Newly defined ABCB5+ dermal mesenchymal stem cells promote healing of chronic iron overload wounds via secretion of interleukin-1 receptor antagonist

• Published in: Stem cells (Dayton, Ohio) Vol. 37; no. 8; pp. 1057 - 1074
• Main Authors: BEKEN, SEPPE VANDER, DE VRIES, JULIANE C., MEIER-SCHIESSER, BARBARA, MEYER, PATRICK, JIANG, DONGSHENG, SINDRILARU, ANCA, FERREIRA, FILIPA F., HAINZL, ADELHEID, SCHATZ, SUSANNE, MUSCHHAMMER, JANA, SCHEURMANN, NATALIE J., KAMPILAFKOS, PANAGIOTIS, SEITZ, ANDREAS M., DÜRSELEN, LUTZ, IGNATIUS, ANITA, KLUTH, MARK A., GANSS, CHRISTOPH, WLASCHEK, MEINHARD, SINGH, KARMVEER, MAITY, PALLAB, FRANK, NATASHA Y., FRANK, MARKUS H., SCHARFFETTER-KOCHANEK, KARIN
• Format: Journal Article
• Language: English
• Published: 13.05.2019
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3022

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 IL2rγ null 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. In chronic wounds, M1 macrophages and their autocrine amplification of inflammasome-generated IL-1β perpetuates a pro-inflammatory environment impeding the progression through normal phases of wound healing. IL-1RA adaptively secreted by ABCB5 + MSCs when exposed to the M1 macrophage imprinted pro-inflammatory wound environment, attenuates this vicious cycle and leads to a shift from pro-inflammatory M1 toward anti-inflammatory, wound healing-promoting M2 macrophages as observed in normal wound healing.