title: Rat BMSCs initiate retinal endogenous repair through NGF/TrkA signaling.
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.
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jian
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: yaocli@yahoo.com.
authors.forename: Yaochen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: qinzyin@aliyun.com.
authors.forename: Zheng Qin
authors.initials: ZQ
authors.lastname: Yin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D063928:Ependymoglial Cells / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D020932:Nerve Growth Factor / Q000502:physiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020917:Receptor, trkA / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D015398:Signal Transduction / Q000502:physiology*; D014796:Visual Perception / Q000502:physiology
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: Bone marrow mesenchymal stem cells; Cell transplantation; Dedifferentiation; Endogenous progenitor cells; Müller cells; NGF/TrkA signaling; Retinitis pigmentosa