Abstract
Mesenchymal stem cells (MSCs) have been spotlighted in the field of cell therapies as a promising tool for the treatment of intractable inflammatory diseases. However, their therapeutic potency still shows a gap between preclinical and clinical settings, and distinctive characteristics of specific tissue-derived MSCs and definitive ways to maximize their beneficial functions have not been fully elucidated yet. We previously identified the unique MSCs population from human palatine tonsil (TMSCs) and revealed their superior properties in proliferation and ROS regulation. Based on these findings, we explored further characteristics of TMSCs particularly focused on immunomodulatory function. We found the merit of TMSCs as a therapeutic agent that retains favorable MSCs properties until relatively late passages and revealed that pre-treatment of TNF-α can enhance the immunomodulatory abilities of TMSCs through the upregulation of the PTGS2/PGE2 axis. TMSCs primed with TNF-α effectively restrained the proliferation and differentiation of T lymphocytes and macrophages in vitro, and more interestingly, these TNF-α-licensed TMSCs exhibited significant prophylactic and therapeutic efficacy in a murine model of autoimmune-mediated acute colitis via clinical and histopathological assessment compared to unprimed naïve TMSCs. These findings provide novel insight into the optimization and standardization of MSCs-based anti-inflammatory therapies, especially targeting inflammatory bowel disease (IBD).
Highlights
Mesenchymal stem cells (MSCs)-based therapy has emerged as one of the most promising alternatives for the treatment of various intractable diseases taking advantage of several mechanismsBiomedicines 2020, 8, 561; doi:10.3390/biomedicines8120561 www.mdpi.com/journal/biomedicinesBiomedicines 2020, 8, 561 such as regeneration, homing, immunomodulation and resident cell activation [1,2]
Given that the anti-inflammatory actions of MSCs are exerted in response to the host microenvironment, pre-treatment with proinflammatory cytokines can be the best way to enhance the immunomodulatory function of MSCs by practicing MSCs in the mimicked in vivo inflammatory milieu in advance [33]
While one study showed that IFN-γ-primed adipose tissue-derived MSCs (AT-MSCs) exhibited further alleviation against experimental obliterative bronchiolitis [35], another literature suggested that bone marrow-derived MSCs (BM-MSCs) primed by IFN-γ alone was insufficient to produce immunosuppressive effects [10]
Summary
Mesenchymal stem cells (MSCs)-based therapy has emerged as one of the most promising alternatives for the treatment of various intractable diseases taking advantage of several mechanismsBiomedicines 2020, 8, 561; doi:10.3390/biomedicines8120561 www.mdpi.com/journal/biomedicinesBiomedicines 2020, 8, 561 such as regeneration, homing, immunomodulation and resident cell activation [1,2]. MSCs have been revealed to exhibit low immunogenicity and exert immunomodulatory function by actively interacting with both innate and adaptive immune cells [6,7], most likely through the secretion of regulatory mediators including indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), prostaglandin E2 (PGE2 ), transforming growth factor beta (TGF-β), and interleukin 10 (IL-10) [8,9,10,11] Based on this unique feature, accumulating evidence has reported the safety and efficacy of MSCs through the regulation of host immune microenvironment in autoimmune diseases (e.g., rheumatoid arthritis [12], diabetes, [13] and inflammatory bowel disease [14]), allergic disorders (e.g., rhinitis [15], asthma [16] and atopic dermatitis [17]), and even recently, infectious diseases like COVID-19 [18]. There have been strong needs for advanced approaches to enhance MSCs function and efficacy along with intensive studies on the unique characterization of MSCs derived from specific tissues and standardization of therapy protocol
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