Fässler R, Rohwedel J, Maltsev V, Bloch W, Lentini S, Guan K, Gullberg D, Hescheler J, Addicks K, Wobus A M
Max-Planck-Institute of Biochemistry, Martinsried, Germany.
J Cell Sci. 1996 Dec;109 ( Pt 13):2989-99. doi: 10.1242/jcs.109.13.2989.
Cellular interactions with substrata of the microenvironment are one of the major mechanisms for differentiation and morphogenesis. Many of these interactions are mediated via the beta 1 integrin subfamily of cell surface receptors, which are believed to transduce signals upon cell adhesion. We have used beta 1 integrin-deficient embryonic stem cells to test their ability to differentiate into cardiac muscle cells. We show here by several approaches that beta 1 integrin is important for normal cardiogenesis. First, the in vitro differentiation of beta 1 integrin-deficient embryonic stem cells into cardiac muscle cells is retarded. This is demonstrated by the delayed expression of cardiac muscle-specific genes and action potentials. Second, the specification of cardiac precursor cells into pacemaker-, atrial- and ventricular-like cells is significantly impaired in beta 1 integrin-deficient cells. The occurrence of atrial- and ventricular-like cells is reduced and transient. Only cells exhibiting peacemaker-like action potentials of high frequency and arrhythmias survive. Third, the sarcomeric architecture is incomplete and disarranged in the absence of beta 1 integrin. Fourth, beta 1-deficient embryonic stem cells can contribute to the developing heart in chimaeric mice but many areas with beta 1-null cells contain cell debris. The number of beta 1-null cells decrease from prenatal to postnatal stages and is lost completely in 6-month-old hearts. Thus, we conclude that interactions with the extracellular matrix via beta 1 integrin is necessary for differentiation and the maintenance of a specialized phenotype of cardiac muscle cells.
细胞与微环境基质的相互作用是分化和形态发生的主要机制之一。其中许多相互作用是通过细胞表面受体的β1整合素亚家族介导的，据信这些受体在细胞黏附时转导信号。我们使用β1整合素缺陷的胚胎干细胞来测试它们分化为心肌细胞的能力。我们通过几种方法表明，β1整合素对正常心脏发生很重要。首先，β1整合素缺陷的胚胎干细胞在体外分化为心肌细胞的过程受到阻碍。这通过心肌特异性基因表达的延迟和动作电位得以证明。其次，β1整合素缺陷的细胞中，心脏前体细胞向起搏器样、心房样和心室样细胞的特化明显受损。心房样和心室样细胞的出现减少且短暂。只有表现出高频起搏器样动作电位和心律失常的细胞存活下来。第三，在没有β1整合素的情况下，肌节结构不完整且紊乱。第四，β1缺陷的胚胎干细胞可以在嵌合小鼠的发育心脏中起作用，但许多含有β1缺失细胞的区域含有细胞碎片。从产前到产后阶段，β1缺失细胞的数量减少，在6个月大的心脏中完全消失。因此，我们得出结论，通过β1整合素与细胞外基质的相互作用对于心肌细胞分化和维持其特殊表型是必要的。
