Dataset Information

Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington's disease mouse model.

ABSTRACT:

Objectives

To investigate whether human HLA-homozygous induced pluripotent stem cell (iPSC)-derived neural precursor cells (iPSC-NPCs) can provide functional benefits in Huntington's disease (HD), we transplanted them into the YAC128 transgenic HD mouse model.

Materials and methods

CHAi001-A, an HLA-homozygous iPSC line (A*33:03-B*44:03-DRB1*13:02), was differentiated into neural precursor cells, and then, they were transplanted into 6 months-old YAC128 mice. Various behavioural and histological analyses were performed for five months after transplantation.

Results

Motor and cognitive functions were significantly improved in transplanted animals. Cells transplanted in the striatum showed multipotential differentiation. Five months after transplantation, the donor cells had differentiated into neurons, oligodendrocytes and astrocytes. Transplantation restored DARPP-32 expression, synaptophysin density, myelin basic protein expression in the corpus callosum and astrocyte function.

Conclusion

Altogether, these results strongly suggest that iPSC-NPCs transplantation induces neuroprotection and functional recovery in a mouse model of HD and should be taken forward for clinical trials in HD patients.

SUBMITTER: Park HJ

PROVIDER: S-EPMC8349664 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington's disease mouse model.

Park Hyun Jung HJ Jeon Juhyun J Choi Jiwoo J Kim Ji Yeon JY Kim Hyun Sook HS Huh Ji Young JY Goldman Steven A SA Song Jihwan J

Cell proliferation 20210621 8

<h4>Objectives</h4>To investigate whether human HLA-homozygous induced pluripotent stem cell (iPSC)-derived neural precursor cells (iPSC-NPCs) can provide functional benefits in Huntington's disease (HD), we transplanted them into the YAC128 transgenic HD mouse model.<h4>Materials and methods</h4>CHAi001-A, an HLA-homozygous iPSC line (A*33:03-B*44:03-DRB1*13:02), was differentiated into neural precursor cells, and then, they were transplanted into 6 months-old YAC128 mice. Various behavioural a ...[more]

PMID: 34152047

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Project description:Huntington's disease (HD) is a devastating monogenic, dominant, hereditary, neurodegenerative disease. HD is caused by the expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene, IT15, resulting in an expanded polyglutamine (polyQ) residue in the N-terminus of the HTT protein. HD is characterized by the accumulation of mutant HTT (mHTT) in neural and somatic cells. Progressive brain atrophy occurs initially in the striatum and extends to different brain regions with progressive decline in cognitive, behavioral and motor functions. Astrocytes are the most abundant cell type in the brain and play an essential role in neural development and maintaining homeostasis in the central nervous system (CNS). There is increasing evidence supporting the involvement of astrocytes in the development of neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We have generated neural progenitor cells (NPCs) from induced pluripotent stem cells (iPSCs) of transgenic HD monkeys as a model for studying HD pathogenesis. We have reported that NPCs can be differentiated in vitro into mature neural cells, such as neurons and glial cells, and are an excellent tool to study the pathogenesis of HD. To better understand the role of astrocytes in HD pathogenesis and discover new therapies to treat HD, we have developed an astrocyte differentiation protocol and evaluated the efficacy of RNAi to ameliorate HD phenotypes in astrocytes. The resultant astrocytes expressed canonical astrocyte-specific markers examined by immunostaining and real-time PCR. Flow cytometry (FACS) analysis showed that the majority of the differentiated NPCs (95.7%) were positive for an astrocyte specific marker, glial fibrillary acidic protein (GFAP). Functionalities of astrocytes were evaluated by glutamate uptake assay and electrophysiology. Expression of mHTT in differentiated astrocytes induced cytosolic mHTT aggregates and nuclear inclusions, suppressed the expression of SOD2 and PGC1, reduced ability to uptake glutamate, decreased 4-aminopyridine (4-AP) response, and shifted I/V plot measured by electrophysiology, which are consistent with previous reports on HD astrocytes and patient brain samples. However, expression of small-hairpin RNA against HTT (shHD) ameliorated and reversed aforementioned HD phenotypes in astrocytes. This represents a demonstration of a novel non-human primate (NHP) astrocyte model for studying HD pathogenesis and a platform for discovering novel HD treatments.

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.

Dataset Information

Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington's disease mouse model.

Objectives

Materials and methods

Results

Conclusion

Publications

Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington's disease mouse model.

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