The Vascular Wall as a Source of Stem Cells

Inserm U506, Hopital Paul Brousse, Villejuif, France.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 07/2005; 1044(1):41-50. DOI: 10.1196/annals.1349.006
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We have characterized the emerging hematopoietic system in the human embryo and fetus. Two embryonic organs, the yolk sac and aorta, support the primary emergence of hematopoietic stem cells (HSCs), but only the latter contributes lymphomyeloid stem cells for definitive, adult-type hematopoiesis. A common feature of intra- and extraembryonic hematopoiesis is that in both locations hematopoietic cells emerge in close vicinity to vascular endothelial cells. We have provided evidence that a population of angiohematopoietic mesodermal stem cells, marked by the expression of flk-1 and the novel BB9/ACE antigen, migrate from the paraaortic splanchnopleura into the ventral part of the aorta, where they give rise to hemogenic endothelial cells and, in turn, hematopoietic cells. HSCs also appear to develop from endothelium in the embryonic liver and fetal bone marrow, albeit at a much lower frequency. This would imply that the organism does not function during its whole life on a stock of hematopoietic stem cells established in the early embryo, as is usually accepted. We next examined whether the vessel wall can contribute stem cells for other cell lineages, primarily in the model of adult skeletal muscle regeneration. By immunohistochemistry and flow cytometry, we documented the existence in skeletal muscle, besides genuine endothelial and myogenic cells, of a subset of satellite cells that coexpress endothelial cell markers. This suggested the existence of a continuum of differentiation from vascular cells to endothelial cells that was confirmed in long-term culture. The regenerating capacity of these cells expressing both myogenic and endothelial markers is being investigated in skeletal and cardiac muscle, and the results are being compared with those generated by satellite cells. Altogether, these results point to a generalized progenitor potential of a subset of endothelial, or endothelium-like, cells in blood vessel walls, in pre- and postnatal life.

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Available from: Estelle Oberlin, Oct 13, 2015
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    • "The observation that freshly isolated MVFs can be used lends to the clinical relevance of their application [6]. Despite the relationship between the therapeutic usefulness of MVFs and the wealth of data ascribing a vascular location to stem cells [9] [10], a thorough characterization of the stem cells associated with MVFs is lacking. The robust angiogenic potential of MVFs even in the absence of supplemental proangiogenic factors (e.g., vascular endothelial growth factor) supports the idea that potent stem cells reside within the vessels that contribute to their vigorous network formation in vitro and dynamic remodeling in vivo [4e6,11]. "
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    ABSTRACT: Background: A number of therapies are being developed that use microvessels isolated from adipose tissue (microvascular fragments [MVFs]) to improve tissue perfusion and implant survival. Because it has been demonstrated that stem cells are associated with microvessels, the purpose of these studies was to gain further insight into the stem cells associated with MVFs to better understand their therapeutic potential. Materials and methods: Cells derived from MVF explants were compared with adipose-derived stem cells (ASCs) based on the expression of cell surface proteins for mesenchymal stem cells and their capacity for angiogenic, neurogenic, adipogenic, and osteogenic differentiation. Results: The expression of cell surface proteins for mesenchymal stem cell markers was similar between MVF-derived cells and ASCs; however, the increase in markers consistent with endothelial cells and pericytes was accompanied by an improved ability to form capillary-like networks when cultured on matrigel. MVF-derived cells had increased neuregulin, leptin, and osteopontin expression compared with ASCs when exposed to neurogenic, adipogenic, and osteogenic induction media, respectively. Conclusions: The stem cell functionality of cells derived from MVFs is retained after their isolation. This helps to explain the ability of MVFs to improve tissue perfusion and has implications for the use of MVFs as a means to deliver stem cells within their niche.
    Journal of Surgical Research 05/2014; 192(1). DOI:10.1016/j.jss.2014.05.047 · 1.94 Impact Factor
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    • "BB9 is specific for the somatic isoform of surface ACE (CD143). As outlined above, the first observation was that a protein immunologically similar to ACE is expressed in the embryonic para-aortic splanchnopleura, where blood-cell progenitors are generated (36), suggesting that a local RAS exists within the intra-embryonic sites of definitive hematopoiesis in the mammal. ACE expression was also identified emerging hematopoietic cells from both CD34− and CD34+ areas of human yolk sac, intra-embryonic splanchnopleura, and hemogenic endothelium of the aorta-gonad-mesonephros region and fetal liver (FL) (29). "
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    ABSTRACT: The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM). This system is fundamentally involved and controls the essential steps of primitive and definitive blood-cell production. Hematopoiesis, erythropoiesis, myelopoiesis, thrombopoiesis, formation of monocytic and lymphocytic lineages, as well as stromal elements are regulated by the local BM RAS. The expression of a local BM RAS has been shown in very early, primitive embryonic hematopoiesis. Angiotensin-converting enzyme (ACE-1, CD143) is expressed on the surface of hemangioblasts and isolation of the CD143 positive cells allows for recovery of all hemangioblast activity, the first endothelial and hematopoietic cells, forming the marrow cavity in the embryo. CD143 expression also marks long-term blood-forming CD34+ BM cells. Expression of receptors of the RAS is modified in the BM with cellular maturation and by injury. Ligation of the receptors of the RAS has been shown to modify the status of the BM resulting in accelerated hematopoiesis after injury. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive and definitive hematopoiesis as well as modification of BM recovery by administration of exogenous ligands of the RAS. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of BM recovery after injury as well as neoplastic disorders.
    Frontiers in Endocrinology 10/2013; 4:157. DOI:10.3389/fendo.2013.00157
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    • "The blood vessel, which typically consists of three structural layers: tunica intima, tunica media, and tunica adventitia [48], is distributed throughout nearly all human organs and therefore represents a favorable candidate. Early evidence supporting the hypothesis that the vascular wall serves as a systemic source of stem cells came from a study of the emerging hematopoietic system in the embryo and fetus, where hematopoietic cells emerged in close vicinity to vascular endothelial cells (ECs) in both intra- and extraembryonic blood-forming tissues [22]. Recently, several studies have indicated the possibility that blood vessels in different organs contain multilineage precursors that possess MSC-like features and contribute to tissue repair/regeneration [49, 50]. "
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    ABSTRACT: Mesenchymal stem/stromal cells (MSCs) and MSC-like multipotent stem/progenitor cells have been widely investigated for regenerative medicine and deemed promising in clinical applications. In order to further improve MSC-based stem cell therapeutics, it is important to understand the cellular kinetics and functional roles of MSCs in the dynamic regenerative processes. However, due to the heterogeneous nature of typical MSC cultures, their native identity and anatomical localization in the body have remained unclear, making it difficult to decipher the existence of distinct cell subsets within the MSC entity. Recent studies have shown that several blood-vessel-derived precursor cell populations, purified by flow cytometry from multiple human organs, give rise to bona fide MSCs, suggesting that the vasculature serves as a systemic reservoir of MSC-like stem/progenitor cells. Using individually purified MSC-like precursor cell subsets, we and other researchers have been able to investigate the differential phenotypes and regenerative capacities of these contributing cellular constituents in the MSC pool. In this review, we will discuss the identification and characterization of perivascular MSC precursors, including pericytes and adventitial cells, and focus on their cellular kinetics: cell adhesion, migration, engraftment, homing, and intercellular cross-talk during tissue repair and regeneration.
    Stem cell International 08/2013; 2013(6):983059. DOI:10.1155/2013/983059 · 2.81 Impact Factor
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