Stem cell grafting improves both motor and cognitive impairments in a genetic model of parkinson'S disease, the aphakia (ak) mouse

Jisook Moon, Hyun Seob Lee, Jun Mo Kang, Junpil Park, Amanda Leung, Sunghoi Hong, Sangmi Chung, Kwang Soo Kim

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson'S disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin-based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell-derived cells at different stages of in vitro differentiation: embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement, while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months posttransplantation. Furthermore, we found that NP cell transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase-positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation.

Original languageEnglish
Pages (from-to)1263-1279
Number of pages17
JournalCell Transplantation
Volume22
Issue number7
DOIs
Publication statusPublished - 2013 Jul 5

Fingerprint

Aphakia
Genetic Models
Stem cells
Cell Transplantation
Parkinson Disease
Stem Cells
Neurons
Mesencephalon
Embryoid Bodies
Transplantation
Dopaminergic Neurons
Animals
Animal Models
Grafts
Teratoma
Neurotoxins
Tyrosine 3-Monooxygenase
Tumors
Substantia Nigra
Embryonic Stem Cells

Keywords

  • 4-dihydroxyphenylalanine (L-DOPA)
  • 6-hydroxydopamine (6-OHDA)
  • Aphakia (ak) mouse
  • Dopaminergic neurons
  • Embryonic stem cells (ESCS)
  • L-3
  • Parkinson's disease (PD)
  • Tyrosine hydroxylase (TH)

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering

Cite this

Stem cell grafting improves both motor and cognitive impairments in a genetic model of parkinson'S disease, the aphakia (ak) mouse. / Moon, Jisook; Lee, Hyun Seob; Kang, Jun Mo; Park, Junpil; Leung, Amanda; Hong, Sunghoi; Chung, Sangmi; Kim, Kwang Soo.

In: Cell Transplantation, Vol. 22, No. 7, 05.07.2013, p. 1263-1279.

Research output: Contribution to journalArticle

Moon, Jisook ; Lee, Hyun Seob ; Kang, Jun Mo ; Park, Junpil ; Leung, Amanda ; Hong, Sunghoi ; Chung, Sangmi ; Kim, Kwang Soo. / Stem cell grafting improves both motor and cognitive impairments in a genetic model of parkinson'S disease, the aphakia (ak) mouse. In: Cell Transplantation. 2013 ; Vol. 22, No. 7. pp. 1263-1279.
@article{a3ac4c99845f4bd6a9829d61ed7fd872,
title = "Stem cell grafting improves both motor and cognitive impairments in a genetic model of parkinson'S disease, the aphakia (ak) mouse",
abstract = "Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson'S disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin-based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell-derived cells at different stages of in vitro differentiation: embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement, while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months posttransplantation. Furthermore, we found that NP cell transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase-positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation.",
keywords = "4-dihydroxyphenylalanine (L-DOPA), 6-hydroxydopamine (6-OHDA), Aphakia (ak) mouse, Dopaminergic neurons, Embryonic stem cells (ESCS), L-3, Parkinson's disease (PD), Tyrosine hydroxylase (TH)",
author = "Jisook Moon and Lee, {Hyun Seob} and Kang, {Jun Mo} and Junpil Park and Amanda Leung and Sunghoi Hong and Sangmi Chung and Kim, {Kwang Soo}",
year = "2013",
month = "7",
day = "5",
doi = "10.3727/096368912X657242",
language = "English",
volume = "22",
pages = "1263--1279",
journal = "Cell Transplantation",
issn = "0963-6897",
publisher = "Cognizant Communication Corporation",
number = "7",

}

TY - JOUR

T1 - Stem cell grafting improves both motor and cognitive impairments in a genetic model of parkinson'S disease, the aphakia (ak) mouse

AU - Moon, Jisook

AU - Lee, Hyun Seob

AU - Kang, Jun Mo

AU - Park, Junpil

AU - Leung, Amanda

AU - Hong, Sunghoi

AU - Chung, Sangmi

AU - Kim, Kwang Soo

PY - 2013/7/5

Y1 - 2013/7/5

N2 - Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson'S disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin-based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell-derived cells at different stages of in vitro differentiation: embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement, while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months posttransplantation. Furthermore, we found that NP cell transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase-positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation.

AB - Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson'S disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin-based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell-derived cells at different stages of in vitro differentiation: embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement, while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months posttransplantation. Furthermore, we found that NP cell transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase-positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation.

KW - 4-dihydroxyphenylalanine (L-DOPA)

KW - 6-hydroxydopamine (6-OHDA)

KW - Aphakia (ak) mouse

KW - Dopaminergic neurons

KW - Embryonic stem cells (ESCS)

KW - L-3

KW - Parkinson's disease (PD)

KW - Tyrosine hydroxylase (TH)

UR - http://www.scopus.com/inward/record.url?scp=84879585928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879585928&partnerID=8YFLogxK

U2 - 10.3727/096368912X657242

DO - 10.3727/096368912X657242

M3 - Article

C2 - 23031199

AN - SCOPUS:84879585928

VL - 22

SP - 1263

EP - 1279

JO - Cell Transplantation

JF - Cell Transplantation

SN - 0963-6897

IS - 7

ER -