title: Interleukin-10 regulates fetal extracellular matrix hyaluronan production.
abstract: OBJECTIVE
  Mid-gestational (E14.5) fetal wounds heal regeneratively with attenuated inflammation and high levels of hyaluronan (HA) in their extracellular matrix (ECM), whereas late-gestational (E18.5) fetal wounds heal with scarring. IL-10 plays an essential role in the fetal regenerative phenotype and is shown to recapitulate scarless wound healing postnatally. We hypothesize a novel role of IL-10 as a regulator of HA in the ECM.
  
  
  METHODS
  Murine fetal fibroblasts (FFb) from C57Bl/6 and IL-10-/- mice were evaluated in vitro. Pericellular matrix (PCM) and HA synthesis were quantified using a particle exclusion assay and ELISA. The effects of hyaluronidase and hyaluronan synthase (HAS) inhibitor (4-methylumbelliferone[4-MU]) were evaluated. An ex vivo fetal forearm culture incisional wound model comparing mid-gestation and late-gestation fetuses was used to evaluate IL-10's effect on HA-rich ECM production with pentachrome and immunohistochemistry.
  
  
  RESULTS
  FFb produce a robust HA-rich PCM which is IL-10 dependent and attenuated with hyaluronidase and HAS inhibition. Mid-gestation fetal wounds produce more ground substance and HA than late-gestation fetal wounds. IL-10 in late-gestation fetal wounds results in elevated ground substance levels and HA staining.
  
  
  CONCLUSIONS
  Our data demonstrate that IL-10 regulates an HA-rich ECM deposition, suggesting a novel non-immunoregulatory mechanism of IL-10 in mediating regenerative wound healing.
authors.affiliation: Division of Pediatric, Thoracic and General Surgery, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Alice
authors.initials: A
authors.lastname: King
authors.affiliation: Division of Pediatric, Thoracic and General Surgery, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Swathi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Division of Pediatric, Thoracic and General Surgery, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Louis D
authors.initials: LD
authors.lastname: Le
authors.affiliation: Division of Pediatric, Thoracic and General Surgery, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Emily
authors.initials: E
authors.lastname: Marsh
authors.affiliation: Division of Pediatric Surgery, The Children's Hospital Colorado, Aurora, CO.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.affiliation: Division of Pediatric, Thoracic and General Surgery, The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Sundeep G
authors.initials: SG
authors.lastname: Keswani
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D047109:Fetal Development / Q000502:physiology*; D006820:Hyaluronic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D014945:Wound Healing / Q000502:physiology*
chemical_list: D015415:Biomarkers; C556062:IL10 protein, mouse; D016753:Interleukin-10; D006820:Hyaluronic Acid
keywords: Extracellular matrix; Fetal; Hyaluronan; IL-10; Wound healing