Stem cell mobilization and vasculogenesis stimulated by lactate and oxygen

This investigation assessed the effects of lactate and hyperoxia on recruitment and differentiation of stem/progenitor cells (SPCs). Within 18 hours after Matrigel plugs were implanted subcutaneously in mice, over one million CD34 + SPCs were recruited. Including a lactate source in Matrigel increased SPCs by 3.6‐fold at 18 hours and 5.8‐fold at 5 days. Lactate accelerated CD34 + cell differentiation based on surface marker expression, development of intricate vascular channels, and a higher fraction in the S and G 2 ‐M phases of the cell cycle. If mice were intermittently exposed to hyperbaric oxygen, there were increased numbers of CD34 + cells in blood and Matrigel, accelerated differentiation and more complex vascular channels. Combining a lactate source and hyperoxia had an additive effect on CD34 + cells. If the Matrigel contained oxamate, a lactic dehydrogenase inhibitor; or antibodies that neutralize vascular endothelial growth factor or stromal derived growth factor, CD34 + cell recruitment and differentiation were inhibited. Hypoxia inducible factor‐1α (HIF‐1) was elevated in CD34 + cells from lactate‐supplemented versus un‐supplemented Matrigel. Hyperbaric oxygenation caused significant elevations of HIF‐1 in CD34 + cells in bone marrow, blood and Matrigel. Conclusion: SPCs influence their own homing response by metabolizing lactate and generating growth factors to mediate progressive SPCs mobilization, recruitment and differentiation into vascular channels [N00014‐06‐1‐0363].