%0 Generic %1 B.M.2016 %A B.M., Hiller %A D.J., Marmion %A J.P., Cioni %A M.L., Russo %A J.H., Kordower %B Cell Transplantation %D 2016 %K *Macaca_fascicularis *corpus_striatum *induced_pluripotent_stem_cell *mesencephalon *nerve_cell *transgenic_mouse Huntington_chorea Parkinson_disease Rowett_nude_rat animal_experiment animal_model animal_tissue cell_proliferation controlled_study cryopreservation disease_model endogenous_compound engraftment fetus fetus_cell fiber gene_expression_profiling genetic_polymorphism graft_survival human_versus_animal_comparison immunohistochemistry in_vitro_study in_vivo_culture injection mouse nonhuman parenchyma phenotype preclinical_study protein_expression rat safety thawing wild_type %T Cryopreserved iPSC-derived forebrain neurons survive in the rodent and macaque midbrain %X Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive cognitive and motor decline caused by expansion of CAG trinucleotide repeats, which induces the synthesis and aggregation of huntingtin. There are currently no treatments available for HD. As such, the development of a viable therapy is imperative. Preclinical studies have indicated that transplantation of fetal neurons may provide transient functional benefit in animal models, although this has not been convincingly demonstrated in HD patients. Induced pluripotent stem cells (iPSCs) hold great promise for treating a variety of neurological disorders such as Parkinson's disease and hold many advantages over fetal cells. Further, the cryopreservation of postmitotic neurons derived from iPSCs represents a significant vertical advancement for clinical translation of pluripotent stem cell technologies as they are reliably and reproducibly thawed, allowing for rapid access to large numbers of highly pure, patient-specific cells. In the present study, we examined the engraftment potential of iPSC-derived forebrain lineage neurons (iCell Neurons) after transplantation into the rodent and nonhuman primate brain. iCell Neurons were derived from human blood samples via episomal reprogramming and forebrain patterning then cryopreserved in large master cell banks. After thawing, iCell Neurons retained high viability (75\%) and maintained gene and protein expression profiles consistent with the g-aminobutyric acid (GABA)ergic and glutamatergic phenotypes in vitro. To determine in vivo survival, cryopreserved iCell Neurons were thawed and prepared for transplantation without manipulation or additional subculturing. iCell Neurons were injected bilaterally into the striatum of athymic-Rowett nude (RNU) rats (4.5 x 105 cells/hemisphere; one injection/hemisphere), transgenic R6/2 (CAG120) HD and wild-type littermate mice (3 x 105 cells/hemisphere; one injection/hemisphere), and cynomolgus macaques (3.75 x 106 cells/ hemisphere; three injections/hemisphere). Rats were sacrificed at 3 or 9 months posttransplantation, and mice and monkeys were sacrificed at 5 weeks posttransplantation. Immunohistochemistry indicated robust graft survival and maintenance of neuronal phenotypes with extensive fiber outgrowth into the host parenchyma. Importantly, there was little to no cell proliferation, indicating safety in our initial studies. Future studies will be designed to ascertain whether cryopreserved iCell Neurons will provide functional benefit in transgenic mouse models of HD. %@ 0963-6897

@misc{B.M.2016, abstract = {Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive cognitive and motor decline caused by expansion of CAG trinucleotide repeats, which induces the synthesis and aggregation of huntingtin. There are currently no treatments available for HD. As such, the development of a viable therapy is imperative. Preclinical studies have indicated that transplantation of fetal neurons may provide transient functional benefit in animal models, although this has not been convincingly demonstrated in HD patients. Induced pluripotent stem cells (iPSCs) hold great promise for treating a variety of neurological disorders such as Parkinson's disease and hold many advantages over fetal cells. Further, the cryopreservation of postmitotic neurons derived from iPSCs represents a significant vertical advancement for clinical translation of pluripotent stem cell technologies as they are reliably and reproducibly thawed, allowing for rapid access to large numbers of highly pure, patient-specific cells. In the present study, we examined the engraftment potential of iPSC-derived forebrain lineage neurons (iCell Neurons) after transplantation into the rodent and nonhuman primate brain. iCell Neurons were derived from human blood samples via episomal reprogramming and forebrain patterning then cryopreserved in large master cell banks. After thawing, iCell Neurons retained high viability (75{\%}) and maintained gene and protein expression profiles consistent with the g-aminobutyric acid (GABA)ergic and glutamatergic phenotypes in vitro. To determine in vivo survival, cryopreserved iCell Neurons were thawed and prepared for transplantation without manipulation or additional subculturing. iCell Neurons were injected bilaterally into the striatum of athymic-Rowett nude (RNU) rats (4.5 x 105 cells/hemisphere; one injection/hemisphere), transgenic R6/2 (CAG120) HD and wild-type littermate mice (3 x 105 cells/hemisphere; one injection/hemisphere), and cynomolgus macaques (3.75 x 106 cells/ hemisphere; three injections/hemisphere). Rats were sacrificed at 3 or 9 months posttransplantation, and mice and monkeys were sacrificed at 5 weeks posttransplantation. Immunohistochemistry indicated robust graft survival and maintenance of neuronal phenotypes with extensive fiber outgrowth into the host parenchyma. Importantly, there was little to no cell proliferation, indicating safety in our initial studies. Future studies will be designed to ascertain whether cryopreserved iCell Neurons will provide functional benefit in transgenic mouse models of HD.}, added-at = {2019-06-18T22:58:43.000+0200}, author = {B.M., Hiller and D.J., Marmion and J.P., Cioni and M.L., Russo and J.H., Kordower}, biburl = {https://www.bibsonomy.org/bibtex/2954fbffc5606b3ffdc30106e5b2011ef/fcdi}, booktitle = {Cell Transplantation}, interhash = {de1f33bdb21c74095c1dc13da4b04726}, intrahash = {954fbffc5606b3ffdc30106e5b2011ef}, isbn = {0963-6897}, keywords = {*Macaca_fascicularis *corpus_striatum *induced_pluripotent_stem_cell *mesencephalon *nerve_cell *transgenic_mouse Huntington_chorea Parkinson_disease Rowett_nude_rat animal_experiment animal_model animal_tissue cell_proliferation controlled_study cryopreservation disease_model endogenous_compound engraftment fetus fetus_cell fiber gene_expression_profiling genetic_polymorphism graft_survival human_versus_animal_comparison immunohistochemistry in_vitro_study in_vivo_culture injection mouse nonhuman parenchyma phenotype preclinical_study protein_expression rat safety thawing wild_type}, timestamp = {2019-06-18T22:58:43.000+0200}, title = {{Cryopreserved iPSC-derived forebrain neurons survive in the rodent and macaque midbrain}}, year = 2016 }