title: The effect of growth factors and soluble Nogo-66 receptor protein on transplanted neural stem/progenitor survival and axonal regeneration after complete transection of rat spinal cord.
abstract: Adult central mammalian axons show minimal regeneration after spinal cord injury due to loss of oligodendrocytes, demyelination of surviving axons, absence of growth-promoting molecules, and inhibitors of axonal outgrowth. In the present study, we attempted to address these impediments  to regeneration by using a combinatory strategy to enhance cell survival and regeneration after complete spinal cord transection (SCT) in adult rats. The strategy comprised: 1) adult rat brain-derived neural stem/progenitor cells (NSPCs) preseeded on laminin-coated chitosan channels; 2) extramedullary  chitosan channels to promote axonal regrowth and reduce the barrier caused by scarring; 3) local delivery of a novel rat soluble Nogo-66 receptor protein [NgR(310)ecto-Fc, referred to as NgR] to block the inhibitory effect of myelin-based inhibitors; and 4) local delivery of basic fibroblast  growth factor, epidermal growth factor, and platelet-derived growth factor to enhance survival and promote differentiation of transplanted cells. Compared with our previous studies where brain-derived NSPCs preseeded in extramedullary chitosan channels were implanted in the same SCT model  but without growth factors and NgR, the present channel-growth factor combination produced greater numbers of surviving NSPCs after SCT. Also, the growth factors promoted preferential differentiation of NSPCs toward oligodendrocytes, while NgR significantly decreased astrocytic differentiation  of NSPCs. NgR alone or in combination with NSPCs significantly enhanced the total number of myelinated fibers in the bridge and increased the area of the bridging tissue between the cord stumps. The combination of NgR, growth factors, and NSPCs had synergistic effect on bridge formation. However,  only a small number of descending corticospinal tract axons grew into the central portions of the bridges as shown by anterograde tracing of the corticospinal tract with BDA. The majority of the regenerated axons in the channels originated from local host neurons adjacent to the tissue bridges.  In conclusion, we showed that growth factors increased survival of transplanted NSPCs whereas NgR enhanced axonal regeneration, but the combination did not have additive effects on functional recovery or regeneration.
authors.affiliation: Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Guo
authors.forename: Tasneem
authors.initials: T
authors.lastname: Zahir
authors.forename: Andrea
authors.initials: A
authors.lastname: Mothe
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Katayama
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002454:Cell Differentiation; D048271:Chitosan / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000502:physiology; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D000070816:Nogo Receptor 1; D009836:Oligodendroglia / Q000166:cytology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: D058851:GPI-Linked Proteins; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C486581:Rtn4r protein, rat; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D048271:Chitosan