Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist

Abstract

Here we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of non-healing wounds. Local administration of dermal ABCB5+-derived MSCs attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron overload mouse model mimicking the non-healing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+-derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained pro-inflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+-derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγnull mice. In conclusion, human dermal ABCB5+ cells represent a novel, easy accessible and marker-enriched source of MSCs which holds substantial promise to successfully treat chronic non-healing wounds in humans.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…Several lines of evidence demonstrated that, among proinflammatory mediators, IL‐1β had the most important pathological role in the development of chronic wounds . IL‐1β induces senescence in resident fibroblasts impairing repair of injured skin.…”

“…IL‐1β induces senescence in resident fibroblasts impairing repair of injured skin. Furthermore, IL‐1β promotes generation of inflammatory M1 phenotype in intradermal macrophages, resulting in the development of a persistent inflammation within the chronic wounds . Accordingly, increased production of IL‐1β correlated with an impaired healing of skin wounds in diabetic mice, while IL‐1Ra‐dependent suppression of IL‐1β signaling resulted in enhanced repair and regeneration of injured skin .…”

“…Moreover, improved healing of chronic wounds were observed in IL‐1R knockout mice as well as in IL‐1Ra‐treated animals, while genetic deletion of IL‐1Ra resulted in delayed wound healing of acute wounds . Inflammasome‐dependent maturation of IL‐1β in dermal‐infiltrated macrophages was crucially important for IL‐1β‐caused impaired wound healing . Suppression of inflammasome in dermal‐infiltrated macrophages almost completely attenuated IL‐1β‐mediated inflammation and delayed wound healing .…”

“…Vander Beken and colleagues recently demonstrated that within the ATP‐binding cassette Subfamily B Member 5 (ABCB5)‐expressing dermal cells exists a subpopulation of MSCs (MSCs ABCB5 ) which were capable to suppress proliferation of IFN‐γ‐producing Th1 and Th17 cells in paracrine manner . The analysis of MSCs ABCB5 ‐derived secretome revealed that IL‐1Ra had crucially important role for their immunomodulatory effects.…”

“…Through the production of IL‐1Ra, MSCs ABCB5 suppressed IL‐1β:IL‐1R/NF‐κB‐signaling pathway and alleviated production of IL‐1β, IL‐6, IL‐12, and IL‐23 in M1 macrophages and DCs, which prevented expansion of inflammatory Th1 and Th17 cells. At the same time, MSCs ABCB5 ‐derived IL‐1Ra induced generation of TGF‐β and IL‐10‐producing M2 macrophages that promoted the wound healing (Figure ) …”