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FAM122A 对于胚胎干细胞的中胚层和心脏分化是必需的。

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells.

机构信息

Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education and Chinese Academy of Medical Sciences Research Unit (2019RU043, Stress and Tumor), Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, People's Republic of China.

出版信息

Stem Cells. 2023 Apr 25;41(4):354-367. doi: 10.1093/stmcls/sxad008.

DOI:10.1093/stmcls/sxad008
PMID:36715298
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10498146/
Abstract

Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved housekeeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multifaceted physiological and pathological processes. However, the in vivo function of FAM122A is largely unknown. In this study, we observed that Fam122 deletion resulted in embryonic lethality with severe defects of cardiovascular developments and significantly attenuated cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impaired mesendodermal specification and cardiac differentiation from mouse embryonic stem cells but showed no influence on pluripotent identity. Mechanical investigation revealed that the impaired differentiation potential was caused by the dysregulation of histone modification and Wnt and Hippo signaling pathways through modulation of PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This research not only significantly extends our understanding of the regulatory network of mesendodermal/cardiac differentiation but also proposes the potential significance of FAM122A in cardiac regeneration.

摘要

中胚层特化和心脏分化是发育生物学和心脏再生医学的关键问题。先前，我们证明了 FAM122A，一种高度保守的管家基因，是蛋白磷酸酶 2A（PP2A）的内源性抑制剂，并参与多种生理和病理过程。然而，FAM122A 的体内功能在很大程度上是未知的。在这项研究中，我们观察到 Fam122 缺失导致胚胎致死，伴有心血管发育的严重缺陷，并显著减弱条件性心脏特异性敲除小鼠的心脏功能。更重要的是，Fam122a 缺陷会损害中胚层特化和心脏从小鼠胚胎干细胞的分化，但对多能性身份没有影响。力学研究表明，通过调节 PP2A 活性，受损的分化潜能是由组蛋白修饰和 Wnt 和 Hippo 信号通路的失调引起的。这些发现表明 FAM122A 是中胚层特化和心脏分化的新型关键调节因子。这项研究不仅显著扩展了我们对中胚层/心脏分化调控网络的理解，还提出了 FAM122A 在心脏再生中的潜在意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/cd6379a6e7b2/sxad008_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/bbf522106161/sxad008_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/ef9cc8268199/sxad008_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/faaf204e8957/sxad008_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/e64f8209be0e/sxad008_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/53f576f7258f/sxad008_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/cd6379a6e7b2/sxad008_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/bbf522106161/sxad008_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/ef9cc8268199/sxad008_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/faaf204e8957/sxad008_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/e64f8209be0e/sxad008_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/53f576f7258f/sxad008_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd9/10498146/cd6379a6e7b2/sxad008_fig5.jpg

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本文引用的文献

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Adaptations in Hippo-Yap signaling and myofibroblast fate underlie scar-free ear appendage wound healing in spiny mice.Hippo-Yap 信号通路和肌成纤维细胞命运的适应性改变是多刺鼠耳创伤无瘢痕愈合的基础。
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Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer.
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Protein Phosphatase 2A Mediates YAP Activation in Endothelial Cells Upon VEGF Stimulation and Matrix Stiffness.蛋白磷酸酶2A在血管内皮生长因子刺激和基质硬度作用下介导内皮细胞中Yes相关蛋白（YAP）的激活。
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