Abstract
Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.
Highlights
Mesenchymal stem/stromal cells (MSCs) have been shown to have immune modulatory, angiogenic, and antiapoptotic effects by secreting exosomes, chemokines, cytokines, and growth factors that promote cell regeneration and survival [1,2,3]
To characterize engineered MSCs (eMSCs)‐IL10, we evaluated their MSC identity using morphological the phenotypic guidelines established by the International Society for Cell & Gene Therapy analysis, flow cytometry, and adipogenic and osteogenic differentiation assays
We evaluated two and five eMSCs-IL10 dose treatment regimens and our data revealed that the 2-dose regimen induced more potent immunosuppression than the 5-dose treatment regimen
Summary
Mesenchymal stem/stromal cells (MSCs) have been shown to have immune modulatory, angiogenic, and antiapoptotic effects by secreting exosomes, chemokines, cytokines, and growth factors that promote cell regeneration and survival [1,2,3]. MSCs are known to be well tolerated in vivo due to their low HLA antigen expression [4,5], some reports have shown that they may be subjected to immune clearance and first-pass effect when administered intravenously [6,7]. They have been widely used in many cellbased clinical trials. Over 10,000 clinical trials that involve a variety of human diseases such as heart disease, stroke, cancer, diabetes, and COVID-19 are on-going or have been completed [8]. Viral transduction is more efficient and can lead to stable gene expression, its clinical utility is limited because it may cause chromosomal instability [11]
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