Modulation of Dopaminergic Neuronal Differentiation from Sympathoadrenal Progenitors

Vukićević, Vladimir; Celis, María F. Rubín de; Diaz-Valencia, Gabriela; Bornstein, Stefan R.; Ehrhart‐Bornstein, Monika

doi:10.1007/s12031-012-9746-0

Cited by 4 publications

(5 citation statements)

References 54 publications

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“…Recently, we established optimal conditions for the enrichment of self-renewing chromaffin progenitors within heterogeneous free-floating chromospheres. 13,14,16,17 Treatment of floating spheres with 2 mM VPA revealed a transient increase of Nestin, Notch2 and Sox10 expression after 24 h; after 7 days of VPA treatment expression levels of these genes had returned to baseline levels. These data suggest that similar to NSC, 11 the HDAC inhibitor VPA induced an increase of the progenitor pool, indicated by the increased progenitor marker expression.…”

Section: Discussionmentioning

confidence: 98%

“…Primary chromaffin cells were isolated as previously described by collagenase and DNase digestion. 14,16 Chromaffin cells were separated from nonchromaffin cells by differential plating, based on the fact that nonchromaffin cells adhere faster than chromaffin cells. The cell suspension was transferred to a new culture flask once for 2 h and additional two times for 1 h. As shown previously, suspension cells also contain a fraction of sympathoadrenal progenitors.…”

Section: Isolation Of Chromaffin Cells and Culture Of Chromospheresmentioning

confidence: 99%

“…15 Thus, a responsiveness of chromaffin progenitors to VPA treatment similar to NSC might be expected. We recently isolated and characterized sympathoadrenal progenitor cells from bovine 13,14,16 and human 17 adrenal medulla and developed methods to expand them as selfrenewing spheroid clusters, termed chromospheres. These progenitor cells express progenitor markers Sox10, Notch2, Hes1 and Nestin and have the capacity to give rise to neurons.…”

Section: Introductionmentioning

confidence: 99%

“…These progenitor cells express progenitor markers Sox10, Notch2, Hes1 and Nestin and have the capacity to give rise to neurons. 13,14,[16][17][18] The derivation of functional neurons from sympathoadrenal progenitor cells proved their potential application in transplantation therapies of neurodegenerative diseases. Based on the similarities of chromaffin progenitors to NSC, we presumed that VPA initiates similar molecular mechanisms governing processes of neuronal differentiation in both cell types.…”

Section: Introductionmentioning

confidence: 99%

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Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells

et al. 2015

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The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker β-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 98%

Section: Isolation Of Chromaffin Cells and Culture Of Chromospheresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells

et al. 2015

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“…The properties of the chromospheres could be potentially improved through different culture manipulations. As an example, chromosphere cells can be transformed into a more neuron-like morphology in culture [ 22 , 43 ], which could potentially enable them to extend projections and to better integrate into the host circuit after grafting. This could be relevant as the lack of innervation of the host striatum by the grafted chromospheres observed in the present work could be a contributing factor to their lower functional potency.…”

Section: Discussionmentioning

confidence: 99%

Intrastriatal Grafting of Chromospheres: Survival and Functional Effects in the 6-OHDA Rat Model of Parkinson's Disease

et al. 2016

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Cell replacement therapy in Parkinson’s disease (PD) aims at re-establishing dopamine neurotransmission in the striatum by grafting dopamine-releasing cells. Chromaffin cell (CC) grafts produce some transitory improvements of functional motor deficits in PD animal models, and have the advantage of allowing autologous transplantation. However, CC grafts have exhibited low survival, poor functional effects and dopamine release compared to other cell types. Recently, chromaffin progenitor-like cells were isolated from bovine and human adult adrenal medulla. Under low-attachment conditions, these cells aggregate and grow as spheres, named chromospheres. Here, we found that bovine-derived chromosphere-cell cultures exhibit a greater fraction of cells with a dopaminergic phenotype and higher dopamine release than CC. Chromospheres grafted in a rat model of PD survived in 57% of the total grafted animals. Behavioral tests showed that surviving chromosphere cells induce a reduction in motor alterations for at least 3 months after grafting. Finally, we found that compared with CC, chromosphere grafts survive more and produce more robust and consistent motor improvements. However, further experiments would be necessary to determine whether the functional benefits induced by chromosphere grafts can be improved, and also to elucidate the mechanisms underlying the functional effects of the grafts.

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Nano‐Enabled Intracellular Bursting of Calcium and Retinoic Acid Regulates Dopaminergic Neuronal Differentiation of NSCs for Parkinson's Disease Therapy

Zhang,

Liu,

Zhou

et al. 2024

Adv Funct Materials

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Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by dopaminergic neuron degeneration. Neural stem cell (NSC) therapy offers promise for replacing these neurons and restoring neural function. However, directing NSCs to become dopaminergic neurons is challenging. Retinoic acid (RA) is a potential regulator, but its insolubility in water limits its use in PD therapy. Herein, nanonizing RA with calcium acetate to create calcium‐retinoic acid nanoparticles (Ca‐RA NPs) is proposed. These nanoparticles can be internalized by NSCs and then dissociated in the acidic environment of lysosomes to lead to a burst of Ca2+ and RA. In vitro results showed that the intracellular bursting of Ca2+ and RA accelerated neuronal differentiation and maturation by 5–10 days compared to spontaneous NSC differentiation. Importantly, Ca‐RA NPs uniquely directed NSCs to dopaminergic neurons, involving the interaction between the calcium ion‐mediated MAPK signaling pathway and the RA‐mediated RA signaling pathway. Animal experiments further validated the efficacy of Ca‐RA‐coated NSCs in restoring motor and cognitive functions in PD mice by rapidly forming dopaminergic neural circuits. Given that both RA and calcium acetate are approved by the FDA, this strategy has the potential for translation into a clinical treatment approach for stem cell therapy of PD.

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Modulation of Dopaminergic Neuronal Differentiation from Sympathoadrenal Progenitors

Cited by 4 publications

References 54 publications

Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells

Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells

Intrastriatal Grafting of Chromospheres: Survival and Functional Effects in the 6-OHDA Rat Model of Parkinson's Disease

Nano‐Enabled Intracellular Bursting of Calcium and Retinoic Acid Regulates Dopaminergic Neuronal Differentiation of NSCs for Parkinson's Disease Therapy

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