包括可能导致人类疾病发展的任何基因突变。由于''ORCL1''突变而患有Lowe综合征的患者已将这些细胞分化为肾脏类器官<ref name=":2">{{Cite journal |vauthors=Hsieh WC, Ramadesikan S, Fekete D, Aguilar RC |date=2018-02-14 |title=Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex |journal=PLOS ONE |volume=13 |issue=2 |page=e0192635 |bibcode=2018PLoSO..1392635H |doi=10.1371/journal.pone.0192635 |pmc=5812626 |pmid=29444177 |doi-access=free}}</ref>。该报告比较了患者iPSC与不相关的对照iPSC分化的肾类器官，并证明患者肾细胞无法调动[[高尔基体]]中的转录因子 SIX2<ref name=":2" />。因为''SIX2''是肾單元前驅细胞的一个明确标记，作者得出结论為，洛氏综合征（近曲小管在吸收的整体衰竭或[[范康尼氏症候群]]）中常见的肾脏疾病可能与肾单元引起的改变有关，其中祖细胞缺乏这种重要的''SIX2''基因表达<ref name=":2" />。 |
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其他研究使用CRISPR来修復患者iPSC细胞中的突变，以创建等位基因对照，该对照可以与iPSC重编程同时进行<ref>{{Cite journal |vauthors=Howden SE, Thomson JA, Little MH |date=May 2018 |title=Simultaneous reprogramming and gene editing of human fibroblasts |journal=Nature Protocols |volume=13 |issue=5 |page=875–898 |doi=10.1038/nprot.2018.007 |pmc=5997775 |pmid=29622803}}</ref> <ref name=":3">{{Cite journal |display-authors=6 |vauthors=Forbes TA, Howden SE, Lawlor K, Phipson B, Maksimovic J, Hale L, Wilson S, Quinlan C, Ho G, Holman K, Bennetts B, Crawford J, Trnka P, Oshlack A, Patel C, Mallett A, Simons C, Little MH |date=May 2018 |title=Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms |journal=American Journal of Human Genetics |volume=102 |issue=5 |page=816–831 |doi=10.1016/j.ajhg.2018.03.014 |pmc=5986969 |pmid=29706353}}</ref> <ref name=":4">{{Cite journal |display-authors=6 |vauthors=Tanigawa S, Islam M, Sharmin S, Naganuma H, Yoshimura Y, Haque F, Era T, Nakazato H, Nakanishi K, Sakuma T, Yamamoto T, Kurihara H, Taguchi A, Nishinakamura R |date=September 2018 |title=Organoids from Nephrotic Disease-Derived iPSCs Identify Impaired NEPHRIN Localization and Slit Diaphragm Formation in Kidney Podocytes |journal=Stem Cell Reports |volume=11 |issue=3 |page=727–740 |doi=10.1016/j.stemcr.2018.08.003 |pmc=6135868 |pmid=30174315}}</ref>。将患者iPSC衍生的类器官与同基因对照进行比较是该领域当前的黄金标准，因为它允许将感兴趣的突变分离为实验模型中的唯一变量<ref>{{Cite journal |vauthors=Engle SJ, Blaha L, Kleiman RJ |date=November 2018 |title=Best Practices for Translational Disease Modeling Using Human iPSC-Derived Neurons |journal=Neuron |volume=100 |issue=4 |page=783–797 |doi=10.1016/j.neuron.2018.10.033 |pmid=30465765 |doi-access=free}}</ref>。在一份报告中，将源自''IFT140''复合杂合突变的Mainzer-Saldino综合征患者iPSC的肾类器官与等基因对照类器官进行比较，其中通过CRISPR 修正了产生无活性 mRNA 转录物的''IFT140''突变体<ref name=":3" />。患者肾类器官表现出与现有动物模型一致的异常[[纖毛|纤毛]]形态，在基因修正的类器官中将其恢复为野生型狀態<ref name=":3" />。比較患者和对照类器官中纯化的上皮细胞的转录組突显了涉及细胞极性、[[细胞连接|细胞-细胞连接]]和[[动力蛋白|动力蛋白运动]]组装的途径，其中一些途径与肾纤毛病表型家族中的其他基因型有关<ref name=":3" />。另一份利用等基因对照的报告表明，先天性肾病综合征患者产生的肾脏类器官的[[腎小球|肾小球]]中去氧[[腎病蛋白|肾上腺素]]定位异常<ref name=":4" />。 |
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最後，諸如上皮代謝之類的事情也可以利用類似方式建模<ref>{{Cite web|title=Metabolites|url=https://www.mdpi.com/journal/metabolites/special_issues/Intestinal_Metabolism|website=www.mdpi.com|language=en|access-date=2022-10-16}}</ref>。 |
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== 個人化醫療 == |
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Clevers小組建立的方法可以從[[直腸]][[活檢]]樣本中培養出的腸類器官，目前已被用於模擬[[囊腫性纖維化]]<ref name="ReferenceB">{{Cite journal |display-authors=6 |vauthors=Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NW, Bijvelds MJ, Scholte BJ, Nieuwenhuis EE, van den Brink S, Clevers H, van der Ent CK, Middendorp S, Beekman JM |date=July 2013 |title=A functional CFTR assay using primary cystic fibrosis intestinal organoids |journal=Nature Medicine |volume=19 |issue=7 |page=939–45 |doi=10.1038/nm.3201 |pmid=23727931 |s2cid=5369669}}</ref>，並促使類器官首次運用於個人化醫療 <ref name="ReferenceC">{{Cite journal |display-authors=6 |vauthors=Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM |date=June 2016 |title=Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis |journal=Science Translational Medicine |volume=8 |issue=344 |page=344ra84 |doi=10.1126/scitranslmed.aad8278 |pmid=27334259 |s2cid=19462535}}</ref>。囊腫性纖維化是一種[[遺傳性疾病]]，由囊腫性纖維化穿膜傳導調節基因（Cystic fibrosis transmembrane conductance regulator，CFTR）的突變引起，該基因編碼位於健康上皮表面維持液體所需的離子通道。Jeffrey Beekman 實驗室於 2013 年進行的研究描述，以毛喉素或霍亂毒素等cAMP升高激動劑刺激結直腸類器官，會以完全 CFTR 依賴性的方式誘導類器官快速腫脹<ref name="ReferenceB" />。非囊腫性纖維化患者的類器官因為液體輸送到類器官管腔而對毛喉素產生反應並膨脹，相較之下，來自囊腫性纖維化患者的類器官則嚴重減少或不存在。 