Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

Parish, Clare L.; Castelo‐Branco, Gonçalo; Rawal, Nina; Tønnesen, Jan; Sørensen, G.; Saltó, Carmen; Kokaia, Mérab; Lindvall, Olle; Arenas, Ernest

doi:10.1172/jci32273

Cited by 164 publications

(146 citation statements)

References 49 publications

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“…Recently, techniques have been established for reliably generating monolayers of induced pluripotent stem cell (iPSC)‐derived NSCs using supplementation with basic fibroblast growth factor (FGFb) and epidermal growth factor (EGF) 54, 55, 56. However, such cultured monolayer NSCs are more transcriptionally homogeneous than in vivo NSCs, and it has been speculated that this lack of heterogeneity is responsible, at least in part, for the challenges of promoting the differentiation of cultured NSCs into diverse neuronal subtypes 56, 57, 58, 59…”

Section: Discussionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInjury‐associated axon‐intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFN γ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen‐specific CD8+ T cells. We sought to determine whether the same is true in human neurons.MethodsA novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast‐derived induced pluripotent stem cell (iPSC)‐derived neuron‐enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFN γ for 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT‐PCR and immunofluorescence.ResultsHuman iPSC‐derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFN γ resulted in upregulation of MHC class I and antigen processing genes in the neuron cell bodies. IFN γ‐induced MHC class I molecules were also anterogradely transported into the distal axon.InterpretationThese results provide conclusive evidence that human axons are competent to express MHC class I molecules, suggesting that inflammatory factors enriched in demyelinated lesions may render axons vulnerable to attack by autoreactive CD8+ T cells in patients with MS. Future work will be aimed at identifying pathogenic anti‐axonal T cells in these patients.

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Section: Discussionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

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“…It forms an important step in the context of current efforts to develop strategies to better define and standardize cell preparations for use in transplantation procedures for PD. Although the limited availability and survival of human VM tissue in current grafting procedures limit the feasibility of flow cytometry, continued development of methods to expand primary VM preparations and improve the yield of grafted DA neurons (39,40) may allow for the introduction of cell sorting in the longer term. The more likely benefit will be as a means to introduce safety and standardization measures to facilitate clinical translation of stem cell-based cell replacement approaches for PD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals transmembrane targets on transplantable midbrain dopamine progenitors

Bye

Jönsson

Björklund

et al. 2015

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

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An important challenge for the continued development of cell therapy for Parkinson's disease (PD) is the establishment of procedures that better standardize cell preparations for use in transplantation. Although cell sorting has been an anticipated strategy, its application has been limited by lack of knowledge regarding transmembrane proteins that can be used to target and isolate progenitors for midbrain dopamine (mDA) neurons. We used a "FACS-array" approach to identify 18 genes for transmembrane proteins with high expression in mDA progenitors and describe the utility of four of these targets (Alcam, Chl1, Gfra1, and Igsf8) for isolating mDA progenitors from rat primary ventral mesencephalon through flow cytometry. Alcam and Chl1 facilitated a significant enrichment of mDA neurons following transplantation, while targeting of Gfra1 allowed for robust separation of dopamine and serotonin neurons. Importantly, we also show that mDA progenitors isolated on the basis of transmembrane proteins are capable of extensive, functional innervation of the host striatum and correction of motor impairment in a unilateral model of PD. These results are highly relevant for current efforts to establish safe and effective stem cell-based procedures for PD, where clinical translation will almost certainly require safety and standardization measures in order to deliver well-characterized cell preparations.Parkinson's disease | cell sorting | Alcam | microarray | transplantation

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“…Cell replacement therapy seems particularly suitable for Parkinson's disease, a common neurodegenerative disease caused by loss of midbrain dopamine neurons (14)(15)(16). Transplantation of fetal midbrain cells has been shown to restore dopamine function in animal models and in human patients (17)(18)(19)(20)(21)(22). More recently, also dopamine neurons derived from embryonic stem cells have been shown to function when grafted into parkinsonian rats (23)(24)(25).…”

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confidence: 99%

Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease

Wernig

Zhao

Pruszak

et al. 2008

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

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747

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The long-term goal of nuclear transfer or alternative reprogramming approaches is to create patient-specific donor cells for transplantation therapy, avoiding immunorejection, a major complication in current transplantation medicine. It was recently shown that the four transcription factors Oct4, Sox2, Klf4, and c-Myc induce pluripotency in mouse fibroblasts. However, the therapeutic potential of induced pluripotent stem (iPS) cells for neural cell replacement strategies remained unexplored. Here, we show that iPS cells can be efficiently differentiated into neural precursor cells, giving rise to neuronal and glial cell types in culture. Upon transplantation into the fetal mouse brain, the cells migrate into various brain regions and differentiate into glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. Electrophysiological recordings and morphological analysis demonstrated that the grafted neurons had mature neuronal activity and were functionally integrated in the host brain. Furthermore, iPS cells were induced to differentiate into dopamine neurons of midbrain character and were able to improve behavior in a rat model of Parkinson's disease upon transplantation into the adult brain. We minimized the risk of tumor formation from the grafted cells by separating contaminating pluripotent cells and committed neural cells using fluorescence-activated cell sorting. Our results demonstrate the therapeutic potential of directly reprogrammed fibroblasts for neuronal cell replacement in the animal model. embryonic stem cells ͉ epigenetic ͉ induced pluripotent stem cells ͉ reprogramming ͉ cell transplantation

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Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

Cited by 164 publications

References 49 publications

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Transcriptome analysis reveals transmembrane targets on transplantable midbrain dopamine progenitors

Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease

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