Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke

In vitro evidence of expedited neuronal differentiation and GDNF secretion

Koichi Hara, Noriyuki Matsukawa, Takao Yasuhara, Lin Xu, Guolong Yu, Mina Maki, Takeshi Kawase, David C Hess, Seung U. Kim, Cesar V. Borlongan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.

Original languageEnglish (US)
Pages (from-to)1240-1251
Number of pages12
JournalJournal of Neuroscience Research
Volume85
Issue number6
DOIs
StatePublished - May 1 2007

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Glial Cell Line-Derived Neurotrophic Factor
Transplantation
Stroke
Therapeutics
Nestin
In Vitro Techniques
Corpus Striatum
Nerve Growth Factors
Tyrosine 3-Monooxygenase
Neurologic Manifestations
Tretinoin
Neuroglia
Sprague Dawley Rats

Keywords

  • Gene expression
  • Ischemia
  • Neuronal differentiation
  • Regeneration
  • Transplantation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke : In vitro evidence of expedited neuronal differentiation and GDNF secretion. / Hara, Koichi; Matsukawa, Noriyuki; Yasuhara, Takao; Xu, Lin; Yu, Guolong; Maki, Mina; Kawase, Takeshi; Hess, David C; Kim, Seung U.; Borlongan, Cesar V.

In: Journal of Neuroscience Research, Vol. 85, No. 6, 01.05.2007, p. 1240-1251.

Research output: Contribution to journalArticle

Hara, Koichi ; Matsukawa, Noriyuki ; Yasuhara, Takao ; Xu, Lin ; Yu, Guolong ; Maki, Mina ; Kawase, Takeshi ; Hess, David C ; Kim, Seung U. ; Borlongan, Cesar V. / Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke : In vitro evidence of expedited neuronal differentiation and GDNF secretion. In: Journal of Neuroscience Research. 2007 ; Vol. 85, No. 6. pp. 1240-1251.
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AU - Matsukawa, Noriyuki

AU - Yasuhara, Takao

AU - Xu, Lin

AU - Yu, Guolong

AU - Maki, Mina

AU - Kawase, Takeshi

AU - Hess, David C

AU - Kim, Seung U.

AU - Borlongan, Cesar V.

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AB - Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.

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