修復CFTR蛋白的療法可以恢復腫脹，這表明可以在臨床前實驗室環境中量化個體對CFTR調節療法的反應。2013年，Schwank等人於更進一步證明腸道囊腫性纖維化類器官的異常表型可以透過CRISPR-Cas9基因編輯進行修復<ref>{{Cite journal |display-authors=6 |vauthors=Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H |date=December 2013 |title=Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients |journal=Cell Stem Cell |volume=13 |issue=6 |page=653–8 |doi=10.1016/j.stem.2013.11.002 |pmid=24315439 |doi-access=free}}</ref>。 |
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2016年，Dekkers等人的後續研究表明，來自囊腫性纖維化患者的腸道類器官之間由毛喉素誘導的腫脹程度差異與已知的診斷和預後標誌物（例如CFTR 基因突變或CFTR功能 的體內生物標記）相關<ref name="ReferenceC">{{Cite journal |display-authors=6 |vauthors=Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM |date=June 2016 |title=Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis |journal=Science Translational Medicine |volume=8 |issue=344 |page=344ra84 |doi=10.1126/scitranslmed.aad8278 |pmid=27334259 |s2cid=19462535}}</ref>。此外，他們證明具有特定CFTR突變的腸道類器官接受CFTR調節劑處裡後的效果與已發表的臨床試驗結果相似。 這促使臨床前研究發現來自具有極其罕見的 CFTR 突變且未經過治療的患者類器官對臨床使用的CFTR調節劑有強烈反應。這些臨床前類器官測試所得到的治療成效被後續Kors van der Ent所帶領的團隊執行的臨床試驗所證實。這些研究首次表明類器官可以應用於個人化醫療。 |
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== 類器官移植 == |
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2022 年，類器官被首次用於移植手術。一名患有潰瘍性結腸炎的患者，藉由採集其健康結腸黏膜的細胞進行體外培養1個月後，將這些細胞生長而成的類器官重新移植回患者身上，取得良好的治療效果<ref>{{Cite news|title=World's first mini organ transportation to a patient with ulcerative colitis|url=https://medicalxpress.com/news/2022-08-world-mini-patient-ulcerative-colitis.html|accessdate=18 September 2022|work=[[Tokyo Medical and Dental University]] via medicalxpress.com|language=en}}</ref><ref>{{Cite journal |last=Watanabe |first=Satoshi |last2=Kobayashi |first2=Sakurako |last3=Ogasawara |first3=Nobuhiko |last4=Okamoto |first4=Ryuichi |last5=Nakamura |first5=Tetsuya |last6=Watanabe |first6=Mamoru |last7=Jensen |first7=Kim B. |last8=Yui |first8=Shiro |date=March 2022 |title=Transplantation of intestinal organoids into a mouse model of colitis |url=https://www.nature.com/articles/s41596-021-00658-3 |journal=Nature Protocols |language=en |volume=17 |issue=3 |page=649–671 |doi=10.1038/s41596-021-00658-3 |issn=1750-2799 |pmid=35110738 |s2cid=246488596 |url-access=subscription}}</ref>。 |
