Transplantation of tissue engineering neural network and formation of neuronal relay into the transected rat spinal cord.
Severe spinal cord injury (SCI) causes loss of neural connectivity and permanent functional deficits. Re-establishment of new neuronal relay circuits after SCI is therefore of paramount importance. The present study tested our hypothesis if co-culture of neurotrophin-3 (NT-3) gene-modified Schwann cells (SCs, NT-3-SCs) and TrkC (NT-3 receptor) gene-modified neural stem cells (NSCs, TrkC-NSCs) in a gelatin sponge scaffold could construct a tissue engineering neural network for re-establishing an anatomical neuronal relay after rat spinal cord transection. Eight weeks after transplantation, the neural network created a favorable microenvironment for axonal regeneration and for survival and synaptogenesis of NSC-derived neurons. Biotin conjugates of cholera toxin B subunit (b-CTB, a transneuronal tracer) was injected into the crushed sciatic nerve to label spinal cord neurons. Remarkably, not only ascending and descending nerve fibers, but also propriospinal neurons, made contacts with b-CTB positive NSC-derived neurons. Moreover, b-CTB positive NSC-derived neurons extended their axons making contacts with the motor neurons located in areas caudal to the injury/graft site of spinal cord. Further study showed that NT-3/TrkC interactions activated the PI3K/AKT/mTOR pathway and PI3K/AKT/CREB pathway affecting synaptogenesis of NSC-derived neurons. Together, our findings suggest that NT-3-mediated TrkC signaling plays an essential role in constructing a tissue engineering neural network thus representing a promising avenue for effective exogenous neuronal relay-based treatment for SCI.
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Bi-Qin
BQ
Lai
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Ming-Tian
MT
Che
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Bao-Ling
BL
Du
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Xiang
X
Zeng
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Yuan-Huan
YH
Ma
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Bo
B
Feng
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
Xue-Chen
XC
Qiu
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Ke
K
Zhang
Department of Human Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Shu
S
Liu
Institute of Spinal Cord Injury, Sun Yat-sen University, Guangzhou, 510120, China; Department of Orthopedics of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Hui-Yong
HY
Shen
Department of Electron Microscope, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Jin-Lang
JL
Wu
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Eng-Ang
EA
Ling
Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China; Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China; Institute of Spinal Cord Injury, Sun Yat-sen University, Guangzhou, 510120, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: zengysh@mail.sysu.edu.cn.
Yuan-Shan
YS
Zeng
D000818:Animals; D001369:Axons / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival; D002772:Cholera Toxin / Q000378:metabolism; D018920:Coculture Techniques; D009412:Nerve Fibers / Q000378:metabolism; D009415:Nerve Net / Q000473:pathology; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D009474:Neurons / Q000473:pathology*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000637:transplantation*; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000628:therapy*; D023822:Tissue Engineering; D054457:Tissue Scaffolds
D020933:Neurotrophin 3; D002772:Cholera Toxin; D019869:Phosphatidylinositol 3-Kinases; D020812:Receptor, trkC
Neuronal relay; Neurotrophin-3; Spinal cord injury; Synaptogenesis; Tissue engineering neural network; TrkC pathway