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In this study, 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 nonhealing wounds. Local administration of dermal ABCB5 + -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing 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 proinflammatory 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 IL2rγ null mice. In conclusion, human dermal ABCB5 + cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074., (© 2019 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019.)

Mesenchymal stem cells (MSCs) have properties which make them promising for the treatment of chronic non-healing wounds. A major so far unmet challenge is the efficient, safe and painless delivery of MSCs to skin wounds. Recently, a surface carrier of medical-grade silicone coated by plasma polymerisation with a thin layer of acrylic acid (ppAAc) was developed, and shown to successfully deliver MSCs to deepithelialised human dermis in vitro. Here we studied the potential of the ppAAc carrier to deliver human adipose tissue derived MSCs (AT-MSCs) to murine full-thickness excisional skin wounds in vivo. Further we investigate the mechanism of action of MSCs in accelerating wound healing in these wounds. AT-MSCs cultured on ppAAc carriers for 4 days or longer fully retained their cell surface marker expression profile, colony-forming-, differentiation- and immunosuppressive potential. Importantly, AT-MSCs delivered to murine wounds by ppAAc carriers significantly accelerated wound healing, similar to AT-MSCs delivered by intradermal injection. More than 80% of AT-MSCs were transferred from carriers to wounds in 3 days. AT-MSCs were detectable in wounds for at least 5 days after wounding. Carrier delivered AT-MSCs were demonstrated to have the capacity to down-modulate TNF-α-dependent inflammation, increase anti-inflammatory M2 macrophage numbers, and induce TGF-β(1)-dependent angiogenesis, myofibroblast differentiation and granulation tissue formation, thereby enhancing overall tissue repair., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.