Abstract
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.
Highlights
Human mesenchymal stem cell-derived extracellular vesicles have emerged as a new therapeutic strategy for many diseases[1,2,3]
Normal lung fibroblasts (NLF) (Fig. 1A and C) and fibroblasts derived from lungs of individuals with idiopathic pulmonary fibrosis (IPF) (Fig. 1B and D) were cultured in the presence of TGFβ1, with or without addition of MSC-derived EVs (mEVs) or fibroblast-derived extracellular vesicles (EVs) (10 μg)
Normal fibroblasts treated with TGFβ1 and mEVs, or with mEVs pre-incubated with anti-IgG, showed significantly lower levels of α-SMA (51%) and FN1-EDA (52%) in comparison to TGFβ1 treatment alone
Summary
Human mesenchymal stem cell-derived extracellular vesicles (mEVs) have emerged as a new therapeutic strategy for many diseases[1,2,3]. Current isolation technology cannot consistently separate these subsets Because of this technical limitation, we use the term “extracellular vesicles” as suggested by the International Society of Extracellular Vesicles[6,7]. EVs are comprised of mRNAs, non-coding RNAs, proteins and membrane lipids derived from donor cells. Horizontal microRNA (miR) transfer[21,22] appears to be important in mEV-mediated tissue recovery[10,23]. It is less well known, the degree to which the cellular responses are dependent on mEV uptake by recipient cells.
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