Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.
Tzu-Pin ShentuTse-Shun HuangMateja Cernelc-KohanJoy ChanSimon S WongCelia R EspinozaChunting TanIrene GramagliaHenri van der HeydeShu ChienJames S HagoodPublished in: Scientific reports (2017)
Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established. We demonstrate that mEVs, but not fibroblast EVs (fEVs), suppress TGFβ1-induced myofibroblastic differentiation of normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. MEVs display increased time- and dose-dependent cellular uptake compared to fEVs. Removal or blocking of Thy-1, or blocking Thy-1-beta integrin interactions, decreased mEV uptake and prevented suppression of myofibroblastic differentiation. MicroRNAs (miRs) 199a/b-3p, 21-5p, 630, 22-3p, 196a-5p, 199b-5p, 34a-5p and 148a-3p are selectively packaged in mEVs. In silico analyses indicated that IPF lung fibroblasts have increased expression of genes that are targets of mEV-enriched miRs. MiR-630 mimics blocked TGFβ1 induction of CDH2 in normal and IPF fibroblasts, and antagomiR-630 abrogated the effect of mEV on CDH2 expression. These data suggest that the interaction of Thy-1 with beta integrins mediates mEV uptake by lung fibroblasts, which blocks myofibroblastic differentiation, and that mEVs are enriched for miRs that target profibrotic genes up-regulated in IPF fibroblasts.
Keyphrases
- idiopathic pulmonary fibrosis
- bone marrow
- extracellular matrix
- interstitial lung disease
- poor prognosis
- mesenchymal stem cells
- cell proliferation
- stem cells
- long non coding rna
- transforming growth factor
- binding protein
- electronic health record
- lps induced
- artificial intelligence
- drug induced
- diabetic rats
- oxidative stress
- genome wide identification
- systemic sclerosis
- inflammatory response
- deep learning
- data analysis
- dna methylation
- bioinformatics analysis