From nerve to blood vessel: a new role of Olfm2 in smooth muscle differentiation from human embryonic stem cell-derived mesenchymal cells

Vascular smooth muscle cell (SMC) differentiation is an important process in vasculogenesis and angiogenesis during embryonic development. The alterations in the differentiated state in SMCs contribute to a variety of major cardiovascular diseases such as atherosclerosis, hypertension, restenosis and vascular aneurysm [1-2] . A better understanding of the cellular and molecular mechanisms that control SMC differentiation is essential to help develop new approaches to both prevent and treat these diseases. Therefore, development of reliable and reproducible in vitro cellular models in order to study the differentiation mechanisms is important although it has been challenging because of intrinsic peculiarities of SMC. SMCs originate from at least eight different progenitors during embryonic development including neural crest, proepicardium, mesothelium, splanchnic mesoderm, secondary heart field, mesoangioblasts, somites and various stem/progenitor cells [1] . SMC populations from different embryological origins are observed in different vessels as well as within the same vessel segments although showing sharp boundaries with no intermixing of cells from different lineages [3 ] . Importantly, SMCs from different origins are regulated differentially and can exhibit a wide range of different phenotypes. Even in adult organs, SMCs are not terminally differentiated because the cells may undergo phenotypic modulation in response to alterations in local environmental cues including growth factors/inhibitors, mechanical influences, inflammatory mediators, cell-cell and cell-matrix interactions [2] . SMC differentiation is a complex but poorly defined process although much progress has been made in identifying molecular mechanisms controlling the expression of SMC specific genes. Accumulating evidence has shown that a precisely coordinated molecular network orchestrates the SMC differentiation program involved in a range of signaling pathways including TGF-b, retinoid, extracellular matrix, Notch, reactive oxygen species, histone deacetylase and microRNA signaling [4] . Several in vitro model systems have been developed to mimic the SMC differentiation in vivo including using C3H10T1/2 cells, neural crest cells, A404, embryoid body and embryonic stem cells. Although these models have significantly contributed to our understanding of SMC differentiation, each of these models has its limitations. In addition, human embryonic stem cell can differentiate to both endothelial cell (EC) and SMC populations in the same differentiation conditions. Though the cells are excellent for in vivo neoangiogenesis and regeneration of blood vessels, they may not be ideal for precisely dissecting the molecular mechanism governing SMC differentiation because SMCs differentiated from embryonic stems cells are heterogenic and thus contain a mixed population. We recently developed a novel in vitro model for TGF-b-induced SMC differentiation from human embryonic stem cell-derived mesenchymal cells (hES-MCs). hES-MCs, derived from H9 human embryonic stem cells, are natural SMC progenitors for mesoderm-derived SMCs that account for most of