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

See related article on pages 1027–1035 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 1α and the chemokine stromal derived cell factor-1 (SDF-1).14 Hypoxia-inducible factor 1α, 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 …