Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

Yasuhara, Takao; Matsukawa, Noriyuki; Hara, Koichi; Yu, Guangli; Xu, Lin; Maki, Mina; Kim, Seung Up; Borlongan, Cesario V.

doi:10.1523/jneurosci.3719-06.2006

Cited by 257 publications

(213 citation statements)

References 108 publications

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“…Successful outcomes of neural stem cell grafts in restoration of function after 6-OHDA-induced nigrostriatal degeneration has been attributed to a combination of neural differentiation and trophic factor production (Yasuhara, Matsukawa et al 2006) in large part based on the observation that a large fraction of adult neural stem cells within transplanted grafts retain detectable nestin expression and never fully mature post-transplantation. Likewise, the in vivo neuroprotective effects of other cell types with demonstrated in vitro multi-lineage potential, including mesenchymal stem cells (MSC) (Scuteri, Cassetti et al 2006), umbilical cord matrix stem cells (Weiss, Medicetty et al 2006), and bone marrow derived stromal cells (BMSCs) (Garcia, Aguiar et al 2004;Carvey, Chen et al 2005;Ye, Chen et al 2005), has been shown to be mediated in part through a mechanism of trophic support.…”

Section: Discussionmentioning

confidence: 99%

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

McCoy

Martinez

Ruhn

et al. 2008

Experimental Neurology

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Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1-week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.

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Section: Discussionmentioning

confidence: 99%

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

McCoy

Martinez

Ruhn

et al. 2008

Experimental Neurology

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“…Thus, in contrast to e-15 Gcgr ϩ/ϩ and PC2 ϩ/ϩ embryos, nestin ϩ cells do not disappear during midgestation but, rather, were abundant in pancreas of e-15 Gcgr Ϫ/Ϫ embryos and a significant number of these cells were IN ϩ or GLU ϩ ( Fig. 2A and B (Koso et al, 2007;Yasuhara et al, 2006) suggests that the pattern of nestin staining is determined by the cellular environment. Cells in vitro that are attached to a surface have filamentous staining while those in vivo show uniformal cytoplasmic staining.…”

Section: Transient Expression Of Nestin By Endocrine Cells Of Mutant mentioning

confidence: 92%

Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling

Kedees¹,

Guz²,

Vuguin³

et al. 2007

Developmental Dynamics

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Nestin, a marker of neural stem cells, is also expressed by cells located in the epithelium of the pancreatic primordium and by a subpopulation of exocrine cells but not by endocrine cells. These findings raised the possibility that the pancreatic epithelium is heterogeneous and comprised of subpopulations of exocrine/ nestin-positive and endocrine/nestin-negative precursor cells. We examined this issue in two mutant mouse models characterized by protracted expression of several embryonal properties in islet cells. One mutant line comprises mice lacking mature glucagon due to abrogation of proprotein convertase-2 (PC2 ؊/؊ ), responsible for the conversion of proglucagon into glucagon, while the second line consists of mice with a global deletion of the glucagon receptor (Gcgr ؊/؊ ). We demonstrate that nestin is transiently expressed by acinar cells and by insulin and glucagon cells of islets of both lines of mice. In addition, the lack of glucagon signaling increased nestin mRNA levels in pancreas of mutant embryos and adult mice. We conclude that nestin؉ cells located in the pancreatic primordium generate the cells of the endocrine and exocrine lineages. Furthermore, our results suggest that nestin expression is regulated by glucagon signaling.

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“…While brain injury has been shown to trigger transient and limited neurogenesis, this endogenous protective mechanism is not capable of reversing the cell death cascade in the CNS. It is, however, recognized that strategies designed to enhance the endogenous neurogenesis are potentially beneficial for treating brain disorders (Borlongan et al, 2011; Borlongan, 2011; Hess & Borlongan, 2008a; Yasuhara et al, 2006). Regenerative medicine has emerged as a new scientific field advancing stem cell therapy for treating brain disorders, with emphasis on either transplanting exogenous stem cells or amplifying endogenous stem cells via neurogenesis (Hess & Borlongan, 2008b; Picard‐Riera, Nait‐Oumesmar, & Baron‐Van Evercooren, 2004).…”

Section: Introductionmentioning

confidence: 99%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI‐189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti‐depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, 2016, ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI‐189 in adult Sprague–Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke‐induced motor and neurological deficits, which was maintained up to 24 weeks post‐stroke. Histopathological assessment of stroke brains from NSI‐189‐treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI‐189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI‐189 treatment characterized by significant attenuation of OGD/R‐mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI‐189 as a therapeutic agent well beyond the initial 6‐hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

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Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

Cited by 257 publications

References 108 publications

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

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