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== 作為發育生物學的模型 == |
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類器官為研究人員提供了研究[[發育生物學]]的模型<ref name="Ader, M. 2014">{{Cite journal |vauthors=Ader M, Tanaka EM |date=December 2014 |title=Modeling human development in 3D culture |journal=Current Opinion in Cell Biology |volume=31 |page=23–8 |doi=10.1016/j.ceb.2014.06.013 |pmid=25033469}}</ref>。自從多能幹細胞被提出後以來，利用二維培養在體外定向誘導多能幹細胞的分化已經取得了巨大的進展<ref name="Ader, M. 2014" />。如今，多能性幹細胞培養的技術進步搭配3D培養技術的發展，使得培養各類器官內的特定細胞組織成為可能<ref name="Ader, M. 2014" />。因此，這些類器官的使用極大地促進了我們對器官發生過程和發育生物學領域的理解<ref name="Ader, M. 2014" />。例如，中樞神經系統的發育中，類器官的研究有助於科學家理解視神經盤形成過程中物理力量的扮演的角色<ref name="Ader, M. 2014" /><ref name="pmid29326547">{{Cite journal |vauthors=Martinez-Morales JR, Cavodeassi F, Bovolenta P |date=2017 |title=Coordinated Morphogenetic Mechanisms Shape the Vertebrate Eye |journal=Frontiers in Neuroscience |volume=11 |page=721 |doi=10.3389/fnins.2017.00721 |pmc=5742352 |pmid=29326547 |doi-access=free}}</ref>。近期的研究則專注於延長皮質類器官的生長週期並且取得顯著的進展。在一些研究中，類器官存在將近一年，並表現出人類胎兒發展階段的部分特徵<ref>{{Cite journal |last=Gordon |first=Aaron |last2=Yoon |first2=Se-Jin |last3=Tran |first3=Stephen S. |last4=Makinson |first4=Christopher D. |last5=Park |first5=Jin Young |last6=Andersen |first6=Jimena |last7=Valencia |first7=Alfredo M. |last8=Horvath |first8=Steve |last9=Xiao |first9=Xinshu |last10=Huguenard |first10=John R. |last11=Pașca |first11=Sergiu P. |date=2021-02-22 |title=Long-term maturation of human cortical organoids matches key early postnatal transitions |journal=Nature Neuroscience |language=en |volume=24 |issue=3 |page=331–342 |doi=10.1038/s41593-021-00802-y |issn=1546-1726 |pmc=8109149 |pmid=33619405}}</ref>。 |
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== 參見 == |
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* [[人工器官]] |
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* [[器官培養]] |
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* [[幹細胞]] |
