Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, ce...

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Published inNature communications Vol. 7; no. 1; p. 13097
Main Authors Samata, Bumpei, Doi, Daisuke, Nishimura, Kaneyasu, Kikuchi, Tetsuhiro, Watanabe, Akira, Sakamoto, Yoshimasa, Kakuta, Jungo, Ono, Yuichi, Takahashi, Jun
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Abstract Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 + cells survive and differentiate into mDA neurons in vivo , resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 + cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients. Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
AbstractList Abstract Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 + cells survive and differentiate into mDA neurons in vivo , resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 + cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients.
Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 cells survive and differentiate into mDA neurons in vivo, resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients.
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 + cells survive and differentiate into mDA neurons in vivo , resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 + cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients. Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1+ cells survive and differentiate into mDA neurons in vivo, resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1+ cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients.
ArticleNumber 13097
Author Samata, Bumpei
Ono, Yuichi
Watanabe, Akira
Sakamoto, Yoshimasa
Takahashi, Jun
Nishimura, Kaneyasu
Doi, Daisuke
Kikuchi, Tetsuhiro
Kakuta, Jungo
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  surname: Doi
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  organization: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University
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  surname: Nishimura
  fullname: Nishimura, Kaneyasu
  organization: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University
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  surname: Kikuchi
  fullname: Kikuchi, Tetsuhiro
  organization: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University
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  surname: Watanabe
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  organization: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University
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  fullname: Kakuta, Jungo
  organization: Group for Seed Biologics, KAN Research Institute Inc
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  surname: Ono
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  surname: Takahashi
  fullname: Takahashi, Jun
  email: jbtaka@cira.kyoto-u.ac.jp
  organization: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Department of Neurosurgery, Kyoto University School of Medicine
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27739432$$D View this record in MEDLINE/PubMed
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Snippet Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson’s...
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's...
Abstract Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for...
Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker,...
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SubjectTerms 13
13/100
631/378/1689
631/532/2064
631/532/2182
692/308/2171
Animals
Antibodies
Brain research
Cell Differentiation - genetics
Cell Separation - methods
Cells, Cultured
Dopaminergic Neurons - cytology
Dopaminergic Neurons - metabolism
Female
Gene expression
Human Embryonic Stem Cells - metabolism
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells - metabolism
Macaca fascicularis
Male
Mesencephalon - cytology
Mesencephalon - metabolism
Mice, Inbred C57BL
multidisciplinary
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson Disease - therapy
Parkinson's disease
Proteins - genetics
Proteins - metabolism
Rats, Sprague-Dawley
Research centers
Science
Science (multidisciplinary)
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Stem Cell Transplantation - methods
Stem cells
Transcription factors
Transplantation, Heterologous
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Title Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1
URI https://link.springer.com/article/10.1038/ncomms13097
https://www.ncbi.nlm.nih.gov/pubmed/27739432
https://www.proquest.com/docview/1828661712
https://search.proquest.com/docview/1835417557
https://pubmed.ncbi.nlm.nih.gov/PMC5067526
https://doaj.org/article/72b25ae7a986456d8a439b751da50607
Volume 7
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