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1 Signaling Contributes to Development of Smooth Muscle Cells from Embryonic Stem Cells
1 Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, VA, USA
2 Department of Medicine, University of Manchester, Manchester, United Kingdom
* To whom correspondence should be addressed. E-mail: gko{at}virginia.edu.
Knockout of transforming growth factor (TGF)
-1 or components of its signaling pathway leads to embryonic death in mice due to impaired yolk sac vascular development before significant smooth muscle cell (SMC) maturation occurs. Thus, the role of TGF-1 in SMC development remains unclear. Embryonic stem cell derived embryoid bodies (ESC-EB) recapitulate many of the events of early embryonic development and represent a more physiological context in which to study SMC development than most other in vitro systems. The present studies showed induction of the SMC selective genes, smooth muscle 
-actin (SMA), SM22, myocardin, smoothelin-B and smooth muscle myosin heavy chain (SMMHC) within a mouse ESC-EB model system. Significantly, SM-2, the SMMHC isoform associated with fully differentiated SMC, was expressed. Importantly, results showed that aggregates of SMMHC expressing cells exhibited visible contractile activity suggesting that all regulatory pathways essential for development of contractile SMC were functional in this in vitro model system. Inhibition of endogenous TGF- using an adenovirus expressing a soluble truncated TGF- type II receptor attenuated the increase in SMC selective gene expression in the ESC-EB, as did an antibody specific for TGF-1. Of interest, results of siRNA experiments provided evidence for differential TGF--Smad signaling for an early versus late SMC marker gene in that SMA promoter activity was dependent on both Smad2 and Smad3 while SMMHC activity was Smad2 dependent. These results are the first to provide direct evidence that TGF-1 signaling through Smad2 and Smad3 plays an important role in the development of SMC from totipotential ESC.
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