The studies we performed targeted the effects of all-trans retinol (vitamin A) and some retinoid derivatives (including tretinoin or all-trans retinoic acid, retinyl propionate, 9-cis retinoic acid, 13-cis retinoic acid), as well as of tazarotenic acid on apoptosis of rat mesenchymal stem cells, cultured after isolation. Tazarotenic acid is considered to be relatively selective and a potent agonist for RARb and RARg and less for RARa. The same time, tazarotenic acid is not binding to RXRs (retinoid X receptors). The relevant analysis of our experimental results demonstrated that 13-cis retinoic acid was the most potent inducer of apoptosis of cultured mesenchymal stem cells of rat origin when compared to other retinoid derivatives, as follows: 13-cis retinoic acid ] 9-cis retinoic acid ] tazarotenic acid ] all-trans retinoic acid ] retinyl propionate ] retinol (or vitamin A). Very interesting and unexpected were the apoptotic effects of 1 �M tazarotenic acid for 24 hours in our experiments, very close to those induced by all-trans retinoic acid (tretinoin). The apoptosis induced by 13-cis retinoic acid, a principal activator of RARb and RARg, and that induced by 9-cis retinoic acid, a major activator of RXRs, suggests different pathways activated by these retinoid derivatives.
We tempted to explore the biochemical effects, represented by apoptosis, triggered by conditioned medium, obtained as a result of culturing mesenchymal stem cells for 24 h, on endothelial progenitor cells. The mesenchymal stem cells were developed on collagen fibers in the presence of thapsigargin, concanavalin A, leptin and ghrelin. Meanwhile, were used the following inhibitors: AG490, a JAK2 inhibitor; PD98059, a MEK/ERK inhibitor; and LY294002, a PI3K/Akt signaling inhibitor. When we analyzed the results, we observed that the conditioned medium, obtained from mesenchymal stem cells cultivation, applied in a 10% concentration for 24 H , induced apoptosis of endothelial progenitor cells in different degrees: 10 �M leptin] ghrelin]]concanavalin A @ apelin. Furthermore, LY294002 and AG490-conditioned medium of mesenchymal stem cells reduced the apoptotic effects induced by leptin on developed endothelial progenitor cells. The very first conclusion is that the inhibition of PI3K/Akt signaling pathway is blocking the apoptotic effects of leptin stimulation of mesenchymal stem cells population. The inhibition of JAK/STAT pathways seems to be less effective.
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