title: Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolismviafibroblast-specific STAT3 signaling.
abstract: The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice-plus syngeneic fibroblast cell-transplant models-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.-Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolismviafibroblast-specific STAT3 signaling.
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: King
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Louis D
authors.initials: LD
authors.lastname: Le
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sukanta S
authors.initials: SS
authors.lastname: Bhattacharya
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Moles
authors.affiliation: Division of Immunology, Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Manish J
authors.initials: MJ
authors.lastname: Butte
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Vinicio A
authors.initials: VA
authors.lastname: de Jesus Perez
authors.affiliation: Center for Children's Surgery, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Liechty
authors.affiliation: Matrix Biology Program, Benaroya Research Institute, Seattle, Washington, USA; and.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.affiliation: Center for Children's Surgery, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
authors.affiliation: Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA; keswani@bcm.edu.
authors.forename: Sundeep G
authors.initials: SG
authors.lastname: Keswani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D006820:Hyaluronic Acid / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D006820:Hyaluronic Acid
keywords: extracellular matrix; fibrosis; inflammatory cytokines; scarless; wound healing