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Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke
OBJECTIVES: Human‐induced pluripotent stem cells (hiPSCs) are a promising cell source for treating ischaemic stroke. Although autologous hiPSCs provide the advantage of avoiding immune rejection, their practical limitations, such as substantial amount of time and costs to generate individual iPSC li...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507302/ https://www.ncbi.nlm.nih.gov/pubmed/32713053 http://dx.doi.org/10.1111/cpr.12884 |
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author | Noh, Jeong‐Eun Oh, Seung‐Hun Lee, Suji Lee, Soohyeon Kim, Young Hoon Park, Hyun Jung Ju, Ji Hyeon Kim, Hyun Sook Huh, Ji Young Song, Jihwan |
author_facet | Noh, Jeong‐Eun Oh, Seung‐Hun Lee, Suji Lee, Soohyeon Kim, Young Hoon Park, Hyun Jung Ju, Ji Hyeon Kim, Hyun Sook Huh, Ji Young Song, Jihwan |
author_sort | Noh, Jeong‐Eun |
collection | PubMed |
description | OBJECTIVES: Human‐induced pluripotent stem cells (hiPSCs) are a promising cell source for treating ischaemic stroke. Although autologous hiPSCs provide the advantage of avoiding immune rejection, their practical limitations, such as substantial amount of time and costs to generate individual iPSC lines, have hampered their widespread application in clinical settings. In this study, we investigated the therapeutic potential of neural precursor cells derived from human HLA‐homozygous induced pluripotent stem cells (hiPSC‐NPCs) following intracerebral transplantation into a rodent model of middle cerebral artery occlusion (MCAo). MATERIALS AND METHODS: We differentiated a GMP‐grade HLA‐homozygous hiPSC line (CMC‐hiPSC‐004) into neural precursor cells for transplantation into rats at the subacute stage of ischaemic stroke (ie at 7 days after the induction of MCAo). To investigate functional recovery, the transplanted animals were subjected to five behavioural tests, namely the rotarod, stepping, mNSS, staircase and apomorphine‐induced rotation tests, for up to 12 weeks, followed by histological analyses. RESULTS: We observed that the hiPSC‐NPC transplantation produced significant behavioural improvements. At 12 weeks post‐transplantation, a high proportion of transplanted cells survived and had differentiated into MAP2(+) mature neurons, GABAergic neurons and DARPP32(+) medium spiny neurons. The transplanted cells formed neuronal connections with striatal neurons in the host brain. In addition, hiPSC‐NPC transplantation gave rise to enhanced endogenous repair processes, including decreases of post‐stroke neuroinflammation and glial scar formation and an increase of proliferating endogenous neural stem cells in the subventricular zone as well as the perilesional capillary networks. CONCLUSIONS: These results strongly suggest that HLA‐homozygous hiPSC‐NPCs may be useful for treating ischaemic stroke patients. |
format | Online Article Text |
id | pubmed-7507302 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75073022020-09-28 Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke Noh, Jeong‐Eun Oh, Seung‐Hun Lee, Suji Lee, Soohyeon Kim, Young Hoon Park, Hyun Jung Ju, Ji Hyeon Kim, Hyun Sook Huh, Ji Young Song, Jihwan Cell Prolif Original Articles OBJECTIVES: Human‐induced pluripotent stem cells (hiPSCs) are a promising cell source for treating ischaemic stroke. Although autologous hiPSCs provide the advantage of avoiding immune rejection, their practical limitations, such as substantial amount of time and costs to generate individual iPSC lines, have hampered their widespread application in clinical settings. In this study, we investigated the therapeutic potential of neural precursor cells derived from human HLA‐homozygous induced pluripotent stem cells (hiPSC‐NPCs) following intracerebral transplantation into a rodent model of middle cerebral artery occlusion (MCAo). MATERIALS AND METHODS: We differentiated a GMP‐grade HLA‐homozygous hiPSC line (CMC‐hiPSC‐004) into neural precursor cells for transplantation into rats at the subacute stage of ischaemic stroke (ie at 7 days after the induction of MCAo). To investigate functional recovery, the transplanted animals were subjected to five behavioural tests, namely the rotarod, stepping, mNSS, staircase and apomorphine‐induced rotation tests, for up to 12 weeks, followed by histological analyses. RESULTS: We observed that the hiPSC‐NPC transplantation produced significant behavioural improvements. At 12 weeks post‐transplantation, a high proportion of transplanted cells survived and had differentiated into MAP2(+) mature neurons, GABAergic neurons and DARPP32(+) medium spiny neurons. The transplanted cells formed neuronal connections with striatal neurons in the host brain. In addition, hiPSC‐NPC transplantation gave rise to enhanced endogenous repair processes, including decreases of post‐stroke neuroinflammation and glial scar formation and an increase of proliferating endogenous neural stem cells in the subventricular zone as well as the perilesional capillary networks. CONCLUSIONS: These results strongly suggest that HLA‐homozygous hiPSC‐NPCs may be useful for treating ischaemic stroke patients. John Wiley and Sons Inc. 2020-07-26 /pmc/articles/PMC7507302/ /pubmed/32713053 http://dx.doi.org/10.1111/cpr.12884 Text en © 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Noh, Jeong‐Eun Oh, Seung‐Hun Lee, Suji Lee, Soohyeon Kim, Young Hoon Park, Hyun Jung Ju, Ji Hyeon Kim, Hyun Sook Huh, Ji Young Song, Jihwan Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title | Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title_full | Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title_fullStr | Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title_full_unstemmed | Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title_short | Intracerebral transplantation of HLA‐homozygous human iPSC‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
title_sort | intracerebral transplantation of hla‐homozygous human ipsc‐derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507302/ https://www.ncbi.nlm.nih.gov/pubmed/32713053 http://dx.doi.org/10.1111/cpr.12884 |
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