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Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

ABSTRACT: Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs' metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction.

SUBMITTER: Showalter MR

PROVIDER: S-EPMC6682414 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

Showalter Megan R MR Wancewicz Benjamin B Fiehn Oliver O Archard Joehleen A JA Clayton Shannon S Wagner Joseph J Deng Peter P Halmai Julian J Fink Kyle D KD Bauer Gerhard G Fury Brian B Perotti Nicholas H NH Apperson Michelle M Butters Janelle J Belafsky Peter P Farwell Gregory G Kuhn Maggie M Nolta Jan A JA Anderson Johnathon D JD

Biochemical and biophysical research communications 20190326 4

Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and ...[more]

PMID: 30926165

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Project description:BackgroundInterstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.MethodsLung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.ResultsHigher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of ?-smooth muscle actin (?-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked ?-SMA activation in CTD-UIP HLFs through a TGF-?1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-?1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.ConclusionsImpairment of TGF-? signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-?1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.

Dataset Information

Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

Publications

Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

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