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通过直接谱系重编程生成小鼠和人类类器官形成肠祖细胞。

Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming.

机构信息

Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

出版信息

Cell Stem Cell. 2017 Oct 5;21(4):456-471.e5. doi: 10.1016/j.stem.2017.08.020. Epub 2017 Sep 21.


DOI:10.1016/j.stem.2017.08.020
PMID:28943029
Abstract

Intestinal organoids hold great promise as a valuable tool for studying and treating intestinal diseases. The currently available sources of human intestinal organoids, tissue fragments or pluripotent stem cells, involve invasive procedures or complex differentiation protocols, respectively. Here, we show that a set of four transcription factors, Hnf4α, Foxa3, Gata6, and Cdx2, can directly reprogram mouse fibroblasts to acquire the identity of fetal intestine-derived progenitor cells (FIPCs). These induced FIPCs (iFIPCs) form spherical organoids that develop into adult-type budding organoids containing cells with intestinal stem cell properties. The resulting stem cells produce all intestinal epithelial cell lineages and undergo self-renewing cell divisions. After transplantation, the induced spherical and budding organoids can reconstitute colonic and intestinal epithelia, respectively. The same combination of four defined transcription factors can also induce human iFIPCs. This alternative approach for producing intestinal organoids may well facilitate application for disease analysis and therapy development.

摘要

肠类器官作为研究和治疗肠道疾病的有价值的工具具有巨大的潜力。目前可用的人类肠类器官来源,组织片段或多能干细胞,分别涉及侵入性程序或复杂的分化方案。在这里,我们表明,一组四个转录因子,Hnf4α、Foxa3、Gata6 和 Cdx2,可以直接重编程小鼠成纤维细胞获得胎儿肠来源祖细胞(FIPCs)的身份。这些诱导的 FIPCs(iFIPCs)形成球体类器官,进一步发育成具有肠干细胞特性的成人型芽状类器官。产生的干细胞产生所有肠上皮细胞谱系,并经历自我更新的细胞分裂。移植后,诱导的球体和芽状类器官可以分别重建结肠和肠上皮。同样的四种定义明确的转录因子组合也可以诱导人类 iFIPCs。这种产生肠类器官的替代方法可能非常有助于疾病分析和治疗开发的应用。

相似文献

[1]
Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming.

Cell Stem Cell. 2017-9-21

[2]
Direct Lineage Reprogramming of Mouse Fibroblasts to Acquire the Identity of Fetal Intestine-Derived Progenitor Cells.

Methods Mol Biol. 2020

[3]
Establishment of 3D Intestinal Organoid Cultures from Intestinal Stem Cells.

Methods Mol Biol. 2017

[4]
Identification of Lgr5-independent spheroid-generating progenitors of the mouse fetal intestinal epithelium.

Cell Rep. 2013-10-31

[5]
Analysis of Aged Dysfunctional Intestinal Stem Cells.

Methods Mol Biol. 2020

[6]
Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2.

Nat Commun. 2014-12-11

[7]
Designer matrices for intestinal stem cell and organoid culture.

Nature. 2016-11-16

[8]
Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury.

Cell Stem Cell. 2013-10-17

[9]
Intestinal organoids: A new paradigm for engineering intestinal epithelium in vitro.

Biomaterials. 2018-12-10

[10]
Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate.

Alcohol Clin Exp Res. 2017-11-7

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[3]
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Exp Mol Med. 2024-10

[6]
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[7]
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[8]
Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture.

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[9]
Lineage Reprogramming: Genetic, Chemical, and Physical Cues for Cell Fate Conversion with a Focus on Neuronal Direct Reprogramming and Pluripotency Reprogramming.

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[10]
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