Soh Boon-Seng, Buac Kristina, Xu Huansheng, Li Edward, Ng Shi-Yan, Wu Hao, Chmielowiec Jolanta, Jiang Xin, Bu Lei, Li Ronald A, Cowan Chad, Chien Kenneth R
1] Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA [3] Stem Cell & Regenerative Medicine Consortium, and the Department of Physiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China [4] Department of Cell and Molecular Biology and Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.
1] Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA [3] Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Cell Res. 2014 Dec;24(12):1420-32. doi: 10.1038/cr.2014.142. Epub 2014 Nov 4.
The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenvironment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides additional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.
前心区（AHF）中的心脏祖细胞（CPCs）位于咽中胚层（PM），在那里它们增殖、迁移，并最终分化为心脏中发现的主要细胞类型，包括心肌细胞。这些祖细胞能够在PM微环境中增殖而不发生过早分化的机制在很大程度上仍不清楚。通过计算机数据挖掘、基因功能丧失研究和体内基因拯救研究，我们确定N-钙黏蛋白以及与经典Wnt信号的相互作用是促进AHF-CPCs在PM中增殖的微环境的关键组成部分。在N-钙黏蛋白突变胚胎中的CPCs在PM中增殖较少且发生过早分化。值得注意的是，激活Wnt信号可部分挽救N-钙黏蛋白缺陷的表型，这表明在早期PM微环境中，N-钙黏蛋白的黏附作用与Wnt信号之间存在微妙的功能相互作用。这项研究揭示了AHF祖细胞早期更新的一种新机制，即N-钙黏蛋白为PM中的祖细胞提供额外的黏附作用，从而使Wnt旁分泌信号能够使细胞增殖而不发生过早分化。