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* [[發育生物學]] |
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== 參考文獻 == |
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<references /> |
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[[Category:發育生物學]] |
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[[Category:幹細胞]] |
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[[Category:組織工程]] |
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[[Category:再生醫學]] |
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2024年2月5日 (一) 14:35的版本
類器官是體外培養生成的立體細胞團，是特定器官的迷你簡化版本，模仿該器官的關鍵功能、結構和生物複雜性。[1] 類器官的培養可以起源於胚胎幹細胞或者成體幹細胞等多能性幹細胞、人工誘導性多能幹細胞以及癌症幹細胞，這些細胞的自我更新以及分化潛能賦予其在立體培養條件下中自組裝的能力。類器官的發展提供科學家與工程師在實驗室中研究疾病與藥物開發的簡化模型。[2]協助個人化醫療、基因和細胞療法、組織工程和再生醫學等領域的發展。[3]
歷史
體外培養器官的始於一個解離再聚集實驗[4] ，科學家亨利·範·彼特斯·威森發現透過機械方式打散的海綿細胞可以自發性地重新聚集並組裝成完整個體[5]。在隨後的幾十年中，多個實驗室成功於兩棲動物[6]和雞胚胎[7]身上取得的器官組織重現解離後自組裝的實驗，在體外生成各類型的器官[4]。1975年，科學家透過共培養角質形成細胞和3T3纖維母細胞，首次在體外觀察到第一個組織樣細胞群的形成[8]。這些透過機械外力打散器官後的細胞再聚集與自組裝的現象促致馬爾科姆·斯坦伯格提出了差異黏附假說（Differential adhesion hypothesis，DAH）[4]。 隨著幹細胞生物學的出現，科學家開始認識到幹細胞在體外形成器官的潛力，因為觀察到當其形成畸胎瘤或擬胚體時，分化的細胞可以組織成類似於在體內發現的各種組織類型[4]。類器官的出現始於細胞培養從二維平面基質轉為三維立體基質的階段，隨著細胞外基質的發展，3D培養基方法的方法成為可能[9]，以允許器官立體結構的發育。[4]20 世纪 80 年代末， 米娜·貝塞爾及其同事證明，富含層粘連蛋白的凝膠可用作乳腺上皮細胞培養分化的基底膜[10][11]。如今，各類器官的培養方法已被提出並逐漸成熟[12]。在20世紀90年代，除了ECM提供細胞生長物理性質上的支持被提出外，還報導了ECM內的成分透過與基於整合素的黏著蛋白通路相互作用而影響基因表現[13]。2006年， Yaakov Nahmias和David Odde展示了血管肝类器官的自组裝在體外環境维持了50多天[14]。2008年，日本理化学研究所的Yoshiki Sasai和他的团队证明，干细胞可以被诱导成神经细胞球並且自组织成独特的层狀構造[15]。2009年，荷蘭皇家藝術與科學研究所和烏特勒支大學的Hans Clevers实验室表明，单个表达LGR5的肠干细胞可以在體外自组织成隐窝绒毛结构並且無須提供间质區位，这使它们成为第一个类器官[16]。2010 年，Mathieu Unbekandt 和Jamie A. Davies证明了利用鼠胚衍生的肾干细胞可产生肾类器官[17]。2014年，王峮及其同事设计了基于I型胶原和层粘连蛋白的凝胶和合成泡沫生物材料，用于培养和運輸肠道类器官[18] ，并将DNA功能化的金纳米颗粒封装到肠道类器官中，成為可供药物運送與基因治療的肠道特洛伊木马（intestinal Trojan horse）[19]。後續的研究显示这些类器官在體外[20]和体内同樣具有显着的生理功能[21] [22]。
其他重大的早期进展包括 2013 年，奥地利科学院分子生物技术研究所的Madeline Lancaster制定了一项流程，可以从多能干细胞开始生成模仿人类大脑细胞组织发育的大脑类器官[23]。荷蘭皇家藝術與科學研究所和烏特勒支大學医学中心的Meritxell Huch與Craig Dorrell证明，来自受损小鼠肝脏的单个Lgr5+细胞可以在基于Rspo1的培养基中複製並扩增數個月並最終形成肝类器官[24]。2014 年，伊利諾大學厄巴納-香檳分校的Artem Shkumatov等人证明，通过調控胚胎干细胞粘附的基质硬度，可以形成心血管类器官。生理上的硬度特性促进了EB的立體性質與心肌分化[25]。2015 年，Takebe 等人通过将多能干细胞衍生的组织特异性祖细胞或相关组织样本与内皮细胞和间质干细胞相结合，展示了一种从不同组织形成器官芽的通用方法。他们认为，通过自组织凝聚原理产生的不太成熟的组织或器官芽可能是移植后重建成熟器官功能的最有效方法，而不是由發育上更加成熟阶段的细胞凝聚物[26]。
