DIFFERENTIATION AND INTEGRITY OF CARDIAC-MUSCLE-CELLS ARE IMPAIRED INTHE ABSENCE OF BETA(1) INTEGRIN

Cellular interactions with substrata of the microenvironment are one o f 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 c ell adhesion, We have used beta(1) integrin-deficient embryonic stem c ells 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 specificatio n of cardiac precursor cells into pacemaker-, atrial- and ventricular- like cells is significantly impaired in beta(1) integrin-deficient cel ls, The occurrence of atrial- and ventricular-like cells is reduced an d transient, Only cells exhibiting pacemaker-like action potentials of high frequency and arrhythmias survive, Third, the sarcomeric archite cture 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 c ells contain cell debris, The number of beta(1)-null cells decreases f rom prenatal to postnatal stages and is lost completely in 6-month-old hearts, Thus, we conclude that interactions with the extracellular ma trix via beta(1) integrin is necessary for differentiation and the mai ntenance of a specialized phenotype of cardiac muscle cells.