Upregulation of TrkB by forskolin facilitated survival of MSC and functional recovery of memory deficient model rats

Mesenchymal stem cells (MSCs) are effective vectors in delivering a gene of interest into degenerating brain. In ex vivo gene therapy, viability of transplanted MSCs is correlated with the extent of functional recovery. It has been reported that BDNF facilitates survival of MSCs but dividing MSCs do not express the BDNF receptor, TrkB. In this study, we found that the expression of TrkB is upregulated in human MSCs by the addition of forskolin (Fsk), an activator of adenylyl cyclase. To increase survival rate of MSCs and their secretion of tropic factors that enhance regeneration of endogenous cells, we pre-exposed hMSCs with Fsk and transduced with BDNF-adenovirus before transplantation into the brain of memory deficient rats, a degenerating brain disease model induced by ibotenic acid injection. Viability of MSCs and expression of a GABA synthesizing enzyme were increased. The pre-treatment improved learning and memory, as detected by the behavioral tests including Y-maze task and passive avoidance test. These results suggest that TrkB expression of hMSCs elevates the neuronal regeneration and efficiency of BDNF delivery for treating degenerative neurological diseases accompanying memory loss.

► TrkB expression of hMSCs were upregulated by treatment of Forskolin.
► Forskolin treatment and transduction of BDNF-adenovirus enhanced survival rate of MSCs.
► Enhanced survival of MSCs facilitated neuronal regeneration when transplanted to rats.
► MSCs expressing BDNF and TrkB promoted expression of GABA synthesizing enzyme, GAD.
► MSCs expressing TrkB improved memory behaviors when transplanted to memory loss rats.