TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.
Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-α (TNF-α)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mφ or following injection into wound margins suppressed the release of TNF-α from activated Mφ and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-β1 (TGF-β1)/TGF-β3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mφ activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Yu
Y
Qi
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Dongsheng
D
Jiang
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Anca
A
Sindrilaru
Department of Dermatology, University of Münster, Münster, Germany.
Agatha
A
Stegemann
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Susanne
S
Schatz
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Nicolai
N
Treiber
Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
Markus
M
Rojewski
Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
Hubert
H
Schrezenmeier
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Seppe
S
Vander Beken
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Meinhard
M
Wlaschek
Department of Dermatology, University of Münster, Münster, Germany.
Markus
M
Böhm
Institute of Orthopaedic Research and Biomechanics, University of Ulm, Ulm, Germany.
Andreas
A
Seitz
Institute of Orthopaedic Research and Biomechanics, University of Ulm, Ulm, Germany.
Natalie
N
Scholz
Institute of Orthopaedic Research and Biomechanics, University of Ulm, Ulm, Germany.
Lutz
L
Dürselen
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Jürgen
J
Brinckmann
Institute of Orthopaedic Research and Biomechanics, University of Ulm, Ulm, Germany.
Anita
A
Ignatius
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany. Electronic address: Karin.Scharffetter-Kochanek@uniklinik-ulm.de.
Karin
K
Scharffetter-Kochanek
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007271:Injections, Intradermal; D008264:Macrophages / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000293:injuries* / Q000473:pathology; D014945:Wound Healing / Q000502:physiology*
D015815:Cell Adhesion Molecules; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse