TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

Abstract

Mesenchymal stem cells (MSCs) have drawn lots of attention as gold standard stem cells in fundamental and clinical researches during the last 20 years. Due to their tissue and vascular repair capacities, MSCs have been used to treat a variety of degenerative disorders. Moreover, MSCs are able to modulate immune cells’ functions, particularly T cells while inducing regulatory T cells (iTregs). MSCs are very sensitive to inflammatory signals. Their biological functions could remarkably vary after exposure to different pro-inflammatory cytokines, notably TNFα. In this article, we have explored the importance of TNFR2 expression in a series of MSCs’ biological and functional properties. Thus, MSCs from wild-type (WT) and TNFR2 knockout (TNFR2 KO) mice were isolated and underwent several ex vivo experiments to investigate the biological significance of TNFR2 molecule in MSC main functions. Hampering in TNFR2 signaling resulted in reduced MSC colony-forming units and proliferation rate and diminished the expression of all MSC characteristic markers such as stem cell antigen-1 (Sca1), CD90, CD105, CD44, and CD73. TNFR2 KO-MSCs produced more pro-inflammatory cytokines like TNFα, IFNγ, and IL-6 and less anti-inflammatory mediators such as IL-10, TGFβ, and NO and induced Tregs with less suppressive effect. Furthermore, the TNFR2 blockade remarkably decreased MSC regenerative functions such as wound healing, complex tube formation, and endothelial pro-angiogenic support. Therefore, our results reveal the TNFα–TNFR2 axis as a crucial regulator of MSC immunological and regenerative functions.

The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy

“…For example, MSCs respond to TGFα/EGF receptor by increasing VEGF production ( De Luca et al, 2011 ). On the other hand, VEGF signaling pathway is defective in TNFR2 KO mice ( Luo et al, 2006 ), and a correlation between TNFR2 expression by MSCs and NO production, that directly induces VEGF, has been recently established ( Beldi et al, 2020a ). Previously, it has been found that VEGF production by TNF-α-primed human bone marrow MSCs was TNFR2 dependent ( Crisostomo et al, 2008 ; Zhang A. et al, 2010 ).…”

“…Nevertheless, it is important to clarify more conclusively the relevance of an inflammatory environment for the MSC-mediated immunomodulation. Two recent publications by Naserian and colleagues ( Beldi et al, 2020a , b ) have provided new and relevant information on the role played by TNF-α signaling in these processes. TNF-α exerts its effects through interaction with two receptors, TNFR1 and TNFR2.…”

“…More recently, extended analysis of these TNFR2 deficient MSCs demonstrated that impeded TNFR2 signaling courses with reduced MSC colony-forming units (CFUs), proliferative rate and expression of diverse MSC cell markers. In addition, these deficient TNFR2 MSC produce more pro-inflammatory molecules (i.e., TNF-α, IFNγ, IL-6), less IL-10, TGFβ and nitric oxide (NO), and show reduced regenerative capabilities for wound healing, vascular tube formation and neoangiogenesis ( Beldi et al, 2020a ).…”

TNFR2: Role in Cancer Immunology and Immunotherapy

“… 126 Moreover, TNFR2-KO MSCs also reduce their proliferation capacity, major characteristics markers (Sca1, CD90, CD105, CD44, and CD73), and functional properties (tissue/cell regeneration functions and endothelial pro-angiogenic support). 127 …”

Post-decellularization techniques ameliorate cartilage decellularization process for tissue engineering applications

“…209,210 Due to the lack of expression of co-stimulatory molecules and the production of several anti-inflammatory mediators, MSCs are immunoprivileged, immunosuppressive and possess immunomodulatory properties. [211][212][213] Both immunomodulatory capacity and low immunogenicity are highly advantageous regarding MSCs as a cell source for reseeding decellularized scaffolds. MSCs cultured on the dECM scaffolds could enhance the biocompatibility of the constructs.…”