Classification and Functional Characterization of Vasa Vasorum-Associated Perivascular Progenitor Cells in Human Aorta

Abstract

SummaryIn the microcirculation, pericytes are believed to function as mesenchymal stromal cells (MSCs). We hypothesized that the vasa vasorum harbor progenitor cells within the adventitia of human aorta. Pericytes, endothelial progenitor cells, and other cell subpopulations were detected among freshly isolated adventitial cells using flow cytometry. Purified cultured pericytes were enriched for the MSC markers CD105 and CD73 and depleted of the endothelial markers von Willebrand factor and CD31. Cultured pericytes were capable of smooth muscle lineage progression including inducible expression of smooth muscle myosin heavy chain, calponin, and α-smooth muscle actin, and adopted a spindle shape. Pericytes formed spheroids when cultured on Matrigel substrates and peripherally localized with branching endothelial cells in vitro. Our results indicate that the vasa vasorum form a progenitor cell niche distinct from other previously described progenitor populations in human adventitia. These findings could have important implications for understanding the complex pathophysiology of human aortic disease.

Notch‐inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate

“…During the formation of new blood capillaries, perivascular cells are recruited by endothelial cells and contribute to the stabilization and regulation of newly formed endothelial capillaries. Interestingly, the perivascular microenvironment of endothelial capillaries within different tissues has been proposed to potentially function as a reservoir for mesenchymal stem/progenitor cells (MSCs) [2][3][4][5][6][7][8]. This has led to the constantly debated hypothesis that during tissue regeneration, MSCs are mobilized from blood capillaries and that MSCs and perivascular cells are closely related cell types.…”

The Dichotomy of Vascular Smooth Muscle Differentiation/De- Differentiation in Health and Disease

“…Indeed, the generation of adventitial vascular progenitor cells from differentiated SMCs may be a normal physiological process that contributes to the vascular stem cell pool and plays an important role in arterial homeostasis and disease [113]. The vasa vasorum and surrounding connective tissue in adult thoracic aortic adventitia is considered a niche for these progenitor cell populations in human vessels that facilitates their role as myogenic progenitors with the potential for multi-lineage progression in atherosclerosis and IMT following injury [20]. Importantly, recent lineage tracing studies that genomic mark and track these adventitial cells following iatrogenic injury using Gli1-Cre transgenic mice provide compelling evidence for their specific role in IMT and neointimal formation in mice [21,22].…”

“…Notwithstanding the 40-year-old phenomenon of SMC de-differentiation and phenotypic switching and the significant evidence of a putative role for de-differentiated SMCs in vascular disease [12,13], there is now compelling evidence to suggest that lesional cells within the adventitial, medial and (neo)intimal layers of arteriosclerotic vessels may also be derived from resident vascular stem cells following iatrogenic injury in rodent models [14][15][16][17][18] and in human arteriosclerotic tissue [19,20]. Indeed, recent lineage tracing analysis of genomic marked stem cells supports this contention [18,21,22].…”

Stromal cells in health and disease

“…MSC are known to be present in bone marrow (BM) and adipose tissue (AT) and can also be found in dental pulp , umbilical cord blood, placenta, and other tissues . Recently, it was found that MSC are also present in the heart and other nonmesenchymal vascularized sources .…”

“…Very rare events such as native BM MSC cannot be assayed directly by a single platform assay because of the sample dilution (at least 1:10) required by the lyse/no wash protocol and the large number of events which must be acquired. Multicolor panels for MSC identification extend a standardized approach for MSC identification in other tissues such as adipose , perivascular tissues , and the dermis .…”