Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta 1 integrin.
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.
Fässler
R
R
Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Rohwedel
J
J
Maltsev
V
V
Bloch
W
W
Lentini
S
S
Guan
K
K
Gullberg
D
D
Hescheler
J
J
Addicks
K
K
Wobus
A M
AM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology*; D018995:Myosin Heavy Chains / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics; D012518:Sarcomeres; D013234:Stem Cells / Q000166:cytology
D019012:Integrin beta1; D018994:Myosin Light Chains; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains