Vascular Wall-Resident Multipotent Stem Cells of Mesenchymal Nature within the Process of Vascular Remodeling: Cellular Basis, Clinical Relevance, and Implications for Stem Cell Therapy

Abstract

Until some years ago, the bone marrow and the endothelial cell compartment lining the vessel lumen (subendothelial space) were thought to be the only sources providing vascular progenitor cells. Now, the vessel wall, in particular, the vascular adventitia, has been established as a niche for different types of stem and progenitor cells with the capacity to differentiate into both vascular and nonvascular cells. Herein, vascular wall-resident multipotent stem cells of mesenchymal nature (VW-MPSCs) have gained importance because of their large range of differentiation in combination with their distribution throughout the postnatal organism which is related to their existence in the adventitial niche, respectively. In general, mesenchymal stem cells, also designated as mesenchymal stromal cells (MSCs), contribute to the maintenance of organ integrity by their ability to replace defunct cells or secrete cytokines locally and thus support repair and healing processes of the affected tissues. This review will focus on the central role of VW-MPSCs within vascular reconstructing processes (vascular remodeling) which are absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. Further, a particular advantage for the therapeutic application of VW-MPSCs for improving vascular function or preventing vascular damage will be discussed.

Figure 1

Vascular wall-resident multipotent stem cells of mesenchymal nature within the process of vascular remodeling. Vascular remodeling is a dynamic and strictly regulated process of structural changes, which often occurs as a result of a pathological trigger: atherosclerosis, thrombosis, hypertension, ischemic diseases, congenital vascular lesions, shear stress, irradiation, and tumor growth are crucially characterized by increased vascular remodeling. An ordered remodeling is an absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. The association with mural cells (pericytes and smooth muscle cells, SMC) is critical for proper vascular development, stabilization, and maintenance and there is an increasing evidence that these cells originate from multipotent mesenchymal stem cells (MSCs). Intima, media (TM), and adventitia with vasa vasorum are fixed layers of the wall of large arteries and veins. The border between media and adventitia is marked by outer elastic membrane (green). The vasculogenic zone is a vascular mural zone located within the adventitia and close to the tunica media which harbors different subsets of vascular wall stem cells. In particular, vascular wall-resident multipotent stem cells of mesenchymal nature (VW-MPSCs) differentiation into SMC may be induced by tumors, inflammation, and hypoxia in tissue areas around blood vessels contributing to morphogenesis of new vessel walls (e.g., tumor vascularization, intimal lesions, or neointima formation). It is hypothesized that VW-MPSCs are the “first line” cells which were mobilized from their niche towards the tumor and activated to differentiate into pericytes and SMC, which in turn stabilize angiogenic blood vessels, which results in a stabilization and thus normalization of angiogenic tumor blood vessels. In contrast to the direct action of MPSCs during tumor progression by getting mobilized from their niche and subsequent differentiation at the site of injury, the protective effect of exogenous applied MPSCs could also be related to the modulation of paracrine characteristics of these cells. Besides the relatively simple extraction of these cells for autologous transplantation VW-MPSCs might be perfectly suited for a therapeutic application for improving vascular function or preventing vascular damage because tissue-specific stem cells differentiate mainly to the tissue type, from which they derive. HSP: hematopoietic stem cell; EPC: endothelial progenitor cell; light blue: VW-MPSCs yellow, endothelial cells; green basement membrane and elastic membrane; blue, SMC.