TNF-α and IFN-γ Participate in Improving the Immunoregulatory Capacity of Mesenchymal Stem/Stromal Cells: Importance of Cell–Cell Contact and Extracellular Vesicles

Abstract

Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions.

IFN-Gamma and TNF-Alpha as a Priming Strategy to Enhance the Immunomodulatory Capacity of Secretomes from Menstrual Blood-Derived Stromal Cells

“…It had already been evidenced that the combination of IFNγ and TNFα could change the expression of immunoregulatory molecules in MSCs [34]. Therefore, once the priming conditions were optimized, the next set of experiments was conducted to characterize the phenotype of IFNγ-and TNFα-primed MenSCs (MenSCs*).…”

Extracellular Vesicles Derived from Primed Mesenchymal Stromal Cells Loaded on Biphasic Calcium Phosphate Biomaterial Exhibit Enhanced Macrophage Polarization

“…Diverse approaches were used in the past to enhance the M2 macrophagemediated healing response by MSC-EVs, most commonly hypoxic pre-conditioning [19,42], inflammatory priming via IFNγ alone [21], or with TNFα+IFNγ [20]. Moreover, it was reported that EVs, particularly from TNFα+IFNγ primed MSC, showed enhanced potential to attenuate inflammation [40,43]. In our study, EVs primed with TNFα+IL1β (MSCp + BCP) were employed, which showed higher levels of TNFα and IL1β (in EV cargo), thereby demonstrating that active soluble cytokines supplied artificially induced MSCs to produce more of the same cytokines, which were at least partly encapsulated within the EV compartment.…”

From Primary MSC Culture of Adipose Tissue to Immortalized Cell Line Producing Cytokines for Potential Use in Regenerative Medicine Therapy or Immunotherapy

“…In the case of INF-gamma, an increased HLA-ABC expression and induction of the HLA-DR antigen could be observed. Interestingly, it is possible to find reports that activation of MSC cells with the mentioned cytokines and LPS may cause various positive therapeutic effects [ 42 , 43 , 44 ].…”