Rat BMSCs initiate retinal endogenous repair through NGF/TrkA signaling

Exp Eye Res. 2015 Mar:132:34-47. doi: 10.1016/j.exer.2015.01.008. Epub 2015 Jan 10.

Abstract

Müller 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 Müller 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 Müller 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 Müller cells dedifferentiation, both in vivo and in vitro. Furthermore, Müller 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 Müller cells in the retinas of rBMSCs-treated rats in vivo or in Müller cells co-cultured with rBMSCs in vitro. Blocking TrkA with K-252a reduced the number of dedifferentiated Müller 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.

Keywords: Bone marrow mesenchymal stem cells; Cell transplantation; Dedifferentiation; Endogenous progenitor cells; Müller cells; NGF/TrkA signaling; Retinitis pigmentosa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Bone Marrow Cells / cytology*
  • Cell Differentiation / physiology
  • Disease Models, Animal
  • Electroretinography
  • Enzyme-Linked Immunosorbent Assay
  • Ependymoglial Cells / physiology*
  • Mesenchymal Stem Cell Transplantation*
  • Nerve Growth Factor / physiology*
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Receptor, trkA / physiology*
  • Retinitis Pigmentosa / pathology
  • Retinitis Pigmentosa / physiopathology
  • Retinitis Pigmentosa / surgery*
  • Signal Transduction / physiology*
  • Visual Perception / physiology

Substances

  • Nerve Growth Factor
  • Receptor, trkA