Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis

PLoS One. 2019 Jul 17;14(7):e0218068. doi: 10.1371/journal.pone.0218068. eCollection 2019.


Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- β1 (TGF β-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-β1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-β (PDGF-β) and Integrin Subunit Beta 6 (ITG-β6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-β1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adipose Tissue* / metabolism
  • Adipose Tissue* / pathology
  • Adipose Tissue* / transplantation
  • Aged
  • Cells, Cultured
  • Connective Tissue Growth Factor / biosynthesis
  • Female
  • Fibroblasts* / metabolism
  • Fibroblasts* / physiology
  • Fibrosis
  • Gene Expression Regulation
  • Humans
  • Integrin beta Chains / biosynthesis
  • Male
  • Matrix Metalloproteinase 8 / biosynthesis
  • Middle Aged
  • Proto-Oncogene Proteins c-sis / biosynthesis
  • Recovery of Function*
  • Scleroderma, Systemic* / metabolism
  • Scleroderma, Systemic* / pathology
  • Scleroderma, Systemic* / therapy
  • Stem Cells* / metabolism
  • Stem Cells* / pathology
  • Transforming Growth Factor beta1 / biosynthesis


  • CCN2 protein, human
  • Integrin beta Chains
  • Proto-Oncogene Proteins c-sis
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • integrin beta6
  • Connective Tissue Growth Factor
  • MMP8 protein, human
  • Matrix Metalloproteinase 8