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

Kimberly A Mace,David M Young,John L Rinn,Agnes C Paquet,Nancy J Boudreau,Howard Y Chang,Terry E Restivo

doi:10.1002/stem.90

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.

Highlights

Tissue repair and regeneration require dramatic and coordinated changes in cell behavior in both wound-resident cells at the site of injury and in distant cells that respond to and are recruited to the injured tissue
To compare recruitment of bone marrow-derived cells (BMDCs) in diabetic and nondiabetic mice, we reconstituted lethally irradiated mice (6 LeprdbÀ/À ‘‘db/db’’ diabetic mice and 4 Leprdbþ/À ‘‘db/þ’’ nondiabetic littermate controls) with bone marrow from donor mice ubiquitously expressing green fluorescent protein (GFP) driven by the chicken b-actin promoter [27]
Parallel sections were analyzed for GFPþ cells, relative to 40,6-diamidino-2-phenylindole (DAPI)-positive cells, in three separate areas near the wound edge to obtain an average for each wound (Fig. 1B)

Summary

Introduction

Tissue repair and regeneration require dramatic and coordinated changes in cell behavior in both wound-resident cells at the site of injury and in distant cells that respond to and are recruited to the injured tissue. Normally homeostatic, respond to injury by increasing expression of genes that induce mitosis, migration, and direct synthesis and remodeling the extracellular matrix This tightly regulated process involves a ‘‘ramping up’’ of growth factor and cytokine release followed by adult stem/progenitor cell mobilization, migration, engraftment, and differentiation in response to injury. Studies investigating the genes involved in this process have identified both transcription factors and ligand/receptor pairs that have previously been implicated in wound healing Genes such as Hif-1a, Hoxa, Cxcl12/Cxcr, and Vegf/Vegfr among others play a variety of roles in wound repair and regeneration [1,2,3,4,5]; much of the genetic control of adult stem and progenitor cell behavior during wound repair and regeneration is largely unknown. In particular we demonstrated that transient gene transfer of HOXA3 to skin wounds of diabetic mice

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