title: γ-secretase inhibitors prevent overgrowth of transplanted neural progenitors derived from human-induced pluripotent stem cells.
abstract: Although transplanted pluripotent stem cell-derived neurons can contribute to functional recovery in animal models of Parkinson's disease, the risk of tumor formation hinders clinical applications of this approach. Removing undifferentiated cells from the donor population is critical to reduce tumorigenesis. Moreover, immature neural progenitors in transplants can proliferate unpredictably, resulting in neural overgrowth and long-term risks of compressing the surrounding host tissue. Because Notch signaling plays a role in maintaining the multipotency and proliferative capacity of neural progenitors, we used γ-secretase inhibitors (GSIs) to dampen Notch signaling in human-induced pluripotent stem cell-derived neural progenitors before transplantation and examined the effects on the growth of proliferative grafts. We observed a marked reduction in the percentage of dividing cells and increased neuronal maturation in GSI-treated samples in vitro. Next, grafts were transplanted into the striata of nonobese diabetic/severe combined immune deficiency mice. Histological analyses performed 8 weeks after the operation showed that grafts pretreated with GSIs--N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester or compound E--were significantly smaller than control samples. Immunohistologic analyses revealed that briefly treating the donor population with GSIs not only reduced the graft volume, but also altered the composition of the graft; control grafts showed neural overgrowth with numerous PAX6+ and Ki67+ neural rosettes, whereas GSI-treated samples developed into mature neuronal grafts containing primarily Tubβ3+ cells. These results suggest that pretreating potentially proliferative progenitors with GSIs may improve the safety of cell replacement therapies using pluripotent stem cells.
authors.affiliation: Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ogura
authors.forename: Asuka
authors.initials: A
authors.lastname: Morizane
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058953:Neural Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000637:transplantation
chemical_list: C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases