Rat BMSCs initiate retinal endogenous repair through NGF/TrkA signaling

Muller cells can completely repair retinal injury by acting as endogenous stem/progenitor cells in lower-order vertebrates. However, a safe and effective approach to activate progenitor potential of retinal Muller cells in higher-order vertebrates, which rarely re-enter the cell cycle, is a bottleneck problem. In the present study, Royal College of Surgeon's (RCS) rats were subjected to rat bone marrow mesenchymal stem cells (rBMSCs) subretinal space transplantation. Electroretinography (ERG) recordings showed that the b-wave amplitudes and ONL thicknesses statistically increased after transplantation. The number of Muller cells expressing proliferative, stem/progenitor and neuronal markers significantly increased after rBMSCs transplantation in vivo or after co-culturing with rBMSCs in vitro. The cultured rBMSCs could secrete nerve growth factor (NGF). In addition, we confirmed that NGF or NGF-neutralizing antibody could activate or depress Muller cells dedifferentiation, both in vivo and in vitro. Furthermore, Miner cells expressing high levels of the NGF receptor neurotrophic tyrosine kinase receptor type 1 (TrkA) were observed in the retinas of rats transplanted with rBMSCs. Moreover, the protein expression of downstream elements of NGF/TrkA signaling, such as p-PI3K, p-Akt and p-CREB, increased in Muller cells in the retinas of rBMSCs-treated rats in vivo or in Muller cells co-cultured with rBMSCs in vitro. Blocking TrkA with K-252a reduced the number of dedifferentiated Muller cells and the expression of NGF/TrkA signaling in vitro. Thus, rBMSCs might initiate endogenous regenerative mechanisms, which may constitute a new therapeutic strategy for retinal dystrophic diseases. (C) 2015 Elsevier Ltd. All rights reserved.