![]() ![]() MSC-mediated immunosuppression is a multifaceted process involving paracrine signaling via secreted soluble factors and transmembrane surface proteins such as interleukin 10 (IL-10), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO-1), programmed death ligand 1 (PD-L1), and human leukocyte antigen G (HLA-G). New MSC products must consider and address the challenges associated with standards for MSC potency and dosing, including route of administration and pharmacological disposition of MSCs prior to delivery. This provides new opportunities to re-think current standard practices utilizing suboptimal injection-based delivery of “naïve” (i.e., heterogeneous, non-primed, non-licensed, non-standardized) MSC suspensions. Clinical administration of MSCs has repeatedly demonstrated safety but has generally failed so far to corroborate therapeutic effects observed in preclinical in vitro and in vivo models. However, >900 MSC clinical trials to date exhibit inconsistent results, and only three MSC therapies are so far approved for immune-related diseases globally (none yet approved in USA). Mesenchymal stromal cells, also called mesenchymal stem cells (MSCs), have long been advocated as a cell therapy for immune-related diseases due to their ability to dynamically respond to and attenuate inflammation through their secretion of anti-inflammatory factors. Ultimately, these results present the combination of IFN-γ priming and MSC sheets as a new strategy to improve MSC-mediated treatment of localized inflammatory diseases. Furthermore, this study’s use of human clinical-grade single-cell-derived clonal bone marrow-derived MSCs, contributes to the future translatability and clinical relevancy of the produced sheets. In addition, IFN-γ primed MSC sheets showed increased ability to inhibit T-cell proliferation via indirect and direct contact, specifically related to increased IDO-1 and PGE2 concentrations. ![]() Here, we demonstrate that MSC sheets produced with IFN-γ priming upregulate expression of immunosuppressive factors indoleamine 2,3-dioxygenase (IDO-1), interleukin-10 (IL-10), programmed death ligand-1 (PD-L1), and prostaglandin E2 (PGE2) in both dose- and duration-dependent manners. To address these limitations, we introduce the combination of in vitro interferon-gamma (IFN-γ) priming, a key stimulator of MSC immunosuppressive potency, and thermoresponsive cultureware to harvest cultured MSCs as directly transplantable scaffold-free immunosuppressive cell sheets. However, progress of culture-expanded MSCs is hindered by inconsistent cell function, poor localization, and insufficient retention when administered as suspended cell injections, thus placing spatiotemporal dosing constraints on therapeutic functions. Mesenchymal stromal cells (MSCs) represent a promising treatment for immune-related diseases due to their diverse immunomodulatory paracrine functions.
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