Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells

Abstract

Human vascular wall-resident CD44+ multipotent stem cells (VW-MPSCs) within the vascular adventitia are capable to differentiate into pericytes and smooth muscle cells (SMC). This study demonstrates HOX-dependent differentiation of CD44(+) VW-MPSCs into SMC that involves epigenetic modification of transgelin as a down-stream regulated gene. First, HOXB7, HOXC6 and HOXC8 were identified to be differentially expressed in VW-MPSCs as compared to terminal differentiated human aortic SMC, endothelial cells and undifferentiated pluripotent embryonic stem cells. Silencing these HOX genes in VW-MPSCs significantly reduced their sprouting capacity and increased expression of the SMC markers transgelin and calponin and the histone gene histone H1. Furthermore, the methylation pattern of the TAGLN promoter was altered. In summary, our findings suggest a role for certain HOX genes in regulating differentiation of human VW-MPSC into SMCs that involves epigenetic mechanisms. This is critical for understanding VW-MPSC–dependent vascular disease processes such as neointima formation and tumor vascularization.

Vascular Wall Progenitor Cells in Health and Disease

“…9 Recently, the same authors determined that VW-MPSCs differentially express Hox genes in comparison to mature ECs and SMCs, and epigenetic silencing of these genes downregulated their invasive sprouting capacity and induced them toward SMC differentiation. 115 It is unknown to what extent different depictions of VWMSCs/MPSCs have in fact been overlapping cell populations, and how they might relate to other vascular wall cells (eg, pericytes, VW-EPCs, and VW-SPCs). VW-MSCs seem situated to differentiate into mature pericytes, SMCs, and perhaps even ECs, and to be recruited to stabilize new vessels or repair pre-existing vessels.…”

“…65 Distinctly, Klein et al 9 isolated a population of CD44 + vascular wall multipotent stem cells (VW-MPSCs) from the adventitial vasculogenic zone of human internal thoracic artery. 115 These cells were initially identified as migratory during arterial ring assays, where they coexpressed αSMA, CD90, and nestin, but not CD34 or CD146. Cultured CD44 + VW-MPSCs expressed Oct-4 and Sox2, exhibited typical MSC characteristics, and formed spontaneous sprouts in matrigel, as well as tight-associations covering cocultured HUVECs during capillary tube formation.…”

Topographic patterns of vascular disease: HOX proteins as determining factors?

“…Furthermore, data from Visconti RP et al . HOX-dependent vascular disease patterns thoracic aorta provided evidence for Hox-dependent differentiation into VSMCs involving epigenetic mechanisms [29] . This raises the interesting possibility that Hox genes may be critical regulators of vascular cell populations that drive phenotype switching between homeostatic/regenerative vs pathological remodeling in vascular tissues in a region-specific manner.…”

The relevance of epigenetics to occlusive cerebral and peripheral arterial disease

“…Cell-specific gene expression [23] Vascular endothelial growth factor receptor 2 Angiogenesis and survival [24] Thymocyte differentiation antigen-1 Fibroblasts Fibrosis [25] α-Smooth muscle actin Fibroblasts; myofibroblasts Fibrosis; differentiation [26,27] Endothelial nitric oxide synthase Endothelial cells Angiogenesis and survival; cell-specific expression and maintaining cardiovascular homoeostasis [24] Homeobox protein-B7, -C6, -C8l; transgelin Stem cells Differentiation, neointima formation and tumour vascularization [28] Thrombospondin-1 Cerebral endothelial cells Angiogenesis [29] Smooth muscle 22α…”