Tissue-resident bone marrow-derived progenitor cells: key players in hypoxia-induced angiogenesis.

Hypoxia is a common feature of many diseases, including myocardial infarction,1 cerebral ischemia,2 pulmonary hypertension,3 and cancer.4 Thus, understanding the role of hypoxia in the pathogenesis of ischemic disease has significant therapeutic implications. Following ischemic injury, the growth of new blood vessels, neovascularization, is critical to maintain tissue reperfusion and homeostasis. Neovascularization occurs via 2 primary mechanisms: angiogenesis, the sprouting of new vessels from preexisting resident endothelium, and vasculogenesis, the organization of progenitor cells into vascular structures. Vasculogenesis was initially defined strictly as a developmental process.5 However, the characterization of bone marrow–derived progenitor cells (BMCs), which are able to differentiate into vascular cells, has suggested that vasculogenesis may also occur in adults.6,7 The remarkable ability of BMCs to contribute to vessel formation suggests a potentially beneficial role for these progenitor cells in regenerative medicine. Indeed, when BMCs are injected into animal models of ischemia, they “home” to sites of injury, migrate into tissues, and are associated with restoration of blood flow.8 Mobilization of BMCs has been reported to have beneficial effects after myocardial infarction9,10 and arterial injury.11 Moreover, recent clinical trials reveal promising results using BMC injection as a treatment for myocardial infarction.12 Previous studies have shown that BMCs are rapidly mobilized and recruited to sites of vessel injury.13 There is keen interest in determining which stimuli cause BMCs to home selectively to areas of ischemia. Recently, a molecular link between hypoxia and BMC mobilization has been reported involving the transcription factor hypoxia-inducible factor 1 and the chemokine stromal derived cell factor-1 (SDF-1).14 Hypoxia-inducible factor 1 , stabilized during hypoxia, upregulates endothelial cell SDF-1 expression that, via its selective receptor CXC chemokine receptor-4, recruits BMCs to hypoxic areas. Because most animal models of ischemia involve inflammation in addition to hypoxia, it is unclear to what extent hypoxia alone is capable of recruiting BMCs to the vessels. Furthermore, an important area of controversy is whether BMCs transdifferentiate into endothelial cells15 or, instead, serve a paracrine function by secreting proangiogenic factors.16 In this issue of Circulation Research, O’Neill et al17 address these questions by studying BMC recruitment and function in angiogenesis induced by hypoxia. In this study, they irradiated wild-type mice and transplanted them with bone marrow obtained from genetically engineered mice with BMCs expressing green fluorescent protein. Once the BMCs engrafted, mobilized cells could easily be identified in tissues by looking for the fluorescent label. Perhaps the most valuable contributions of this article are the animal model of systemic hypoxia and the high-resolution imaging of the spinotrapezius muscle. Their mouse model of systemic hypoxia excludes the effect of injury-induced inflammation, allowing for exclusive examination of hypoxia as a stimulus for BMC recruitment and angiogenesis. The use of wholemount immunohistochemistry enables immediate visualization of all stained components within a thin layer of spinotrapezius muscle, thereby facilitating the identification, quantification, and localization of stained cells with more resolution than previous models. The major advantages of whole-mount preparations are retention of the entire network architecture in 3 dimensions, characterization of individual cells by shape and spatial orientation, and superior colocalization with multiple fluorescent antibody labels. Other advantages of this model as compared with analysis of tissue sections include a much larger sample size in terms of BMC numbers, spatial information on the location of BMCs within the vascular bed, and more effective perfusion to remove BMCs that are nonadherent or weakly associated with the capillary luminal surface. Using this original and convenient approach, the group studied more than 10 000 capillaries and more than 8000 BMCs. They show that BMC mobilization enhances hypoxia-induced angiogenesis, but most importantly they demonstrate that these BMCs do not incorporate and transdifferentiate into the newly formed capillary vessels. Another novel finding in this study was the presence of BMCs in muscle tissue under normal physiologic conditions. The authors describe 2 distinct morphological populations of resident BMCs: round versus elongated cells (Figure). Round BMCs express the monocytic markers CD45 and CD11b, in contrast to elongated BMCs. In addition, elongated BMCs are 3 times more likely to be perivascular than rounded BMCs under basal conditions. These phenotypic differences most likely delineate distinct functional capabilities. At present, it is unclear whether these round cells are derived from the elongated cells. Depending on the severity of tissue damage, these resident BMCs may be sufficient for the local and immediate response to tissue injury and repair, bypassing a The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Institute and Department of Medicine, University of Rochester Medical Center, NY. Correspondence to Bradford C. Berk, Department of Medicine, University of Rochester, Box MED, Rochester, NY 14642. E-mail [email protected] (Circ Res. 2005;97:955-957.) © 2005 American Heart Association, Inc.