HOXA3 modulates injury-induced mobilization and recruitment of bone marrow-derived cells.
The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury are critical for efficient wound healing. Previously we demonstrated that sustained expression of HOXA3 both accelerated wound healing and promoted angiogenesis in diabetic mice. In this study, we have used green fluorescent protein-positive bone marrow chimeras to investigate the effect of HOXA3 expression on recruitment of BMDCs to wounds. We hypothesized that the enhanced neovascularization induced by HOXA3 is due to enhanced mobilization, recruitment, and/or differentiation of BMDCs. Here we show that diabetic mice treated with HOXA3 displayed a significant increase in both mobilization and recruitment of endothelial progenitor cells compared with control mice. Importantly, we also found that HOXA3-treated mice had significantly fewer inflammatory cells recruited to the wound compared with control mice. Microarray analyses of HOXA3-treated wounds revealed that indeed HOXA3 locally increased expression of genes that selectively promote stem/progenitor cell mobilization and recruitment while also suppressing expression of numerous members of the proinflammatory nuclear factor kappaB pathway, including myeloid differentiation primary response gene 88 and toll-interacting protein. Thus HOXA3 accelerates wound repair by mobilizing endothelial progenitor cells and attenuating the excessive inflammatory response of chronic wounds.
Mace
Kimberly A
KA
Department of Surgery, University of California San Francisco, San Francisco, California 94143-1302, USA. kimberly.mace@manchester.ac.uk
Restivo
Terry E
TE
Rinn
John L
JL
Paquet
Agnes C
AC
Chang
Howard Y
HY
Young
David M
DM
Boudreau
Nancy J
NJ
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007962:Leukocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing / Q000502:physiology*
D018398:Homeodomain Proteins; C080331:Hoxa3 protein, mouse