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

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/nm1075

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