Cargando…

Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells

Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in cla...

Descripción completa

Detalles Bibliográficos
Autores principales: Cheng, Yu-Shan, Yang, Shu, Hong, Junjie, Li, Rong, Beers, Jeanette, Zou, Jizhong, Huang, Wenwei, Zheng, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822217/
https://www.ncbi.nlm.nih.gov/pubmed/33375166
http://dx.doi.org/10.3390/cells10010008
_version_ 1783639582586175488
author Cheng, Yu-Shan
Yang, Shu
Hong, Junjie
Li, Rong
Beers, Jeanette
Zou, Jizhong
Huang, Wenwei
Zheng, Wei
author_facet Cheng, Yu-Shan
Yang, Shu
Hong, Junjie
Li, Rong
Beers, Jeanette
Zou, Jizhong
Huang, Wenwei
Zheng, Wei
author_sort Cheng, Yu-Shan
collection PubMed
description Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects.
format Online
Article
Text
id pubmed-7822217
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-78222172021-01-23 Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells Cheng, Yu-Shan Yang, Shu Hong, Junjie Li, Rong Beers, Jeanette Zou, Jizhong Huang, Wenwei Zheng, Wei Cells Article Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects. MDPI 2020-12-22 /pmc/articles/PMC7822217/ /pubmed/33375166 http://dx.doi.org/10.3390/cells10010008 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cheng, Yu-Shan
Yang, Shu
Hong, Junjie
Li, Rong
Beers, Jeanette
Zou, Jizhong
Huang, Wenwei
Zheng, Wei
Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title_full Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title_fullStr Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title_full_unstemmed Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title_short Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells
title_sort modeling cns involvement in pompe disease using neural stem cells generated from patient-derived induced pluripotent stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822217/
https://www.ncbi.nlm.nih.gov/pubmed/33375166
http://dx.doi.org/10.3390/cells10010008
work_keys_str_mv AT chengyushan modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT yangshu modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT hongjunjie modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT lirong modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT beersjeanette modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT zoujizhong modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT huangwenwei modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells
AT zhengwei modelingcnsinvolvementinpompediseaseusingneuralstemcellsgeneratedfrompatientderivedinducedpluripotentstemcells