Resident vascular progenitor cells--diverse origins, phenotype, and function

Abstract

The fundamental contributions that blood vessels make toward organogenesis and tissue homeostasis are reflected by the considerable ramifications that loss of vascular wall integrity has on pre- and postnatal health. During both neovascularization and vessel wall remodeling after insult, the dynamic nature of vascular cell growth and replacement vitiates traditional impressions that blood vessels contain predominantly mature, terminally differentiated cell populations. Recent discoveries have verified the presence of diverse stem/progenitor cells for both vascular and non-vascular progeny within the mural layers of the vasculature. During embryogenesis, this encompasses the emergence of definitive hematopoietic stem cells and multipotent mesoangioblasts from the developing dorsal aorta. Ancestral cells have also been identified and isolated from mature, adult blood vessels, showing variable capacity for endothelial, smooth muscle, and mesenchymal differentiation. At present, the characterization of these different vascular wall progenitors remains somewhat rudimentary, but there is evidence for their constitutive residence within organized compartments in the vessel wall, most compellingly in the tunica adventitia. This review overviews the spectrum of resident stem/progenitor cells that have been documented in macro- and micro-vessels during developmental and adult life and considers the implications for a local, vascular wall stem cell niche(s) in the pathogenesis and treatment of cardiovascular and other diseases.

Fig 1. Vascular origins of stem cells during embryogenesis

The formation of blood islands from mesodermal cells in the yolk sac ultimately gives rise to both extraembryonic vasculogenesis and primitive hematopoiesis (a). Within the developing embryo, the first intraembryonic site to exhibit hematopoietic activity is the para-aortic splanchnopleura and subsequent aorta-gonad-mesonephros (AGM) region (days 9.5 to 12.5 postcoitum in mice), which comprises the dorsal aorta and its surrounding splanchnic mesoderm (b). Recent consensus indicates that definitive hematopoietic stem cells (HSCs) emerge from hemogenic endothelium in the aorta's ventral floor. This process may involve budding of HSCs into the aortic lumen (1) or the abluminal bending of endothelial cells into HSCs (endothelial hematopoietic transition), so that they appear in the surrounding mesenchyme (2) [16]. Circulation of the HSC progeny results in robust engraftment in subsequent sites of hematopoiesis (3). In addition, multipotent mesoangioblasts, devoid of hematopoietic potential, reside in the roof and lateral walls of the dorsal embryonic aorta. Although their developmental role is unclear, these cells may accompany newly branching blood vessels into other tissues (4).

Fig. 2. Hemangioblast ancestry of endothelial and hematopoietic lineages

Schematic diagram showing the purported derivation of endothelial and hematopoietic cells from a common bipotent, hemangioblast ancestor.

Fig. 3. Extramedullary hematopoiesis in advanced carotid plaque

Carotid plaque excised surgically at the time of carotid endarterectomy, showing dense calcification, hemorrhage and the presence of bone marrow elements (inset box). Hematoxylin and Eosin. ×10 (a), ×100 (b). Images were kindly provided by Dr Dylan Miller, Mayo Clinic, Rochester, MN.

Fig. 4. Mural distribution of VW-PCs

Different populations of vascular wall-resident progenitor cells (VW-PCs) have been identified within the discrete layers of the vessel wall. Progenitor cells with endothelial potential (EPCs) occupy both the subendothelial space in the intima and the inner region of the tunica adventitia (“vasculogenic zone”) which also has a rich supply of smooth muscle progenitors (SPCs) and multipotent mesenchymal stromal/stem cells (MSCs) or pericytes. Immunophenotypic profiles used to isolate and study these cells include Sca-1⁺, c-Kit⁺VEGFR2⁺ and CD34⁺CD31^-. In addition, pericytes/MSCs have been demonstrated in the other mural layers and distinct side population cells with bipotent smooth muscle and endothelial plasticity have been localized to the tunica media. The local activation and migration of VW-PCs is believed to contribute to cell turnover during physiologic and pathogenic vascular remodeling and neovascularization, while there may also be dynamic, bidirectional exchange of progenitor cells between the vessel wall and peripheral circulation throughout adult life.