Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells

Cell, Journal Year: 2016, Volume and Issue: 167(2), P. 566 - 580.e19

Published: Oct. 1, 2016

Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and relationship to commonly used rodent models remain be defined. We performed single-cell RNA sequencing examine development in mouse. found 25 molecularly defined including five subtypes radial glia-like cells four progenitors. In mouse, two mature fetal dopaminergic neuron diversified into adult classes during postnatal development. Cell types were generally conserved across species, but with clear differences proliferation, developmental timing, Additionally, we developed a method quantitatively assess fidelity neurons derived from pluripotent stem cells, at level. Thus, our study provides insight molecular programs controlling foundation replacement therapies.

Language: Английский

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Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons

Cell stem cell, Journal Year: 2016, Volume and Issue: 19(2), P. 248 - 257

Published: July 29, 2016

Language: Английский

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Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 588 - 595

Published: May 1, 2022

Abstract The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark Parkinson’s disease (PD). Nevertheless, molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed protocol to enrich and transcriptionally profile from patients PD matched controls, sampling total 387,483 nuclei, including 22,048 profiles. We identified ten populations spatially localized each SNpc using Slide-seq. A single subtype, marked by expression gene AGTR1 confined ventral tier SNpc, was highly susceptible in showed strongest upregulation targets TP53 NR2F2 , nominating processes degeneration. This same vulnerable population specifically enriched for heritable risk PD, highlighting importance cell-intrinsic determining differential PD-associated

Language: Английский

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Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model

Nature Biotechnology, Journal Year: 2017, Volume and Issue: 35(5), P. 444 - 452

Published: April 10, 2017

Language: Английский

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Physical Activity and Brain Health

Genes, Journal Year: 2019, Volume and Issue: 10(9), P. 720 - 720

Published: Sept. 17, 2019

Physical activity (PA) has been central in the life of our species for most its history, and thus shaped physiology during evolution. However, only recently health consequences a sedentary lifestyle, highly energetic diets, are becoming clear. It also acknowledged that lifestyle diet can induce epigenetic modifications which modify chromatin structure gene expression, causing even heritable metabolic outcomes. Many studies have shown PA reverse at least some unwanted effects contribute delaying brain aging degenerative pathologies such as Alzheimer’s Disease, diabetes, multiple sclerosis. Most importantly, improves cognitive processes memory, analgesic antidepressant effects, induces sense wellbeing, giving strength to ancient principle “mens sana corpore sano” (i.e., sound mind body). In this review we will discuss potential mechanisms underlying on health, focusing hormones, neurotrophins, neurotransmitters, release is modulated by PA, well intra- extra-cellular pathways regulate expression genes involved.

Language: Английский

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Cell-based therapies for Parkinson disease—past insights and future potential

Nature Reviews Neurology, Journal Year: 2015, Volume and Issue: 11(9), P. 492 - 503

Published: Aug. 4, 2015

Language: Английский

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Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease

Cell stem cell, Journal Year: 2016, Volume and Issue: 20(1), P. 135 - 148

Published: Oct. 27, 2016

Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, predicting long-term graft outcome already at progenitor stage remains a challenge. Here, we took an unbiased approach identify predictive markers expressed dopamine neuron correlate with animal model Parkinson's disease through gene expression analysis >30 batches grafted human embryonic stem (hESC)-derived progenitors. We found many commonly used did not accurately predict vivo subtype-specific maturation. Instead, identified specific set associated caudal midbrain high dopaminergic yield after vivo. Using these markers, developed good manufacturing practice (GMP) differentiation protocol highly efficient reproducible production transplantable from hESCs.

Language: Английский

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Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Feb. 4, 2019

Abstract Midbrain dopamine (mDA) neurons constitute a heterogenous group of cells that have been intensely studied, not least because their degeneration causes major symptoms in Parkinson’s disease. Understanding the diversity mDA – previously well characterized anatomically requires systematic molecular classification at genome-wide gene expression level. Here, we use single cell RNA sequencing isolated mouse expressing transcription factor Pitx3 , marker for neurons. Analyses include during development up until adulthood and results are validated by histological characterization newly identified markers. This identifies seven neuron subgroups divided two branches developing -expressing Five them express dopaminergic markers, while glutamatergic GABAergic respectively. Analysis also indicate evolutionary conservation humans. comprehensive will provide valuable resource elucidating subgroup function mammalian brain.

Language: Английский

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Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(3), P. 304 - 312

Published: March 1, 2021

Language: Английский

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Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 24(1), P. 34 - 46

Published: Dec. 7, 2020

Language: Английский

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