Preconditioning of Human Mesenchymal Stem Cells to Enhance Their Regulation of the Immune Response

Abstract

Mesenchymal stem cells (MSCs) have attracted the attention of researchers and clinicians for their ability to differentiate into a number of cell types, participate in tissue regeneration, and repair the damaged tissues by producing various growth factors and cytokines, as well as their unique immunoprivilege in alloreactive hosts. The immunomodulatory functions of exogenous MSCs have been widely investigated in immune-mediated inflammatory diseases and transplantation research. However, a harsh environment at the site of tissue injury/inflammation with insufficient oxygen supply, abundance of reactive oxygen species, and presence of other harmful molecules that damage the adoptively transferred cells collectively lead to low survival and engraftment of the transferred cells. Preconditioning of MSCs ex vivo by hypoxia, inflammatory stimulus, or other factors/conditions prior to their use in therapy is an adaptive strategy that prepares MSCs to survive in the harsh environment and to enhance their regulatory function of the local immune responses. This review focuses on a number of approaches in preconditioning human MSCs with the goal of augmenting their capacity to regulate both innate and adaptive immune responses.

Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

“…Increasing Evidence have demonstrated that pre-conditioning could enhance the therapeutic effects of MSCs. 55,56 Compared to in vivo inflammatory licensing by the recipient environment alone, in vitro inflammatory licensing prior to clinical use could enhance the immunomodulatory ability of MSCs exposed to inflammatory macrophages and secretome from primed MSCs possessed biologically active. 57 TLR4 activation by LPS stimulation could enhance the paracrine capacity of BMSCs, releasing large amounts of cytokines and exosomes, to represent a physiologically significant mechanism for tissue repair.…”

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

“…The cargo of USMSC-EVs in this study contained many chemokines (CXCL5, CCL3, CCL4, CCL11, CCL20), which might attract immune cells to the site of injury. However, research has strongly shown that MSCs primed with pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β) show enhanced immunosuppressive abilities [14,[21][22][23]. Specifically, research using EVs secreted from pro-inflammatory primed MSCs has shown positive immunosuppressive effects by polarising pro-inflammatory immune cells into anti-inflammatory immune cells in vitro [24][25][26][27][28][29].…”

“…This study found no significant difference in growth kinetics of protein cargo between UCMSCs grown in normoxia and hypoxia, and research was divided on whether hypoxia has a stimulatory [30] or inhibitory [31,32] effect on MSC proliferation; albeit studies varied between the use of 1%-5% O 2 . Some groups have advocated for the use of hypoxia when growing cells in culture as it more closely mimics the oxygen levels that MSCs are exposed to in vivo [22], with neonatal-derived tissues rarely exceeding 5% in vivo [23]. The lack of change in growth may be because the cells were first isolated under normal oxygen (21%) conditions, and exposure to low oxygen (5%) at an earlier stage may be an influencing factor in cell proliferation.…”

Trained murine mesenchymal stem cells have anti‐inflammatory effect on macrophages, but defective regulation on T‐cell proliferation

“…Recent studies indicate that proinflammatory stimulation may have prolonged effects on the function of MSCs. MSCs preconditioned by transient exposure to inflammatory cytokines alone or combined with PAMP enhanced immunomodulation and tissue regeneration (10)(11)(12). We recently observed that when MSCs were exposed to LPS repeatedly, NF-kB activation was significantly increased compared with single LPS exposure (13).…”