title: Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates.
abstract: : Previous studies have demonstrated that neural stem/progenitor cells (NS/PCs) promote functional recovery in rodent animal models of spinal cord injury (SCI). Because distinct differences exist in the neuroanatomy and immunological responses between rodents and primates, it is critical to determine the effectiveness and safety of allografted embryonic stem cell (ESC)-derived NS/PCs (ESC-NS/PCs) in a nonhuman primate SCI model. In the present study, common marmoset ESC-NS/PCs were grafted into the lesion epicenter 14 days after contusive SCI in adult marmosets (transplantation group). In the control group, phosphate-buffered saline was injected instead of cells. In the presence of a low-dose of tacrolimus, several grafted cells survived without tumorigenicity and differentiated into neurons, astrocytes, or oligodendrocytes. Significant differences were found in the transverse areas of luxol fast blue-positive myelin sheaths, neurofilament-positive axons, corticospinal tract fibers, and platelet endothelial cell adhesion molecule-1-positive vessels at the lesion epicenter between the transplantation and control groups. Immunoelectron microscopic examination demonstrated that the grafted ESC-NS/PC-derived oligodendrocytes contributed to the remyelination of demyelinated axons. In addition, some grafted neurons formed synaptic connections with host cells, and some transplanted neurons were myelinated by host cells. Eventually, motor functional recovery significantly improved in the transplantation group compared with the control group. In addition, a mixed lymphocyte reaction assay indicated that ESC-NS/PCs modulated the allogeneic immune rejection. Taken together, our results indicate that allogeneic transplantation of ESC-NS/PCs from a nonhuman primate promoted functional recovery after SCI without tumorigenicity.
  
  
  CONCLUSIONS
  This study demonstrates that allogeneic embryonic stem cell (ESC)-derived neural stem/progenitor cells (NS/PCs) promoted functional recovery after transplantation into the injured spinal cord in nonhuman primates. ESC-NS/PCs were chosen because ESC-NS/PCs are one of the controls for induced pluripotent stem cell-derived NS/PCs and because ESC derivatives are possible candidates for clinical use. This translational research using an allograft model of a nonhuman primate is critical for clinical application of grafting NS/PCs derived from various allogeneic pluripotent stem cells, especially induced pluripotent stem cells, into injured spinal cord at the subacute phase.
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwai
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Soraya
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Yoshiomi
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Itakura
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hori
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Hikishima
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Hayao
authors.initials: H
authors.lastname: Ebise
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Negishi
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Habu
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan hidokano@a2.keio.jp masa@a8.keio.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan; Central Institute for Experimental Animals, Kawasaki, Japan; Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan; Department of Immunology, Juntendo University, Tokyo, Japan hidokano@a2.keio.jp masa@a8.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
keywords: Allograft; Cell transplantation; Embryonic stem cells; Neural stem cells; Primates; Spinal cord injury