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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 IL2rγnullmice. 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 Cells2019;37:1057–1074 In chronic wounds, M1 macrophages and their autocrine amplification of inflammasome‐generated interleukin‐1 (IL‐1) beta perpetuates a proinflammatory environment impeding the progression through normal phases of wound healing. IL‐1 receptor antagonist adaptively secreted by ATP‐binding cassette subfamily B member 5+mesenchymal stem cells when exposed to the M1 macrophage imprinted proinflammatory wound environment, attenuates this vicious cycle, and leads to a shift from proinflammatory M1 toward anti‐inflammatory, wound healing‐promoting M2 macrophages as observed in normal wound healing.

Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+stromal precursors at the edge of nonhealing diabetic wounds in a murine db/dbmodel, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/dbmice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors–based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis.

Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4Aand repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner—by reinstatement of IGF-1 and p16 levels—restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.