Influence of MSC immunomodulatory basal fitness on their mechanisms of action
alloantibody
PROLIFERATION, RECRUITMENT
Several factors can influence the fitness and overall phenotype of MSCs that may in turn influence their mechanisms of action, as discussed here with emphasis on effects mediating immunomodulatory fitness. Donor heterogeneity represents a major variable and includes a multitude of factors, such as donor health status, age, BMI and sex, that can influence the in vitro clonogenic potential, paracrine functions, and proclivity toward senescence of MSCs [In support of the immunomodulatory mechanism of action of MSCs in OA, we and others have investigated the relationships between the baseline immunomodulatory fitness of donor MSCs in vitro and their clinical efficacy. In our clinical trial, we measured the levels of IFN‐γ-induced expression of immunomodulatory genes (prostaglandin-endoperoxide synthase 2, Delivery strategies are also likely to influence mechanisms of action, and the administration of freshly thawed cryopreserved MSCs can influence their cell viability and apoptotic status [The tissue sources for MSCs represent an important variable that could also influence MSC mechanisms of action. To date, bone marrow, adipose tissue and umbilical tissues represent the most commonly used MSC sources in OA clinical trials. An elegant study by Ménard et al. investigated matched human MSC(AT) and MSC(M) from 14 donors and demonstrated distinct transcriptional profiles that were imprinted by the tissue of origin in each MSC population, with different sets of immunomodulatory genes and chemokines upregulated in MSC(AT) and MSC(M). MSC(AT) displayed reduced HLADR expression, as well as augmented neutrophil recruitment and suppression of T-cell proliferation in vitro, whereas MSC(M) were better able to suppress natural killer (NK) cell proliferation in experiments with paired donors [The choice of autologous versus allogeneic MSCs is another factor that may impact mechanisms of action. An advantage of allogeneic MSC sources is that they offer the ability to select healthy donors and screen for MSCs with high fitness levels, as we have postulated [In contrast, autologous sourcing would circumvent alloantibody production, but donor site morbidity and variable basal MSC therapeutic fitness, which can be impacted by donor factors including age, sex, BMI, physical activity and health status, must be factored in with its use. For example, MSCs obtained from older donors may be more prone to senescence, which may limit the cell numbers required for specific dosing, skew their secretory phenotype and diminish their functional immunomodulatory properties [