特性
Lancaster 和 Knoblich [4]將類器官定義為從幹細胞或器官前驅細胞發育而來的器官特異性細胞類型的集合，透過細胞分選和空間限制的譜系定型以類似於體內的方式進行自組織，並表現出以下特徵特性：
培養過程
类器官的生長通常需要在立體培养基中培养干细胞或祖细胞[4]。干细胞具有自我更新和分化成各种细胞類型的能力，并且能够用於了解发育和疾病进展的过程[27]。因此，源自干细胞的类器官能够在器官水平上研究生理学[28]。立體培养基可以使用细胞外基质水凝胶（例如Matrigel或 Cultrex BME）制成，这是一种富含层粘连蛋白的细胞外基质，由 Engelbreth-Holm-Swarm肿瘤細胞株分泌[29]，可以通过将干细胞嵌入 基质中来制备类器官[4]。当多能性幹细胞用于创建类器官时，细胞通常（但并非总是）形成擬胚體[4]。然后用模式因子对这些拟胚体进行处理，以驱动所需类器官特征的形成[4]。此外，也可以使用目標器官中提取的成体干细胞創建类器官，并在立體培养基中培养[30]。
生物化學的特性已被纳入类器官培养中，藉由添加形态发生素、形态发生抑制剂或生长因子，可以誘導胚胎干细胞或成体干细胞發育成為类器官。血管化技術可用於賦予微環境在生理上接近其相對應部位的特性。可以藉由微流体系统、血管内皮生长因子输送系统和内皮细胞涂层模块来達成可促进氧气或营养物质进入类器官内部的血管系统[9]。利用源自患者的诱导多能干细胞(iPSC) [31]和基于CRISPR/Cas9的基因编辑[32]技术，可以生成基因組編輯或突變的多能幹細胞（PSCs），並改變信號傳遞特性，以控制器官模型內的內在性質。
類型
使用類器官可以概括多種器官結構[4]。本節旨在透過提供一份精簡的器官模型清單，概述目前該領域的現狀，並根據最新文獻對每個器官模型進行簡要概述，並提供其在研究中的應用示例。
腦類器官
脑类器官是指體外培養的类似于大脑的微型器官。大脑类器官於旋转生物反应器在三维環境下中培养人类多能干细胞产生，并需要数月的时间发育[23]。這對脑部发育、生理学和功能的研究中具有潜在的应用。腦类器官可能会对外部刺激产生「简单的感觉」，神经科学家也对这些器官可能发展出感知能力表示担忧。他们提出，该技术的进一步发展需要受到严格的监督[33] [34] [35]。2023年，研究人员建造了一台混合生物计算机，将实验室培养的人脑类器官与传统电路相结合，可以完成语音识别等任务[36]。脑类器官目前正用于研究和开发类器官智能（OI）技术。 [37]
胃腸道類器官
胃腸道類器官是指概括胃腸道結構的類器官。胃腸道起源於內胚層，在發育過程中形成一個管狀構造，可以分為三個不同的區域，與其他器官一起產生胃腸道的以下部分：[4]
胃腸道類器官又可細分為以下數種：
腸類器官
迄今为止，肠类器官[16]属于直接由肠组织或多能干细胞产生的肠道类器官[4]。促使人类多能干细胞形成肠类器官的方法是，首先使用激活素A 驱動细胞进入中内胚层状态，然后对Wnt3a和Fgf4信号通路进行上调，因为它们已被证明可以促进組織走向后肠道細胞命运[4]。肠类器官也可以由肠干细胞产生，从成体组织中提取并在立體培养基中培养[30]。这些成体干细胞衍生的类器官通常被称为肠类器官或类结肠类器官，具体取决于它们的起源部分，并且是从人类和小鼠肠道中建立的[16] [38] [39]。肠类器官由围绕中央管腔的单层极化肠上皮细胞组成。因此，通过概括肠道的功能、生理学和组织，并维持结构中正常存在的所有细胞类型（包括肠干细胞），概括肠道的隐窝绒毛结构[4]。因此，肠类器官是研究肠道营养转运[40] [41]、药物吸收和递送[42] [43]、纳米材料和纳米医学[44] [45]、肠泌素分泌[46] [47]和各种肠道病原体感染[48] [49]等議題的有力模型。
例如，王峮团队利用肠类器官衍生的粘膜模型设计了人工病毒纳米顆粒作为口服药物递送载体（ODDV）[50]，并展示了利用新建立的结肠类器官作为高通量药物筛选、毒性分析工具的新概念。测试和口服药物开发[51]。肠类器官还以如此高的保真度再现了隐窝绒毛结构，以至于它们已成功移植到小鼠肠道中，因此被高度视为有价值的研究模型[4]。肠类器官已被利用的研究领域之一是干细胞生态位。肠类器官被用来研究肠干细胞區位的性质，並证明了IL-22在维持肠干细胞中的重要作用[52]以及其他細胞類型（如神經元和成纖維細胞）在維持腸道幹細胞的重要性[30]。在感染生物学领域，人们已经探索各類基于肠道类器官的模型系统。一方面，只需将类器官与感兴趣的肠道病原体混合即可大量感染[53]。然而，为了模擬更接近自然情況下，由肠腔开始的感染途徑，需要使用病原体进行显微注射[54] [55]。此外，肠类器官的极性可以反转[56]，甚至可以解离成单个细胞并以二维单层培养[57] [58] ，以便使上皮的顶端和基底外侧更容易接近。最後，肠类器官也显示出用於治疗的潜力[59]。
