title: Bone marrow derived mesenchymal stem cells inhibit the proliferative and profibrotic phenotype of hypertrophic scar fibroblasts and keloid fibroblasts through paracrine signaling.
abstract: BACKGROUND
  Hypertrophic scars and keloids, characterized by over-proliferation of fibroblasts and aberrant formation of the extracellular matrix (ECM), are considered fibrotic diseases. Accumulating evidence indicates that mesenchymal stem cells (MSCs) promote scar-free wound healing and inhibit fibrotic tissue formation, making them a potentially effective therapeutic treatment for hypertrophic scars and keloids.
  
  
  OBJECTIVE
  To investigate the paracrine effects of bone marrow derived MSCs (BMSCs) on the biological behavior of hypertrophic scar fibroblasts (HSFs) and keloid fibroblasts (KFs).
  
  
  METHODS
  Proliferative and profibrotic phenotype changes of the fibroblasts were analyzed by immunofluorescence staining, in-cell western blot, and real-time PCR.
  
  
  RESULTS
  BMSC-conditioned medium inhibited HSF and KF proliferation and migration, but did not induce apoptosis. Interestingly, normal skin fibroblast-conditioned medium exhibited no inhibitory effects on HSF or KF proliferation and migration. Furthermore, BMSC-conditioned medium significantly decreased expression of profibrotic genes, including connective tissue growth factor, plasminogen activator inhibitor-1, transforming growth factor-β1, and transforming growth factor-β2, in HSFs and KFs at both transcriptional and translational levels. In contrast, the expression of antifibrotic genes, such as transforming growth factor-β3 and decorin, was substantially enhanced under the same culture conditions. Finally, we observed that BMSC-conditioned medium suppressed the ECM synthesis in HSFs and KFs, as indicated by decreased expression of collagen I and fibronectin and low levels of hydroxyproline in cell culture supernatant.
  
  
  CONCLUSIONS
  These findings suggest that BMSCs attenuate the proliferative and profibrotic phenotype associated with HSFs and KFs and inhibit ECM synthesis through a paracrine signaling mechanism.
authors.affiliation: Department of Aesthetic, Plastic, and Burn Surgery, Shangdong Provincial Hospital, Shangdong University, No. 324 Jing 5 wei 7 Road, Jinan 250021, China; Department of Plastic Surgery, People's Hospital of Jimo, No. 4 Jianmin Road, Jimo 266200, China.
authors.forename: Fengjun
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Ru-Lin
authors.initials: RL
authors.lastname: Huang
authors.affiliation: Department of Plastic Surgery, People's Hospital of Jimo, No. 4 Jianmin Road, Jimo 266200, China.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Plastic Surgery, People's Hospital of Jimo, No. 4 Jianmin Road, Jimo 266200, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Aesthetic, Plastic, and Burn Surgery, Shangdong Provincial Hospital, Shangdong University, No. 324 Jing 5 wei 7 Road, Jinan 250021, China. Electronic address: huoran2015@126.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Huo
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058575:Decorin / Q000037:antagonists & inhibitors; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D005353:Fibronectins / Q000037:antagonists & inhibitors; D006801:Humans; D007627:Keloid / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D019899:Paracrine Communication; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*; D055815:Young Adult
chemical_list: D024042:Collagen Type I; D017077:Culture Media, Conditioned; C546878:DCN protein, human; D058575:Decorin; C067625:FN1 protein, human; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; C509044:TGFB3 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D055513:Connective Tissue Growth Factor
keywords: BMSC; Hypertrophic scar; Keloid; Profibrotic; Proliferative