Pharmacologic increase in HIF1alpha enhances hematopoietic stem and progenitor homing and engraftment

摘要

Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl pros-taglandin E_2 (dmPGE_2). While exploring regulatory molecules involved in dmPGE_2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-alpha (HIF1alpha) is required for dmPGE_2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIFla is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE_2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIFla in enhancement of hematopoietic transplantation.