HOXA3 Modulates Injury-Induced Mobilization and Recruitment of Bone Marrow-Derived Cells

Abstract

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 κB 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.

Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells

“…The diabetic environment dramatically alters the composition of BMDCs in the wound, which consists predominantly of inflammatory cells, 10,35 contributing to the development of chronic wounds in patients and animal models of diabetes. 10,36 Gene transfer of HOXA3 to wounds of diabetic mice partially rescues this phenotype, as more endothelial progenitor cells are mobilized and accumulate in wound tissue, while inflammatory cell accumulation is suppressed.…”

“…10,20 This results in a suppression of the exacerbated inflammatory response characteristic of diabetic wounds and accelerates wound repair. We therefore wanted to test whether overexpression of Hoxa3 could alter proliferation, differentiation, chemotaxis, or adhesion of BMD stem/progenitor cells.…”

“…10 This is associated with dramatically improved angiogenesis and accelerated wound closure in diabetic wounds. 20 Here we show for the first time that Gr-1 ϩ CD11b ϩ cells are recruited to injured tissue, but that their recruitment/retention kinetics are aberrant in the diabetic environment.…”

“…In patients and animal models with diabetes, BMDCs contribute to an impaired healing/chronic wound environment by prolonging the inflammatory response and/or failing to promote the regenerative phase of wound healing. [8][9][10] Gr-1 ϩ CD11b ϩ cells are a subset of BMD myeloid cells that are recruited to tumors in vivo and can function as immune suppressor cells with proangiogenic capacity in the tumor microenvironment. [11][12][13][14][15][16] They consist of a heterogeneous population containing monocytic and granulocytic myeloid progenitors and committed cells.…”

Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

“…In both humans and mice (3), diabetes impairs the orderly transition from an early, inflammatory phase of repair to a later, prohealing stage, preventing timely healing. Excessive numbers of myeloid cells are found in the wound (2,4), and they display a persistent proinflammatory, M1-like (classical) or M1/M2 (mixed) phenotype, instead of a clear transition to an M2-like (alternative) state (5,6).…”