Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis

S. Zanotti, S. Gibertini, F. Blasevich, C. Bragato, A. Ruggieri, S. Saredi, M. Fabbri, P. Bernasconi, L. Maggi, R. Mantegazza, M. Mora

Research output: Contribution to journalArticlepeer-review

Abstract

Exosomes, natural carriers of mRNAs, non-coding RNAs and proteins between donor and recipient cells, actively contribute to cell-cell communication. We investigated the potential pro-fibrotic role of exosomes released by muscle-derived fibroblasts of Duchenne muscular dystrophy (DMD) patients, and of miRNAs carried by exosomes. By fibrosis focused array analysis we found that exosomes from DMD fibroblasts, had significantly higher levels of miR-199a-5p, a miRNA up-regulated in fibrotic conditions, compared to control exosomes, while levels in myoblast-derived exosomes were not increased. In control fibroblasts, exposure to DMD fibroblast-derived exosomes induced a myofibroblastic phenotype with increase in α-smooth actin, collagen and fibronectin transcript and protein expression, soluble collagen production and deposition, cell proliferation, and activation of Akt and ERK signaling, while exposure to control exosomes did not. Transfecting control fibroblasts or loading control exosomes with miR-199a-5p mimic or inhibitor induced opposing effects on fibrosis-related mRNAs and proteins, on collagen production and Akt and ERK pathways. Finally, injection of DMD fibroblast-derived exosomes into mouse tibialis anterior muscle after cardiotoxin-induced necrosis, produced greater fibrosis than control exosomes. Our findings indicate that exosomes produced by local fibroblasts in the DMD muscle are able to induce phenotypic conversion of normal fibroblasts to myofibroblasts thereby increasing the fibrotic response. This conversion is related to transfer of high levels of miR-199a-5p and to reduction of its target caveolin-1; both, therefore, are potential therapeutic targets in muscle fibrosis. © 2018 International Society of Matrix Biology
Original languageEnglish
Pages (from-to)77-100
Number of pages24
JournalMatrix Biology
Volume74
DOIs
Publication statusPublished - 2018

Keywords

  • Duchenne muscle dystrophy
  • Exosomes
  • Fibroblasts
  • Fibrosis
  • miRNAs
  • Myofibroblasts
  • alpha smooth muscle actin
  • cardiotoxin
  • caveolin 1
  • ceramide
  • collagen
  • fibronectin
  • microRNA
  • microRNA 199a 5p
  • mitogen activated protein kinase
  • protein kinase B
  • unclassified drug
  • adult
  • Akt signaling
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • cell proliferation
  • cell transdifferentiation
  • cell transfer
  • cellular distribution
  • controlled study
  • Duchenne muscular dystrophy
  • electric potential
  • enzyme activation
  • exosome
  • fibroblast
  • genetic transfection
  • human
  • human cell
  • MAPK signaling
  • microarray analysis
  • mouse
  • mRNA expression level
  • muscle biopsy
  • myoblast
  • myofibroblast
  • nonhuman
  • organelle biogenesis
  • pathogenesis
  • phenotype
  • priority journal
  • protein expression
  • skeletal muscle
  • tibialis anterior muscle
  • transcription regulation
  • upregulation

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