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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. ​

文献信息 ​

DOI10.1038/nature07935
PMID19329995
期刊Nature
影响因子48.5
JCR 分区Q1
发表年份2009
被引次数3690
关键词Lgr5干细胞, 肠道上皮, 器官样体
文献类型Journal Article
ISSN0028-0836
页码262-5
期号459(7244)
作者Toshiro Sato, Robert G Vries, Hugo J Snippert, Marc van de Wetering, Nick Barker, Daniel E Stange, Johan H van Es, Arie Abo, Pekka Kujala, Peter J Peters, Hans Clevers

一句话小结 ​

本研究揭示了小肠隐窝底部的Lgr5(+)干细胞能够在长期培养条件下自我组织形成绒毛样上皮，且这一过程可以通过单个干细胞启动并维持其层次结构。这一发现为理解肠道上皮的自我更新机制及其在再生医学中的应用提供了重要的基础。

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Lgr5干细胞 · 肠道上皮 · 器官样体

摘要 ​

肠道上皮是成年哺乳动物中自我更新速度最快的组织。我们最近展示了小肠隐窝底部存在约六个周期性Lgr5(+)干细胞。在这里，我们描述了建立长期培养条件，使得单个隐窝经历多次隐窝分裂事件，同时生成具有所有分化细胞类型的绒毛样上皮区域。单个分选的Lgr5(+)干细胞也能够启动这些隐窝-绒毛类器官。追踪实验表明，Lgr5(+)干细胞的层次结构在类器官中得以维持。我们得出结论，肠道隐窝-绒毛单元是自我组织的结构，可以在没有非上皮细胞生态位的情况下，由单个干细胞构建而成。

英文摘要 ​

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.

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主要研究问题 ​

  1. Lgr5(+)干细胞在体外培养中如何维持其自我更新和分化能力？
  2. 这种无间质细胞环境下的培养方法对于其他类型的干细胞有何启示？
  3. 在不同的培养条件下，Lgr5(+)干细胞的增殖和分化模式会有什么变化？
  4. 是否可以通过调节培养基成分来进一步优化单个Lgr5(+)干细胞的组织构建效率？
  5. 这种研究对肠道疾病模型的建立和治疗策略的开发有何潜在影响？

核心洞察 ​

  1. 研究背景和目的
    肠道上皮是成年哺乳动物中自我更新速度最快的组织。Lgr5(+)干细胞被认为是肠道上皮再生的关键，但其在体外培养和自我组织能力的研究相对较少。本研究旨在探讨单个Lgr5(+)干细胞在无间充质细胞环境下，如何在体外建立肠道隐窝-绒毛结构，进而了解其自我组织机制和潜在的再生能力。

  2. 主要方法和发现
    研究团队开发了长期培养条件，使单个隐窝能够经历多次隐窝分裂事件，同时生成绒毛状的上皮域，且所有分化细胞类型均可在其中存在。此外，单纯分选的Lgr5(+)干细胞能够启动这些隐窝-绒毛类器官的形成。追踪实验表明，Lgr5(+)干细胞的层级结构在这些类器官中得以维持。这一发现表明，即使在缺乏非上皮细胞的环境中，Lgr5(+)干细胞仍能自我组织形成完整的肠道结构。

  3. 核心结论
    该研究得出的核心结论是，肠道隐窝-绒毛单元能够自我组织形成，且这一过程可以由单个Lgr5(+)干细胞在无间充质细胞的条件下完成。这表明，Lgr5(+)干细胞具备强大的自我组织能力和再生潜力，能够在体外独立构建复杂的肠道结构。

  4. 研究意义和影响
    本研究的意义在于为肠道再生和修复提供了新的思路，揭示了Lgr5(+)干细胞在组织工程和再生医学中的潜在应用价值。通过理解肠道上皮的自我组织机制，可以为疾病模型的建立、药物筛选以及个性化治疗提供新的策略。此外，该研究也为干细胞生物学和组织工程领域提供了重要的理论基础和实验方法，促进了相关领域的进一步探索与发展。

参考文献 ​

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  9. Peptide growth factors in the intestine. - A U Dignass;A Sturm - European journal of gastroenterology & hepatology (2001)
  10. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. - L Li;L A Milner;Y Deng;M Iwata;A Banta;L Graf;S Marcovina;C Friedman;B J Trask;L Hood;B Torok-Storb - Immunity (1998)

引用本文的文献 ​

  1. The tortoise and the hair: slow-cycling cells in the stem cell race. - Elaine Fuchs - Cell (2009)
  2. Stem cells and solid cancers. - Stuart A C McDonald;Trevor A Graham;Stefanie Schier;Nicholas A Wright;Malcolm R Alison - Virchows Archiv : an international journal of pathology (2009)
  3. Telomeres and disease. - Peter M Lansdorp - The EMBO journal (2009)
  4. Colon cancer stem cells. - Lucia Ricci-Vitiani;Eros Fabrizi;Elisabetta Palio;Ruggero De Maria - Journal of molecular medicine (Berlin, Germany) (2009)
  5. The stem cells of small intestinal crypts: where are they? - C S Potten;R Gandara;Y R Mahida;M Loeffler;N A Wright - Cell proliferation (2009)
  6. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. - Bin-Bing S Zhou;Haiying Zhang;Marc Damelin;Kenneth G Geles;Justin C Grindley;Peter B Dirks - Nature reviews. Drug discovery (2009)
  7. Stable expression of neurogenin 1 induces LGR5, a novel stem cell marker, in an immortalized human neural stem cell line HB1.F3. - Jun-ichi Satoh;Shinya Obayashi;Hiroko Tabunoki;Taeko Wakana;Seung U Kim - Cellular and molecular neurobiology (2010)
  8. Stem cells in gastroenterology and hepatology. - Michael Quante;Timothy C Wang - Nature reviews. Gastroenterology & hepatology (2009)
  9. Bronchiolar progenitor cells. - Huaiyong Chen;Keitaro Matsumoto;Barry R Stripp - Proceedings of the American Thoracic Society (2009)
  10. Quantitative proteomics by metabolic labeling of model organisms. - Joost W Gouw;Jeroen Krijgsveld;Albert J R Heck - Molecular & cellular proteomics : MCP (2010)

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