為了更準確地再現體內腸道，開發了腸道類器官和免疫細胞的共培養方式[58]。此外，器官晶片模型将肠道类器官与其他細胞或體內環境（例如内皮细胞、免疫细胞以及蠕动）结合起来[60] [61]。
胃類器官
胃类器官部分地概括了胃的生理性質。通过在三维培养条件下对FGF 、 WNT 、 BMP 、视黄酸和EGF信号通路进行时间尺度上的調控，可以從多能干细胞直接生成胃類器官[62]。胃类器官也可以由LGR5+的胃成体干细胞产生[63]。胃类器官已被用作研究癌症[64] [65]以及其他人类疾病发育的模型[62]。例如，一项研究[65]调查了患者转移性肿瘤背后的潜在遗传變化，发现相較於同一患者身上的原发性肿瘤，转移性肿瘤的TGFBR2基因的两个等位基因均发生突变。为了进一步评估TGFBR2在转移中的作用，研究人员创建了TGFBR2基因敲落的类器官，透過这种类器官，他们证明TGFBR2活性降低会导致體內與體外環境下的惡性肿瘤侵袭與转移。
舌類器官
舌类器官是概括舌头生理学各方面的类器官。在立體培养条件下，透過EGF 、 WNT和TGF-β的調控，使用表达BMI1 的上皮幹细胞培養出上皮舌类器官[66]。然而，这种类器官培养物缺乏味觉受体[66]。相較之下，含有味觉细胞的味蕾类器官則是使用LGR5+或CD44+的輪狀乳突幹細胞/前驅細胞[67]或者Lgr5+或LGR6+的味觉幹细胞创建的[68]。
其他
- 细胞排斥性微量滴定板的最新进展使得能够快速、经济高效地筛选大分子药物（例如针对胰腺癌 3D 模型的库）。这些模型在表型和表达谱上与David Tuveson博士实验室发现的模型一致。
- 上皮类器官[16] [80]
- 肺类器官[81]
- 肾类器官[17] [82] [83] [84]
- 原肠胚（胚胎类器官） [85] [86] [87] [88] —— 可以生成所有胚胎轴並且在前后轴的方向與Hox基因表达的形式共線。 [88]
- 囊胚類器官 [89] [90] [91]
- 子宫内膜类器官[92]
- 心脏类器官[93] —— 2018 年，中空心脏类器官被提出，並表現心搏且可以對刺激產生反應而改變跳動速度[94]。
- 视网膜类器官[95] [96]
- 乳腺癌类器官[97]
- 结直肠癌类器官[98]
- 胶质母细胞瘤类器官[99]
現今，來自患者的外植體（patient derived explants，PDX）或直接來自癌症組織的三維器官模型已經可以輕易製備，並且可將其用於現有核准藥物的高通量篩選。
由腦微血管內皮細胞（BMECs）、星形細胞和周細胞組成的自組裝細胞聚集體正逐漸成為物質穿膜和微流體模型的潛在替代方案。這些器官模型能夠生成血腦屏障（BBB）的許多特徵，如緊密連接的表達、分子運輸蛋白和藥物排出泵，因此可以用來模擬藥物穿越BBB的過程。此外，它們可以作為評估BBB與相鄰腦組織之間相互作用的模型，並提供了一個了解新藥物克服BBB的綜合能力以及其對腦組織的影響的平台。此類模型具有高度可擴展性，且比微流體裝置更容易製造和操作。然而，它們對於重建BBB的形態和生理學以及模擬生理流動和剪應力的能力有限。[103]
基礎研究
类器官能够協助研究细胞與細胞間、細胞與环境之間的相互作用以及疾病和藥物如何影響他們的作用。體外培养使该系统易于操作及监测。器官的實際體積過大使得物質滲透受到限制而不易培養，但类器官的小尺寸可以規避此问题。另一方面，類器官并不表现出所有器官特征，并且与其他器官的相互作用在体外也无法重现。虽然腸道類器官的第一個研究方向是用於探討幹细胞特性的调控[16]，但如今也用于研究营养物质的摄取、药物转运和肠泌素的分泌等議題[104]。这对于吸收不良疾病以及肥胖、胰岛素抵抗和糖尿病等代谢疾病具有重要意义。
疾病模型
类器官提供建立人类疾病细胞模型的机会，可以在实验室中进行研究以更好地了解疾病的原因并确定可能的治疗方法。类器官在这方面的潛力首次在小头畸形的遗传研究中顯現，其中患者细胞被用来制造脑类器官，这种类器官较小并且在早期神经元生成中表现出异常[23]。另一个案例是将CRISPR应用于人类多能干细胞，在与两种不同肾脏疾病（多囊肾病和局灶节段性肾小球硬化症）相关的基因中引入靶向突变[83]。这些经过 CRISPR修饰的多能干细胞随后被培养成人类肾类器官，表现出疾病特异性表型。来自患有多囊肾病突变的干细胞的肾脏类器官由肾小管形成了巨大的半透明囊肿结构。当在悬浮的情况下培养时，这些包囊的大小在數個月內达到直径1厘米[105]。与局灶节段性肾小球硬化症相关的基因发生突变的肾类器官，其足细胞（该疾病中受影响的过滤细胞）之间出现了細胞连接的缺陷[106]。重要的是，这些疾病表型在具有相同遗传背景但缺乏CRISPR突变的对照类器官中不存在[83] [105] [106]。将这些类器官表型与小鼠和人类的患病组织进行比较，发现它们与早期发育缺陷有相似之处[105] [106]。
