Vascular Wall-Resident CD44+ Multipotent Stem Cells Give Rise to Pericytes and Smooth Muscle Cells and Contribute to New Vessel Maturation

Abstract

Here, we identify CD44(+)CD90(+)CD73(+)CD34(−)CD45(−) cells within the adult human arterial adventitia with properties of multipotency which were named vascular wall-resident multipotent stem cells (VW-MPSCs). VW-MPSCs exhibit typical mesenchymal stem cell characteristics including cell surface markers in immunostaining and flow cytometric analyses, and differentiation into adipocytes, chondrocytes and osteocytes under culture conditions. Particularly, TGFß1 stimulation up-regulates smooth muscle cell markers in VW-MPSCs. Using fluorescent cell labelling and co-localisation studies we show that VW-MPSCs differentiate to pericytes/smooth muscle cells which cover the wall of newly formed endothelial capillary-like structures in vitro. Co-implantation of EGFP-labelled VW-MPSCs and human umbilical vein endothelial cells into SCID mice subcutaneously via Matrigel results in new vessels formation which were covered by pericyte- or smooth muscle-like cells generated from implanted VW-MPSCs. Our results suggest that VW-MPSCs are of relevance for vascular morphogenesis, repair and self-renewal of vascular wall cells and for local capacity of neovascularization in disease processes.

Vascular Wall Progenitor Cells in Health and Disease

“…63 Conversely, it is easy to envisage pathological sequelae resulting from VW-PC activation and specification, including their participation in adventitial and plaque inflammation, 11 neointimal hyperplasia, 5,7,62 vascular calcification, 49,111,132 and growth of adventitial and plaque microvessels. 9,30 Consistent with a pathogenic role for VW-PCs, is an emerging outside-in paradigm of vascular disease that recognizes the importance of adventitial inflammation and vasa vasorum expansion in initiating and perpetuating deleterious remodeling changes, which extend to the other mural layers. 125 Several groups have corroborated that there is early proliferation and subsequent migration of adventitial cells to the neointima, in response to intimal denudation injury.…”

“…2 As discussed in the following sections, these consist of lineage-committed endothelial progenitor cells (EPCs) 4 and smooth muscle progenitor cells (SPCs), 5,6 multipotent vascular stem cells (MVSCs), 7 mesenchymal stem/stromal cells (MSCs), 8,9 adventitial macrophage progenitor cells (AMPCs), and circulation-derived HSCs. 10,11 …”

“…55,56 To this end, there are now several reports identifying SMC-relevant progenitor/stem cells in the vasculature itself ( Table 2). These encompass medial and adventitial SPCs, 29,57 microvascular pericytes and adventitial MSCs, 9,58,59 medial MVSCs 7 and vascular ECs capable of endothelial-to-mesenchymal transformation. 46,48 By their nature, SPCs are specified for SMC fate but do not express differentiated SMC marker proteins, such as αSMA (Acta2), SM22α (Tagln), SM-calponin (Cnn1), and SMmyosin heavy chain (Myh11).…”

“…This capacity to facilitate angiogenesis and neovascularization was augmented by the presence of VEGF and FGF-2, or TGF-β alone, with the latter also significantly increasing expression of SMC markers. 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).…”

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction

“…Different mesenchymal cell populations have been isolated from the adventitial layer of murine and human vessels 9, 10, 11, 12, 13, 14, 15. In a seminal study, we discovered the presence of CD133 + /CD34 + /KDR + cells endowed with potent vasculogenic activity in the human fetal aorta 14.…”