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Histone deacetylase inhibitors (HDACi) have received a great amount of attention for their antitumoral properties. Suberoyl anilide hydroxamic acid (SAHA) and MS-275 are among the more promising HDACi for cancer treatments. Although these HDACi compounds exert low toxicity on normal cells, the therapies based on these molecules can cause side effects that can greatly impair the functions of the bone marrow microenvironment. This is a complex system that contains several types of stem cells, such as mesenchymal stem cells (MSCs). We conducted comparative studies on the effects of SAHA and MS-275 on human MSCs in order to ascertain if these compounds can impair the physiology of MSCs. Both SAHA and MS-275 induced an arrest in the cell cycle along with the induction of apoptotic pathways as evidenced by fl ow cytometry, annexin assay, detection of activated caspase 9, and molecular analysis of Bax/Bcl-2 expression. The MS-275 treatment induced an increase of senescent cells, whereas in cells treated with SAHA, we detected a reduction of senescent cells compared to the control. We hypothesize that SAHA preferentially transactivates apoptotic genes, thereby inducing a great majority of the damaged cells to die by programmed cell death rather than senescence. Following the HDACi treatment, we observed a decrease in the expression of some genes that are involved in the regulation of stem cell properties. This suggests that SAHA and MS-275 could also be involved in the impairment of the stemness characteristics of MSCs. The phenomena that were induced by HDACi treatment were associated with an upregulation of several cyclin kinase inhibitors. By contrast, the p53-p21 pathway is apparently not involved in these processes.

Mesenchymal stem cells (MSCs) are of particular interest because they are being tested using cell and gene therapies for a number of human diseases. MSCs represent a rare population in tissues. Therefore, it is essential to grow MSCs in vitro before putting them into therapeutic use. This is compromised by senescence, limiting the proliferative capacity of MSCs. We analyzed the in vitro senescence of rat MSCs, because this animal is a widespread model for preclinical cell therapy studies. After initial expansion, MSCs showed an increased growth doubling time, lost telomerase activity, and expressed senescence-associated beta-galactosidase. Senescence was accompanied by downregulation of several genes involved in stem cell self-renewal. Of interest, several genes involved in DNA repair also showed a significant downregulation. Entry into senescence occurred with characteristic changes in Retinoblastoma (RB) expression patterns. Rb1 and p107 genes expression decreased during in vitro cultivation. In contrast, pRb2/p130 became the prominent RB protein. This suggests that RB2/P130 could be a marker of senescence or that it even plays a role in triggering the process in MSCs.