Is it Possible to Improve the Success Rate of Cellular Therapy Based on Mesenchymal Stromal Cells?

Many clinical trials currently aim to treat several diseases with mesenchymal stromal cells (MSCs) or related cell-types. Nevertheless, besides some successes, MSC therapies have experienced many failures. There are some issues to be analyzed that may improve the success rate of MSC therapy. We have to consider that MSCs used in therapy are non-clonal populations of stromal cells because the clonal MSC cultures use is not possible due to insufficient number of daughter cells being produced. The use of non-clonal cell populations produces per se a higher variability in outcomes. Notwithstanding, the issue is not ‘non-clonal’ versus ‘clonal’ MSCs; rather, the issue is the standardization of the procedures to produce MSCs for therapeutic use. Some investigators carried out meta-analysis studies to identify the potential variables affecting therapies based on MSCs. Immunogenicity, donor variance, ex vivo expansion differences, and cryopreservation are among the main factors that can compromise the effectiveness of MSC transplants. In some trials, MSC samples are heavily expanded in culture, while in other trials MSCs are grown for a limited number of in vitro passages. These different approaches may greatly affect the MSC properties. Cell in vitro growth is limited by senescence, which is a cellular response to endogenous or exogenous genotoxic stress that results in an irreversible cell cycle arrest. Senescent cells are non-functional cells that may o affect the activity of surrounding healthy cells. Factors secreted by senescent cells could constitute a danger signal that sensitizes normal neighboring cells to sense. The use of lipoaspirates, a rich source of adipose-derived MSCs (A-MSCs) may represent a valid alternative to avoid the extensive time and manipulation necessary to expand sufficient MSCs destined to clinical application. Anyway, it should be emphasized that also the use of lipoaspirate samples may have a different percentage of senescent cells due to inter-donor variability. The donor heterogeneity may affect the biological properties of MSCs even before their ex vivo expansion. Also, the immunoregulatory properties of MSCs may have a significant inter-donor variability. The development of standardized procedures that couple those regulating MSC ex vivo expansion along with the use of reliable assays could contribute to overcoming any divergence in clinical outcome and lead to a faster translation of MSCs into clinical practice. Currently, several private companies and research teams are working in this direction to improve the success rate of MSC based therapy. The present proposal research aims to develop standardized procedure for the successful preparation of MSCs destined to clinical use.