正如Takahashi和Yamanaka于 2007 年首次發表的那样，诱导多能干细胞（iPSC）也可以从患者皮肤纖維母细胞中重编程[107]。这些干细胞携带患者的确切遗传背景，包括可能导致人类疾病发展的任何基因突变。由于ORCL1突变而患有Lowe综合征的患者已将这些细胞分化为肾脏类器官[108]。该报告比较了患者iPSC与不相关的对照iPSC分化的肾类器官，并证明患者肾细胞无法调动高尔基体中的转录因子 SIX2[108]。因为SIX2是肾單元前驅细胞的一个明确标记，作者得出结论為，洛氏综合征（近曲小管在吸收的整体衰竭或范康尼氏症候群）中常见的肾脏疾病可能与肾单元引起的改变有关，其中祖细胞缺乏这种重要的SIX2基因表达[108]。
其他研究使用CRISPR来修復患者iPSC细胞中的突变，以创建等位基因对照，该对照可以与iPSC重编程同时进行[109] [110] [111]。将患者iPSC衍生的类器官与同基因对照进行比较是该领域当前的黄金标准，因为它允许将感兴趣的突变分离为实验模型中的唯一变量[112]。在一份报告中，将源自IFT140复合杂合突变的Mainzer-Saldino综合征患者iPSC的肾类器官与等基因对照类器官进行比较，其中通过CRISPR 修正了产生无活性 mRNA 转录物的IFT140突变体[110]。患者肾类器官表现出与现有动物模型一致的异常纤毛形态，在基因修正的类器官中将其恢复为野生型狀態[110]。比較患者和对照类器官中纯化的上皮细胞的转录組突显了涉及细胞极性、细胞-细胞连接和动力蛋白运动组装的途径，其中一些途径与肾纤毛病表型家族中的其他基因型有关[110]。另一份利用等基因对照的报告表明，先天性肾病综合征患者产生的肾脏类器官的肾小球中去氧肾上腺素定位异常[111]。
最後，諸如上皮代謝之類的事情也可以利用類似方式建模[113]。
個人化醫療
Clevers小組建立的方法可以從直腸活檢樣本中培養出的腸類器官，目前已被用於模擬囊腫性纖維化[114]，並促使類器官首次運用於個人化醫療 [115]。囊腫性纖維化是一種遺傳性疾病，由囊腫性纖維化穿膜傳導調節基因（Cystic fibrosis transmembrane conductance regulator，CFTR）的突變引起，該基因編碼位於健康上皮表面維持液體所需的離子通道。Jeffrey Beekman 實驗室於 2013 年進行的研究描述，以毛喉素或霍亂毒素等cAMP升高激動劑刺激結直腸類器官，會以完全 CFTR 依賴性的方式誘導類器官快速腫脹[114]。非囊腫性纖維化患者的類器官因為液體輸送到類器官管腔而對毛喉素產生反應並膨脹，相較之下，來自囊腫性纖維化患者的類器官則嚴重減少或不存在。 修復CFTR蛋白的療法可以恢復腫脹，這表明可以在臨床前實驗室環境中量化個體對CFTR調節療法的反應。2013年，Schwank等人於更進一步證明腸道囊腫性纖維化類器官的異常表型可以透過CRISPR-Cas9基因編輯進行修復[116]。
2016年，Dekkers等人的後續研究表明，來自囊腫性纖維化患者的腸道類器官之間由毛喉素誘導的腫脹程度差異與已知的診斷和預後標誌物（例如CFTR 基因突變或CFTR功能 的體內生物標記）相關[115]。此外，他們證明具有特定CFTR突變的腸道類器官接受CFTR調節劑處裡後的效果與已發表的臨床試驗結果相似。 這促使臨床前研究發現來自具有極其罕見的 CFTR 突變且未經過治療的患者類器官對臨床使用的CFTR調節劑有強烈反應。這些臨床前類器官測試所得到的治療成效被後續Kors van der Ent所帶領的團隊執行的臨床試驗所證實。這些研究首次表明類器官可以應用於個人化醫療。
類器官移植
2022 年，類器官被首次用於移植手術。一名患有潰瘍性結腸炎的患者，藉由採集其健康結腸黏膜的細胞進行體外培養1個月後，將這些細胞生長而成的類器官重新移植回患者身上，取得良好的治療效果[117][118]。
作為發育生物學的模型
類器官為研究人員提供了研究發育生物學的模型[119]。自從多能幹細胞被提出後以來，利用二維培養在體外定向誘導多能幹細胞的分化已經取得了巨大的進展[119]。如今，多能性幹細胞培養的技術進步搭配3D培養技術的發展，使得培養各類器官內的特定細胞組織成為可能[119]。因此，這些類器官的使用極大地促進了我們對器官發生過程和發育生物學領域的理解[119]。例如，中樞神經系統的發育中，類器官的研究有助於科學家理解視神經盤形成過程中物理力量的扮演的角色[119][120]。近期的研究則專注於延長皮質類器官的生長週期並且取得顯著的進展。在一些研究中，類器官存在將近一年，並表現出人類胎兒發展階段的部分特徵[121]。
參見
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