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Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1


The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell–derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells1,2. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion3. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood4. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

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Figure 1: SDF-1 expression is directly proportional to reduced tissue oxygen tension in vivo.
Figure 2: Regulation of SDF-1 expression in endothelial cells.
Figure 3: Functional interactions between endothelial cells and progenitor cells mediated by HIF-1-induced SDF-1 expression.
Figure 4: Dependence of EPC recruitment on HIF-1-induced expression of SDF-1.


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We thank L.E. Huang and G.L. Semenza for HIF plasmids, and R. Schneider and E. Fisher for critically reviewing the manuscript. This study was supported by the National Institutes of Health/National Institute for Biomedical Imaging and Bioengineering (grant EB002265 to G.C.G.), the Sarnoff Endowment for Cardiovascular Research (G.C.G) and the Juvenile Diabetes Research Foundation (O.M.T).

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Correspondence to Geoffrey C Gurtner.

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Ceradini, D., Kulkarni, A., Callaghan, M. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10, 858–864 (2004).

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