Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) is out of the question. Yet, recent drawbacks have resulted in a strategic shift towards the application of MSC-derived cell-free products such as extracellular vesicles (EVs). Recent reports revealed that functional properties of MSCs, including EV secretion patterns, correlate with microenvironmental cues. These findings highlight the urgent need for defining the optimal circumstances for EV preparation. Considering the limitations of primary cells, we employed immortalized cells as an alternative source to prepare therapeutically sufficient EV numbers. Herein, the effects of different conditional environments are explored on human TERT-immortalized MSCs (hTERT-MSCs). The latter were transduced to overexpress IDO1, PTGS2, and TGF-β1 transgenes either alone or in combination, and their immunomodulatory properties were analyzed thereafter. Likewise, EVs derived from these various MSCs were extensively characterized. hTERT-MSCs-IDO1 exerted superior inhibitory effects on lymphocytes, significantly more than hTERT-MSCs-IFN-γ. As such, IDO1 overexpression promoted the immunomodulatory properties of such enriched EVs. Considering the limitations of cell therapy like tumor formation and possible immune responses in the host, the results presented herein might be considered as a feasible model for the induction of immunomodulation in off-the-shelf and cell-free therapeutics, especially for autoimmune diseases.
Highlights
Mesenchymal stem cells (MSCs) have been widely applied in cell-based regenerative m edicine[1,2]
The chemical treatment with IFN-γ had no adverse effects on the viability of hTERT-mesenchymal stem cells (MSCs) at both 250 U/ml and 500 U/ml concentrations after 72 h, as demonstrated by the MTT assay
Immunocytochemistry experiments revealed that IFN-γ remarkably induced IDO1 and PTGS2 expressions in the hTERT-MSCs at 72 h post-treatment at the protein level
Summary
Mesenchymal stem cells (MSCs) have been widely applied in cell-based regenerative m edicine[1,2]. In addition to other experiments, these observations made a meaningful shift from cell-based therapies to strategies like managing an immunological microenvironment[28,29,30] This could be obtained by applying active components of the stem cells’ supernatant, mainly their extracellular vesicles (EVs)[29,31,32,33]. It is advisable to manipulate parental cells of EVs to provide a tool for cargo transport of enriched desirable agents[39,40] It seems that EVs are proper candidates to overcome the concerns regarding the therapeutic application of engineered cells. We first investigated the potential of using immortalized hTERT-MSCs as a proper substitute for primary cells to overcome the problems associated with heterogeneity of the cells, as well as other limitations such as low proliferation capacity and cellular senescence observed during culture of primary mesenchymal stem cells
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