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Neuronal Properties, In Vivo Effects, and Pathology of a Huntington's Disease Patient-Derived Induced Pluripotent Stem Cells

Jeon, Iksoo; Lee, Nayeon; Li, Jia-Yi LU ; Park, In-Hyun; Park, Kyoung Sun; Moon, Jisook; Shim, Sung Han; Choi, Chunggab; Chang, Da-Jeong and Kwon, Jihye, et al. (2012) In Stem Cells 30(9). p.2054-2062
Abstract
Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can be used to model different human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. Here, we analyzed neuronal properties of an iPSC line derived from a patient with a juvenile form of Huntington's disease (HD) carrying 72 CAG repeats (HD-iPSC). Although its initial neural inducing activity was lower than that of human embryonic stem cells, we found that HD-iPSC can give rise to GABAergic striatal neurons, the neuronal cell type that is most susceptible to degeneration in HD. We then transplanted HD-iPSC-derived neural precursors into a rat model of HD with a unilateral excitotoxic striatal lesion and... (More)
Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can be used to model different human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. Here, we analyzed neuronal properties of an iPSC line derived from a patient with a juvenile form of Huntington's disease (HD) carrying 72 CAG repeats (HD-iPSC). Although its initial neural inducing activity was lower than that of human embryonic stem cells, we found that HD-iPSC can give rise to GABAergic striatal neurons, the neuronal cell type that is most susceptible to degeneration in HD. We then transplanted HD-iPSC-derived neural precursors into a rat model of HD with a unilateral excitotoxic striatal lesion and observed a significant behavioral recovery in the grafted rats. Interestingly, during our in vitro culture and when the grafts were examined at 12 weeks after transplantation, no aggregate formation was detected. However, when the culture was treated with a proteasome inhibitor (MG132) or when the cells engrafted into neonatal brains were analyzed at 33 weeks, there were clear signs of HD pathology. Taken together, these results indicate that, although HD-iPSC carrying 72 CAG repeats can form GABAergic neurons and give rise to functional effects in vivo, without showing an overt HD phenotype, it is highly susceptible to proteasome inhibition and develops HD pathology at later stages of transplantation. These unique features of HD-iPSC will serve as useful tools to study HD pathology and develop novel therapeutics. Stem Cells 2012; 30: 20542062 (Less)
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published
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keywords
Huntington's disease, Induced pluripotent stem cells, GABAergic neurons, Quinolinic acid, Behavioral recovery, Aggregate formation
in
Stem Cells
volume
30
issue
9
pages
2054 - 2062
publisher
AlphaMed Press
external identifiers
  • wos:000307820200025
  • scopus:84864601969
ISSN
1549-4918
DOI
10.1002/stem.1135
language
English
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yes
id
6669071b-2bc2-4585-885d-e776e45967c5 (old id 3055756)
date added to LUP
2012-10-05 07:14:55
date last changed
2017-10-22 04:23:15
@article{6669071b-2bc2-4585-885d-e776e45967c5,
  abstract     = {Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can be used to model different human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. Here, we analyzed neuronal properties of an iPSC line derived from a patient with a juvenile form of Huntington's disease (HD) carrying 72 CAG repeats (HD-iPSC). Although its initial neural inducing activity was lower than that of human embryonic stem cells, we found that HD-iPSC can give rise to GABAergic striatal neurons, the neuronal cell type that is most susceptible to degeneration in HD. We then transplanted HD-iPSC-derived neural precursors into a rat model of HD with a unilateral excitotoxic striatal lesion and observed a significant behavioral recovery in the grafted rats. Interestingly, during our in vitro culture and when the grafts were examined at 12 weeks after transplantation, no aggregate formation was detected. However, when the culture was treated with a proteasome inhibitor (MG132) or when the cells engrafted into neonatal brains were analyzed at 33 weeks, there were clear signs of HD pathology. Taken together, these results indicate that, although HD-iPSC carrying 72 CAG repeats can form GABAergic neurons and give rise to functional effects in vivo, without showing an overt HD phenotype, it is highly susceptible to proteasome inhibition and develops HD pathology at later stages of transplantation. These unique features of HD-iPSC will serve as useful tools to study HD pathology and develop novel therapeutics. Stem Cells 2012; 30: 20542062},
  author       = {Jeon, Iksoo and Lee, Nayeon and Li, Jia-Yi and Park, In-Hyun and Park, Kyoung Sun and Moon, Jisook and Shim, Sung Han and Choi, Chunggab and Chang, Da-Jeong and Kwon, Jihye and Oh, Seung-Hun and Shin, Dong Ah and Kim, Hyun Sook and Do, Jeong Tae and Lee, Dong Ryul and Kim, Manho and Kang, Kyung-Sun and Daley, George Q. and Brundin, Patrik and Song, Jihwan},
  issn         = {1549-4918},
  keyword      = {Huntington's disease,Induced pluripotent stem cells,GABAergic neurons,Quinolinic acid,Behavioral recovery,Aggregate formation},
  language     = {eng},
  number       = {9},
  pages        = {2054--2062},
  publisher    = {AlphaMed Press},
  series       = {Stem Cells},
  title        = {Neuronal Properties, In Vivo Effects, and Pathology of a Huntington's Disease Patient-Derived Induced Pluripotent Stem Cells},
  url          = {http://dx.doi.org/10.1002/stem.1135},
  volume       = {30},
  year         = {2012},
}