Resident Vascular Progenitor Cells Research Articles

Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4.

The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors express the stem cell markers, Sca1 and CD34 (adventitial sca1-positive progenitor cells [AdvSca1]), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo. Although emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and heterogeneity, and contribution to vessel remodeling. Using 2 in vivo fate-mapping approaches combined with a smooth muscle cell (SMC) epigenetic lineage mark, we report that a subpopulation of AdvSca1 cells is generated in situ from differentiated SMCs. Our data establish that the vascular adventitia contains phenotypically distinct subpopulations of progenitor cells expressing SMC, myeloid, and hematopoietic progenitor-like properties and that differentiated SMCs are a source to varying degrees of each subpopulation. SMC-derived AdvSca1 cells exhibit a multipotent phenotype capable of differentiating in vivo into mature SMCs, resident macrophages, and endothelial-like cells. After vascular injury, SMC-derived AdvSca1 cells expand in number and are major contributors to adventitial remodeling. Induction of the transcription factor Klf4 in differentiated SMCs is essential for SMC reprogramming in vivo, whereas in vitro approaches demonstrate that Klf4 is essential for the maintenance of the AdvSca1 progenitor phenotype. We propose that generation of resident vascular progenitor cells from differentiated SMCs is a normal physiological process that contributes to the vascular stem cell pool and plays important roles in arterial homeostasis and disease.

Adventitia and perivascular cells.

The past few years have seen significant advances in our understanding of the multiple and dynamic roles of the adventitia and its companion perivascular tissues for vessel wall homeostasis and disease. It is now becoming clear that signals originating from within the adventitia and from perivascular cells play essential roles in regulation of vascular development, physiology, artery wall remodeling, immune surveillance, and vascular disease.1–4 The adventitia is in contact with and completely surrounds the media and is the interface between the vessel wall and its neighboring tissues. It contains many different interacting cell types including fibroblasts, microvascular endothelium, nerves, resident macrophages, T cells, B cells, mast cells, and dendritic cells.5–9 The adventitia is also home to resident vascular progenitor cells whose formation and maintenance depend, in part, on sonic hedgehog signaling.1,10–12 Perivascular cells are in close contact with the adventitia, particularly for the aorta and coronary arteries. Perivascular tissue includes adipocytes, lymphatic vessels, perivascular nerves, and stromal cells exhibiting mesenchymal stem cell–like properties.3,13 The adventitia and periadventitial cells function in concert. They are linked by microvessels, nerves, and migratory cells to regulate vascular physiology, homeostasis, structural remodeling, and exert major influences on the progression or regression of vascular disease. Crosstalk between intima, media, and adventitia further links the adventitia-periadventitial unit to the rest of the vessel wall. Much of the work advancing our concepts of the adventitia and periadventitial tissues has been published in ATVB , and some of those key studies are discussed in this highlights article. In the following summary, areas that have attracted the most interest over the past 2 years in ATVB are reviewed including the multiple roles of perivascular adipose tissue (PVAT) on control of vascular physiology and remodeling, adventitial progenitor …

Stem/Progenitor cells in vascular regeneration.

A series of studies has been presented in the search for proof of circulating and resident vascular progenitor cells, which can differentiate into endothelial and smooth muscle cells and pericytes in animal and human studies. In terms of pluripotent stem cells, including embryonic stem cells, iPS, and partial-iPS cells, they display a great potential for vascular lineage differentiation. Development of stem cell therapy for treatment of vascular and ischemic diseases remains a major challenging research field. At the present, there is a clear expansion of research into mechanisms of stem cell differentiation into vascular lineages that are tested in animal models. Although there are several clinical trials ongoing that primarily focus on determining the benefits of stem cell transplantation in ischemic heart or peripheral ischemic tissues, intensive investigation for translational aspects of stem cell therapy would be needed. It is a hope that stem cell therapy for vascular diseases could be developed for clinic application in the future.

Characterization of Resident Vascular Progenitor Cells in Human Aortas

Characterization of Resident Vascular Progenitor Cells in Human Aortas

Progenitor cells in pulmonary vascular remodeling.

Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow–derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow–derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure.

Resident Vascular Progenitor Cells—Diverse Origins, Phenotype, and Function

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.

Bone marrow-derived cells do not repair endothelium in a mouse model of chronic endothelial cell dysfunction

AimsBone marrow (BM)-derived endothelial progenitor cells (EPCs) in the circulation replace damaged vascular endothelium. We assessed the hypothesis that a BM transplant from healthy animals would restore normal arterial endothelium and prevent hypertension in young endothelial nitric oxide synthase-deficient (eNOS−/−) mice.Methods and resultsRadiation or busulfan-induced BM ablation in eNOS−/− mice on day 6, day 14, or day 28 was followed by a BM transplant consisting of enhanced green fluorescent protein positive (EGFP+) cells from C57BL/6J mice. Peripheral blood cell chimerism was always greater than 85% at 4 months after BM transplant. Molecular assays of heart, kidney, and liver revealed low-level chimerism in all treatment groups, consistent with residual circulating EGFP+ blood cells. When aorta, coronary, renal, hepatic, and splenic arteries in BM-transplanted eNOS−/− mice were examined by confocal microscopy, there were no EGFP- or eNOS-positive endothelial cells detected in these vessels in any of the treatment groups. Likewise, telemetry did not detect any reduction in blood pressure. Thus, no differences were observed in our measurements using several different treatment protocols.ConclusionWe found no evidence for BM-derived EPC renewal of endothelium in this eNOS-deficient mouse model of a chronic vascular disease or in wild-type mice during postnatal growth. Hence, renewal of chronic dysfunctional endothelium and endothelial homeostasis may be dependent on resident vascular progenitor cells.

Endothelial Progenitor Cells

See related article, pages 314–322 The formation of coronary collateral vessels constitutes a compensatory adaptation of the heart to ischemia. This vascular response increases blood supply to the myocardium reducing the area of hypoxic damage and, ultimately, infarct size. The recruitment of collateral vessels within the coronary circulation is favored by multiple episodes of ischemia, which provide the stimuli necessary for the growth of vascular structures and increased blood flow. The degree of collateralization significantly influences the prognosis of an ischemic episode, which is more severe with diabetes, metabolic syndrome, or in the elderly, the patient population mostly affected by coronary artery disease.1 Originally, angiogenesis, ie, sprouting of vessels from the preexisting circulation, was considered the exclusive mechanism of vascular remodeling and growth. The identification of circulating endothelial progenitor cells (EPCs) has modified this view.2 Migration and homing of EPCs to ischemic regions leads to de novo formation of vascular structures. In analogy with vessel development in the embryo, this process has been called vasculogenesis. Also, circulating EPCs participate in reendothelization of damaged vessels, together with resident vascular progenitor cells.3 EPCs represent a heterogeneous cell population of multiple origins and distinct phenotypes, which are able to give rise to functionally competent endothelial cells.4 In the hierarchy established in the hematopoietic system, progenitors identify cells with lower differentiation potential than stem cells (SCs). However, EPCs possess degrees of stemness, which include self-renewal, clonogenicity, and differentiation capacity.4 EPCs represent various subsets of progenitor cells that have distinct phenotypes but share the ability to differentiate into mature endothelial cells. During embryogenesis, hematopoietic cells and endothelial cells develop temporally and spatially in close association. Blood cells are surrounded by layers of endothelial cells suggesting a joint origin of these lineages from a common precursor, the embryonic hemangioblast.4 …