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Mouse embryonic stem cells can differentiate via multiple paths to the same state [array]

ABSTRACT: In embryonic development, cells must differentiate through stereotypical sequences of intermediate states to generate mature states of a particular fate. By contrast, direct programming can generate similar fates through alternative routes, by directly expressing terminal transcription factors. Yet the cell state transitions defining these new routes are unclear. We applied single-cell RNA sequencing to compare two mouse motor neuron differentiation protocols: a standard protocol approximating the embryonic lineage, and a direct programming method. Both undergo similar early neural commitment. Then, rather than transitioning through spinal intermediates like the standard protocol, the direct programming path diverges into a novel transitional state. This state has specific and abnormal gene expression. It opens a 'loop' or 'worm hole' in gene expression that converges separately onto the final motor neuron state of the standard path. Despite their different developmental histories, motor neurons from both protocols structurally, functionally, and transcriptionally resemble motor neurons from embryos.

ORGANISM(S): Mus musculus

PROVIDER: GSE97360 | GEO | 2017/10/17

SECONDARY ACCESSION(S): PRJNA381499

REPOSITORIES: GEO

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Mouse embryonic stem cells can differentiate via multiple paths to the same state [RNA-seq]

Project description:In embryonic development, cells must differentiate through stereotypical sequences of intermediate states to generate mature states of a particular fate. By contrast, direct programming can generate similar fates through alternative routes, by directly expressing terminal transcription factors. Yet the cell state transitions defining these new routes are unclear. We applied single-cell RNA sequencing to compare two mouse motor neuron differentiation protocols: a standard protocol approximating the embryonic lineage, and a direct programming method. Both undergo similar early neural commitment. Then, rather than transitioning through spinal intermediates like the standard protocol, the direct programming path diverges into a novel transitional state. This state has specific and abnormal gene expression. It opens a 'loop' or 'worm hole' in gene expression that converges separately onto the final motor neuron state of the standard path. Despite their different developmental histories, motor neurons from both protocols structurally, functionally, and transcriptionally resemble motor neurons from embryos.

2017-10-17 | GSE97390 | GEO

Mus musculus

Project description:Transcriptional mechanisms controlling direct motor neuron programming

| PRJNA145957 | ENA

A multi-step transcriptional and chromatin cascade underlies motor neuron programming (single-cell RNA-seq)

Project description:Direct programming via the overexpression of transcription factors (TFs) aims to control cell fate at a precision that will be instrumental for clinical applications. However, direct programming of terminal fates remains an obscure process. Taking advantage of the rapid and uniquely efficient programming of spinal motor neurons by overexpression of Ngn2, Isl1 and Lhx3, we have characterized gene expression, chromatin and transcription factor binding time-course dynamics during complete motor neuron programming. Our studies point to a surprisingly dynamic programming process. Promoter chromatin and expression analysis reveals at least three distinct phases of gene activation, while programming factor binding shifts from one set of targets to another, controlling regulatory region activity and gene expression. Furthermore, our evidence suggest that the enhancers and genes activated in the final stage of motor neuron processing are dependent on the combined activities of Isl1 and Lhx3 factors with Ebf and Onecut TFs that are themselves activated midway through the programming process. Our results suggest an unexpected multi-stage model of motor neuron programming in which the programming TFs require activation of a set of intermediate regulators before they complete the programming process.

2016-12-07 | GSE81275 | GEO

A multi-step transcriptional and chromatin cascade underlies motor neuron programming (RNA-Seq)

2016-12-07 | GSE80561 | GEO

A multi-step transcriptional and chromatin cascade underlies motor neuron programming (ATAC-Seq)

2016-12-07 | GSE80511 | GEO

A multi-step transcriptional and chromatin cascade underlies motor neuron programming (Histone modification ChIP-seq)

2016-12-07 | GSE80482 | GEO

A multi-step transcriptional and chromatin cascade underlies motor neuron programming (transcription factor ChIP-seq)

2016-12-07 | GSE80321 | GEO

Efficient generation of lower induced Motor Neurons by coupling Ngn2 expression with developmental cues

Project description:Human pluripotent stem cells (hPSCs) are a powerful tool for disease modelling of hard-to-access tissues (such as the brain). Current protocols either direct neuronal differentiation with small molecules or use transcription-factor-mediated programming. In this study, we couple overexpression of transcription factor Neurogenin2 (Ngn2) with small molecule patterning to differentiate hPSCs into lower induced Motor Neurons (liMoNes/liMNs). This approach induces canonical MN markers including motor neuron (MN) specific marker Hb9/MNX1 activation in >95% of cells. liMNs resemble bona fide hPSC-derived MN, exhibit spontaneous electrical activity, express synaptic markers and can contact muscle cells in vitro. Pooled, multiplexed single-cell RNA sequencing on 50 hPSC-lines reveals reproducible populations of distinct subtypes of cervical and brachial MNs that resemble their in vivo, embryonic counterparts. Combining small molecule patterning with Ngn2 overexpression facilitates high-yield, reproducible production of disease-relevant MN subtypes, which is fundamental in propelling our knowledge of MN biology and its disruption in disease.

2022-12-05 | GSE219112 | GEO

Accelerated high-yield generation of limb-innervating motor neurons from human stem cells

Project description:Human pluripotent stem cells are a promising source of diverse cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons, is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that induce up to 50% motor neurons within 3 weeks from human pluripotent stem cells with defined subtype identities that are relevant to neurodegenerative diseases. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1 and column-specific markers that mirror those observed in vivo in human fetal spinal cord. They also exhibited spontaneous and induced activity, and projected axons towards muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1+/LHX3-). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays.

2013-02-06 | GSE41795 | GEO

Accelerated high-yield generation of limb-innervating motor neurons from human stem cells

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