title: Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina.
abstract: Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20 h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential.
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan. ahara@gifu-u.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Ayako
authors.initials: A
authors.lastname: Taguchi
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aoki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hatano
authors.forename: Masayuki
authors.initials: M
authors.lastname: Niwa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003864:Depression, Chemical; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013724:Teratoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control
chemical_list: D005493:Folic Acid Antagonists; D019394:Ki-67 Antigen; D050814:Octamer Transcription Factor-3; D008727:Methotrexate