Abstract
High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFRα+) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFRα+ mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFRα+ mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFRα+ mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFRα+ mesenchymal cells showed massive inflammation of the grafts compared to mice that had normal levels of these cells even after HMGB1 administration, suggesting that BM-PDGFRα+ mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM-PDGFRα+ mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on these cells. Finally, we showed the therapeutic activity of the HMGB1/BM-PDGFRα+ mesenchymal cell axis in an allergic contact dermatitis model. The results illustrated the contribution of the HMGB1/BM-PDGFRα+ mesenchymal cell axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases.
Highlights
Skin regeneration is a coordinated process with mutual interactions among various cell types, extracellular matrix and signaling molecules
We previously reported that bone marrow (BM)-derived platelet-derived growth factor receptor-alpha (PDGFRα )+ mesenchymal cells accumulated in skin grafts[26]
To analyze the migration and function of endogenous BM-derived Mesenchymal stromal cells (MSCs) in skin, we first examined whether PDGFRα, which is known to be expressed in MSCs, could be a marker for BM-derived MSCs
Summary
Skin regeneration is a coordinated process with mutual interactions among various cell types, extracellular matrix and signaling molecules. Hong et al reported that in a rabbit eye model of alkali burn, substance P, an injury-inducible factor, increased the number of stromal-like cells in circulation and enhanced wound healing[25]. These findings suggest that the activation of endogenous MSCs could be used to suppress inflammatory reactions and promote the regeneration process of damaged tissues. Systemic recombinant HMGB1 administration mobilised endogenous PDGFRα + mesenchymal cells from BM into circulation in the absence of damage, suggesting that HMGB1 could be used to stimulate endogenous PDGFRα + mesenchymal cells for tissue regeneration It is still unclear whether HMGB1-induced PDGFRα + mesenchymal cells in circulation migrate to injury/inflammatory sites and promote the regeneration process
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