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逐渐分化与细胞周期退出脱耦产生表皮干细胞层的异质性。

Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer.

机构信息

Department of Genetics, Yale School of Medicine, New Haven, CT, USA.

Department of Biochemistry and Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.

出版信息

Nat Cell Biol. 2022 Dec;24(12):1692-1700. doi: 10.1038/s41556-022-01021-8. Epub 2022 Nov 10.

DOI:10.1038/s41556-022-01021-8
PMID:36357619
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9729105/
Abstract

Highly regenerative tissues continuously produce terminally differentiated cells to replace those that are lost. How they orchestrate the complex transition from undifferentiated stem cells towards post-mitotic, molecularly distinct and often spatially segregated differentiated populations is not well understood. In the adult skin epidermis, the stem cell compartment contains molecularly heterogeneous subpopulations whose relationship to the complete trajectory of differentiation remains unknown. Here we show that differentiation, from commitment to exit from the stem cell layer, is a multi-day process wherein cells transit through a continuum of transcriptional changes with upregulation of differentiation genes preceding downregulation of typical stemness genes. Differentiation-committed cells remain capable of dividing to produce daughter cells fated to further differentiate, demonstrating that differentiation is uncoupled from cell cycle exit. These cell divisions are not required as part of an obligate transit-amplifying programme but help to buffer the differentiating cell pool during heightened demand. Thus, instead of distinct contributions from multiple progenitors, a continuous gradual differentiation process fuels homeostatic epidermal turnover.

摘要

高度再生的组织不断产生终末分化的细胞来替代那些丢失的细胞。它们如何协调从未分化的干细胞向有丝分裂后、分子上不同且通常空间上分离的分化群体的复杂转变，目前还不太清楚。在成年皮肤表皮中，干细胞区室包含分子异质性亚群，其与分化的完整轨迹的关系尚不清楚。在这里，我们表明从分化开始到退出干细胞层是一个多日的过程，在此过程中，细胞经历了一个连续的转录变化，分化基因的上调先于典型干性基因的下调。分化起始的细胞仍然能够分裂产生注定要进一步分化的子细胞，这表明分化与细胞周期退出是解耦的。这些细胞分裂不是必需的，因为它们是一种强制性的过渡扩增程序的一部分，但有助于在需求增加时缓冲分化细胞库。因此，不是来自多个前体细胞的不同贡献，而是一个连续的逐渐分化过程为表皮的动态平衡提供动力。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/345a595ed385/41556_2022_1021_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/43e5cb678284/41556_2022_1021_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/b97c538daf9a/41556_2022_1021_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/4e9d6cca803a/41556_2022_1021_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/fbce987b3008/41556_2022_1021_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/9853280539f3/41556_2022_1021_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/536b38edd8b7/41556_2022_1021_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/83f3d9c8b255/41556_2022_1021_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/7bd218982429/41556_2022_1021_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/90202e791218/41556_2022_1021_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/307f6dfa676e/41556_2022_1021_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/b8ebf9efa500/41556_2022_1021_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/9fe109d9b2cc/41556_2022_1021_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3af/9729105/345a595ed385/41556_2022_1021_Fig13_ESM.jpg

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