Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease

Bouchez, Gaëlle; Sensebé, Luc; Vourc’h, Patrick; Garreau, Lucette; Bodard, Sylvie; Rico, Angélique; Guilloteau, Denis; Charbord, Pierre; Besnard, Jean‐Claude; Chalon, Sylvie

doi:10.1016/j.neuint.2008.02.003

Cited by 141 publications

(108 citation statements)

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“…Human MSCs, pre-induced towards a neuronal phenotype and transplanted in the totally dopaminergic deafferented striatum of rats, led to an improved functional recovery for up to 4 months compared to naïve hMSCs (Levy et al, 2008). A similar recovery has been observed in a rat partial lesion model of PD, in which dopaminergic fibers are spared in the striatum (Bouchez et al, 2008). Moreover, microdialysis demonstrated that part of the striatal pool of dopamine was restored upon MSCs transplantation.…”

Section: Adult Cell Therapysupporting

confidence: 55%

Tissue Engineering for Tissue and Organ Regeneration

Eberli¹

2011

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Section: Adult Cell Therapysupporting

confidence: 55%

Tissue Engineering for Tissue and Organ Regeneration

Eberli¹

2011

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“…Currently, microdialysisbased HPLC (HPLC) (31)(32)(33) and CFE amperometric recordings (34,35) have been used independently by different laboratories to assess evoked DA release from the striatum in vivo. The major advantage of microdialysis-based HPLC is to identify the substances secreted in the cell-grafted striatum (33), but its spatiotemporal resolution is too low to distinguish the DA release site (residual cells or pNSC-DAn).…”

Section: Significancementioning

confidence: 99%

Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo

Kang

Teng

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Embryonic stem cell-based therapies exhibit great potential for the treatment of Parkinson's disease (PD) because they can significantly rescue PD-like behaviors. However, whether the transplanted cells themselves release dopamine in vivo remains elusive. We and others have recently induced human embryonic stem cells into primitive neural stem cells (pNSCs) that are self-renewable for massive/transplantable production and can efficiently differentiate into dopaminelike neurons (pNSC-DAn) in culture. Here, we showed that after the striatal transplantation of pNSC-DAn, (i) pNSC-DAn retained tyrosine hydroxylase expression and reduced PD-like asymmetric rotation; (ii) depolarization-evoked dopamine release and reuptake were significantly rescued in the striatum both in vitro (brain slices) and in vivo, as determined jointly by microdialysis-based HPLC and electrochemical carbon fiber electrodes; and (iii) the rescued dopamine was released directly from the grafted pNSC-DAn (and not from injured original cells). Thus, pNSC-DAn grafts release and reuptake dopamine in the striatum in vivo and alleviate PD symptoms in rats, providing proofof-concept for human clinical translation.is a chronic progressive neurodegenerative disorder characterized by the specific loss of dopaminergic neurons in the substantia nigra pars compacta and their projecting axons, resulting in loss of dopamine (DA) release in the striatum (1). During the last two decades, cell-replacement therapy has proven, at least experimentally, to be a potential treatment for PD patients (2-7) and in animal models (8-15). The basic principle of cell therapy is to restore the DA release by transplanting new DA-like cells. Until recently, obtaining enough transplantable cells was a major bottleneck in the practicability of cell therapy for PD. One possible source is embryonic stem cells (ESCs), which can develop infinitely into self-renewable pluripotent cells with the potential to generate any type of cell, including DA neurons (DAns) (16,17).Recently, several groups including us have introduced rapid and efficient ways to generate primitive neural stem cells (pNSCs) from human ESCs using small-molecule inhibitors under chemically defined conditions (12,18,19). These cells are nonpolarized neuroepithelia and retain plasticity upon treatment with neuronal developmental morphogens. Importantly, pNSCs differentiate into DAns (pNSC-DAn) with high efficiency (∼65%) after patterning by sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8) in vitro, providing an immediate and renewable source of DAns for PD treatment. Importantly, the striatal transplantation of human ESC-derived DA-like neurons, including pNSC-DAn, are able to relieve the motor defects in a PD rat model (11-13, 15, 19-23) Regarding question 1, a recent study using nafion-coated carbon fiber electrodes (CFEs) reported that the amperometric current is rescued in vivo by ESC (pNSC-DAn-like) therapy (19). Both norepinephrine (NE) and serotonin are present in the striatum (24, 25). However, CFE am...

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“…Because this is the area where contact with the transplantation of MSCs-of either human or rodent origin-into the striatum of rats lesioned with 6-OHDA host tissue may favor the fusion process, we tend to exclude this possibility. exerts protective and/or regenerative effects on nigrostriatal neurons (13,36,49). Our results, in particular, are in Interestingly, hMSCs transplanted in sham-lesioned animals integrated and survived to a similar extent as keeping with those reported by Bouchez et al (13).…”

Section: Survival and Phenotypic Changes In Transplanted Hmscsmentioning

confidence: 99%

“…exerts protective and/or regenerative effects on nigrostriatal neurons (13,36,49). Our results, in particular, are in Interestingly, hMSCs transplanted in sham-lesioned animals integrated and survived to a similar extent as keeping with those reported by Bouchez et al (13). In this case, unlike in previous studies where the hMSC those transplanted into 6-OHDA-lesioned animals.…”

Section: Survival and Phenotypic Changes In Transplanted Hmscsmentioning

confidence: 99%

Transplantation of Undifferentiated Human Mesenchymal Stem Cells Protects against 6-Hydroxydopamine Neurotoxicity in the Rat

et al. 2010

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Stem cells have been increasingly recognized as a potential tool to replace or support cells damaged by the neurodegenerative process that underlies Parkinson's disease (PD). In this frame, human adult mesenchymal stem cells (hMSCs) have been proposed as an attractive alternative to heterologous embryonic or neural precursor cells. To address this issue, in this study we implanted undifferentiated hMSCs into the striatum of rats bearing a lesion of the nigrostriatal pathway induced by local injection of 6-hydroxydopamine (6-OHDA), a widely recognized rodent model of PD. Before grafting, cultured hMSCs expressed markers of both undifferentiated and committed neural cells, including nestin, GAP-43, NSE, β-tubulin III, and MAP-2, as well as several cytokine mRNAs. No glial or specific neuronal markers were detected. Following transplantation, some hMSCs acquired a glial-like phenotype, as shown by immunoreactivity for glial fibrillary acid protein (GFAP), but only in animals bearing the nigrostriatal lesion. More importantly, rats that received the striatal graft showed increased survival of both cell bodies and terminals of dopaminergic, nigrostriatal neurons, coupled with a reduction of the behavioral abnormalities (apomorphine-induced turning behavior) associated with the lesion. No differentiation of the MSCs toward a neuronal (dopaminergic) phenotype was observed in vivo. In conclusion, our results suggest that grafted hMSCs exert neuroprotective effects against nigrostriatal degeneration induced by 6-OHDA. The mechanisms underlying this effect remain to be clarified, although it is likely that the acquisition of a glial phenotype by grafted hMSCs may lead to the release of prosurvival cytokines within the lesioned striatum.

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Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease

Cited by 141 publications

References 50 publications

Tissue Engineering for Tissue and Organ Regeneration

Tissue Engineering for Tissue and Organ Regeneration

Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo

Transplantation of Undifferentiated Human Mesenchymal Stem Cells Protects against 6-Hydroxydopamine Neurotoxicity in the Rat

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