Dataset Information

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

ABSTRACT: Huntington's disease (HD) is a devastating, autosomal-dominant inheritance disorder with the progressive loss of medium spiny neurons (MSNs) and corticostriatal connections in the brain. Cell replacement therapy has been proposed as a potential therapeutic strategy to treat HD. Among various types of stem cells, human-induced pluripotent stem cells (iPSCs) have received special attention to develop disease modeling and cell therapy for HD. In the present study, the therapeutic effects of neural precursor cells (NPCs) derived from a human iPSC line (1231A3-NPCs) were investigated in the quinolinic acid (QA)-lesioned rat model of HD. 1231A3-NPCs were transplanted into the ipsilateral striatum 1 week after QA lesioning, and the transplanted animals showed significant behavioral improvements for up to 12 weeks based on the staircase, rotarod, stepping, apomorphine-induced rotation, and cylinder tests. Transplanted 1231A3-NPCs also partially replaced the lost neurons, enhanced endogenous neurogenesis, reduced inflammatory responses, and reconstituted the damaged neuronal connections. Taken together, these results strongly indicate that NPCs derived from iPSCs can potentially be useful to treat HD in the future.

SUBMITTER: Yoon Y

PROVIDER: S-EPMC7530284 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

Yoon Yongwoo Y Kim Hyun Sook HS Hong Chang Pyo CP Li Endan E Jeon Iksoo I Park Hyun Jung HJ Lee Nayeon N Pei Zhong Z Song Jihwan J

Frontiers in neuroscience 20200918

Huntington's disease (HD) is a devastating, autosomal-dominant inheritance disorder with the progressive loss of medium spiny neurons (MSNs) and corticostriatal connections in the brain. Cell replacement therapy has been proposed as a potential therapeutic strategy to treat HD. Among various types of stem cells, human-induced pluripotent stem cells (iPSCs) have received special attention to develop disease modeling and cell therapy for HD. In the present study, the therapeutic effects of neural ...[more]

PMID: 33071737

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Project description:Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by neuronal loss and motor dysfunction. Although there is no effective treatment, stem cell transplantation offers a promising therapeutic strategy, but the safety and efficacy of this approach needs to be optimized. The purpose of this study was to test the potential of intra-striatal transplantation of induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) for treating HD. For this purpose, we developed mouse adenovirus-generated iPSCs, differentiated them into neural stem cells in vitro, labeled them with Hoechst, and transplanted them bilaterally into striata of 10-month old wild type (WT) and HD YAC128 mice. We assessed the efficiency of these transplanted iPS-NSCs to reduce motor deficits in YAC128 mice by testing them on an accelerating rotarod task at 1 day prior to transplantation, and then weekly for 10 weeks. Our results showed an amelioration of locomotor deficits in YAC128 mice that received iPS-NSC transplantations. Following testing, the mice were sacrificed, and their brains were analyzed using immunohistochemistry and Western blot (WB). The results from our histological examinations revealed no signs of tumors and evidence that many iPS-NSCs survived and differentiated into region-specific neurons (medium spiny neurons) in both WT and HD mice, as confirmed by co-labeling of Hoechst-labeled transplanted cells with NeuN and DARPP-32. Also, counts of Hoechst-labeled cells revealed that a higher proportion were co-labeled with DARPP-32 and NeuN in HD-, compared to WT- mice, suggesting a dissimilar differentiation pattern in HD mice. Whereas significant decreases were found in counts of NeuN- and DARPP-32-labeled cells, and for neuronal density measures in striata of HD vehicle controls, such decrements were not observed in the iPS-NSCs-transplanted-HD mice. WB analysis showed increase of BDNF and TrkB levels in striata of transplanted HD mice compared to HD vehicle controls. Collectively, our data suggest that iPS-NSCs may provide an effective option for neuronal replacement therapy in HD.

Project description:PURPOSE:While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants. PROCEDURES:Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur in ten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6 weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants. RESULTS:Implants in group 1 showed a significantly increased two-dimensional area at week 2 (p?=?0.0092), 4 (p?=?0.003), and 6 (p?=?0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1 were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance. CONCLUSIONS:ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.

Dataset Information

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

Publications

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

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