title: Transplantation of bone marrow stromal cell-derived neural precursor cells ameliorates deficits in a rat model of complete spinal cord transection.
abstract: After severe spinal cord injury, spontaneous functional recovery is limited. Numerous studies have demonstrated cell transplantation as a reliable therapeutic approach. However, it remains unknown whether grafted neuronal cells could replace lost neurons and reconstruct neuronal networks in the injured spinal cord. To address this issue, we transplanted bone marrow stromal cell-derived neural progenitor cells (BM-NPCs) in a rat model of complete spinal cord transection 9 days after the injury. BM-NPCs were induced from bone marrow stromal cells (BMSCs) by gene transfer of the Notch-1 intracellular domain followed by culturing in the neurosphere method. As reported previously, BM-NPCs differentiated into neuronal cells in a highly selective manner in vitro. We assessed hind limb movements of the animals weekly for 7 weeks to monitor functional recovery after local injection of BM-NPCs to the transected site. To test the sensory recovery, we performed functional magnetic resonance imaging (fMRI) using electrical stimulation of the hind limbs. In the injured spinal cord, transplanted BM-NPCs were confirmed to express neuronal markers 7 weeks following the transplantation. Grafted cells successfully extended neurites beyond the transected portion of the spinal cord. Adjacent localization of synaptophysin and PSD-95 in the transplanted cells suggested synaptic formations. These results indicated survival and successful differentiation of BM-NPCs in the severely injured spinal cord. Importantly, rats that received BM-NPCs demonstrated significant motor recovery when compared to the vehicle injection group. Volumes of the fMRI signals in somatosensory cortex were larger in the BM-NPC-grafted animals. However, neuronal activity was diverse and not confined to the original hind limb territory in the somatosensory cortex. Therefore, reconstruction of neuronal networks was not clearly confirmed. Our results indicated BM-NPCs as an effective method to deliver neuronal lineage cells in a severely injured spinal cord. However, reestablishment of neuronal networks in completed transected spinal cord was still a challenging task.
authors.affiliation: Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Aizawa-Kohama
authors.forename: Toshiki
authors.initials: T
authors.lastname: Endo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kitada
authors.forename: Shohei
authors.initials: S
authors.lastname: Wakao
authors.forename: Akira
authors.initials: A
authors.lastname: Sumiyoshi
authors.forename: Dai
authors.initials: D
authors.lastname: Matsuse
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Morita
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Riera
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kawashima
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000473:pathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods; D017154:Stromal Cells / Q000166:cytology / Q000637:transplantation*