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Da-Jeong Chang,
Nayeon Lee,
Chunggab Choi, Iksoo Jeon,
Seung-Hun Oh,
Dong Ah Shin,
Tae-Sun Hwang,
Hong J Lee,
Seung U Kim,
Hyeyoung Moon,
Kwan Soo Hong,
Kyung-Sun Kang,
Jihwan Song
[show abstract]
[hide abstract]
ABSTRACT: Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the strokedamaged patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contra-lateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contra-laterally transplanted neural stem cells were migrated to the peri-infarct area, showing a patho-tropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were co-localized with Nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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Da-Jeong Chang,
Nayeon Lee,
In-Hyun Park,
Chunggab Choi, Iksoo Jeon,
Jihye Kwon,
Seung-Hun Oh,
Dong Ah Shin,
Jeong Tae Do,
Dong Ryul Lee,
Hyunseung Lee,
Hyeyoung Moon,
Kwan Soo Hong,
George Q Daley,
Jihwan Song
[show abstract]
[hide abstract]
ABSTRACT: Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) is the major type of stroke, but there are currently very limited therapeutic options for its cure. Neural stem cells (NSCs) or neural precursor cells (NPCs) derived from various sources are known to survive and improve neurological functions when they are engrafted in animal models of stroke. Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients are novel cells that promise the autologous cell therapy for stroke. In this study, we successfully differentiated iPSCs derived from human fibroblasts into NPCs and found their robust therapeutic potential in a rodent MCAo stroke model. We observed the significant graftinduced behavioral recovery, as well as extensive neural tissue formation. Animal MRI results indicated that the majority of contra-laterally transplanted iPSC-derived NPCs migrated to the peri-infarct area, showing a patho-tropism critical for tissue recovery. The transplanted animals exhibited the significant reduction of stroke-induced inflammatory response, gliosis and apoptosis, and the contribution to the endogenous neurogenesis. Our results demonstrate that iPSC-derived NPCs are effective cells for the treatment of stroke.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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Jung-Il Chae,
Dong-Wook Kim,
Nayeon Lee,
Young-Joo Jeon, Iksoo Jeon,
Jihye Kwon,
Jumi Kim,
Yunjo Soh,
Dong-Seok Lee,
Kang Seok Seo, [......],
Byoung Chul Park,
Sung Hyun Kang,
Joohyun Ryu,
Seung-Hun Oh,
Dong Ah Shin,
Dong Ryul Lee,
Jeong Tae Do,
In-Hyun Park,
George Q Daley,
Jihwan Song
[show abstract]
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ABSTRACT: HD (Huntington's disease) is a devastating neurodegenerative genetic disorder caused by abnormal expansion of CAG repeats in the HTT (huntingtin) gene. We have recently established two iPSC (induced pluripotent stem cell) lines derived from a HD patient carrying 72 CAG repeats (HD-iPSC). In order to understand the proteomic profiles of HD-iPSCs, we have performed comparative proteomic analysis among normal hESCs (human embryonic stem cells; H9), iPSCs (551-8) and HD-iPSCs at undifferentiated stages, and identified 26 up- and down-regulated proteins. Interestingly, these differentially expressed proteins are known to be involved in different biological processes, such as oxidative stress, programmed cell death and cellular oxygen-associated proteins. Among them, we found that oxidative stress-related proteins, such as SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families are particularly affected in HD-iPSCs, implying that HD-iPSCs are highly susceptible to oxidative stress. We also found that BTF3 (basic transcription factor 3) is up-regulated in HD-iPSCs, which leads to the induction of ATM (ataxia telangiectasia mutated), followed by activation of the p53-mediated apoptotic pathway. In addition, we observed that the expression of cytoskeleton-associated proteins was significantly reduced in HD-iPSCs, implying that neuronal differentiation was also affected. Taken together, these results demonstrate that HD-iPSCs can provide a unique cellular disease model system to understand the pathogenesis and neurodegeneration mechanisms in HD, and the identified proteins from the present study may serve as potential targets for developing future HD therapeutics.
Biochemical Journal 06/2012; 446(3):359-71. · 4.90 Impact Factor
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Iksoo Jeon,
Nayeon Lee,
Jia-Yi Li,
In-Hyun Park,
Kyoung Sun Park,
Jisook Moon,
Sung Han Shim,
Chunggab Choi,
Da-Jeong Chang,
Jihye Kwon,
Seung-Hun Oh,
Dong Ah Shin,
Hyun Sook Kim,
Jeong Tae Do,
Dong Ryul Lee,
Manho Kim,
Kyung-Sun Kang,
George Q Daley,
Patrik Brundin,
Jihwan Song
[show abstract]
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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 05/2012; 30(9):2054-62. · 7.78 Impact Factor
