Human Huntington’s Disease iPSC-Derived Cortical Neurons Display Altered Transcriptomics, Morphology, and Maturation

Mehta, Shagun; Tom, Colton M; Wang, Yizhou; Bresee, Catherine; Rushton, David J.; Mathkar, Pranav; Tang, Jie; Mattis, Virginia B.

doi:10.1016/j.celrep.2018.09.076

Cited by 83 publications

(93 citation statements)

References 69 publications

(87 reference statements)

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“…The published RNA-seq data of three cortical sub-regions (dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and orbital frontal cortex) at nine developmental stages (8,12,13,16,17,21,24, and 37 pcw and 4 months) of human brains were obtained from Allen Brain Atlas (http://www.brainspan.org/static/download.html). This dataset was compared with the organoids RNA-seq data of the current study to assess the degree of transcriptome correlation.…”

Section: Correlation Of Transcriptome Between Organoids and Human Bramentioning

confidence: 99%

“…Indeed, studies examining neurogenesis using mouse HD stem cells have given conflicting results showing that mutant HTT both impairs neurogenesis [21] and promotes it [13,22]. Efforts to examine the impact of mutant HTT on neurodevelopment and neurogenesis using human pluripotent stem cells (hPSCs) having been similarly unclear [18,19,[23][24][25][26] (reviewed in [27]). Mutant HTT was shown to impact early ectodermal development, reflected in an altered phenotypic signature, in an in vitro model of neurulation [28].…”

Section: Introductionmentioning

confidence: 99%

“…Mutant HTT was shown to impact early ectodermal development, reflected in an altered phenotypic signature, in an in vitro model of neurulation [28]. Based on transcriptional analyses of hPSCs [26], neural progenitors [23,25], and neurons [24], a number of studies 2/26 have also suggested that mutant HTT impairs neural progenitor differentiation and delays neuronal maturation. However, assessment of cortical neurogenesis showed no effect of mutant HTT on the quantity or timeline of differentiation of deep and upper layer cortical neurons [24].…”

Section: Introductionmentioning

confidence: 99%

“…Based on transcriptional analyses of hPSCs [26], neural progenitors [23,25], and neurons [24], a number of studies 2/26 have also suggested that mutant HTT impairs neural progenitor differentiation and delays neuronal maturation. However, assessment of cortical neurogenesis showed no effect of mutant HTT on the quantity or timeline of differentiation of deep and upper layer cortical neurons [24]. These studies have largely relied on directed differentiation of embryonic or induced pluripotent stem cells in two-dimensional culture systems to induce neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

Zhang

Ooi

Utami

et al. 2019

Preprint

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Huntington disease (HD) manifests in both adult and juvenile forms. Mutant HTT gene carriers are thought to undergo normal brain development followed by a degenerative phase, resulting in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD have raised the possibility of abnormal neurodevelopment.Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Using a panel of isogenic HD human embryonic pluripotent stem cells and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in an HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids, driven by cell intrinsic processes. Transcriptional profiling and imaging analysis revealed impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors, collectively contributing to premature neuronal differentiation. We demonstrate increased activity of the ATM-p53 pathway, an up-stream regulator of cell cycle processes, and show that treatment with ATM antagonists partially rescues the blunted neuroepithelial progenitor expansion in HD organoids. Our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our results 1/26further support the view that HD, at least in its early-onset forms, may not be a purely neurodegenerative disorder, and that abnormal neurodevelopment may be a component of HD pathophysiology.

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Section: Correlation Of Transcriptome Between Organoids and Human Bramentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

Zhang

Ooi

Utami

et al. 2019

Preprint

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“…iPSC differentiation and treatment iPSC generation was previously performed at Cedar's Sinai Medical Center using nonintegrating methods (HD iPSC Consortium, 2012;Mattis et al, 2015;Mehta et al, 2018). These iPSCs were fully reprogrammed as previously demonstrated by testing for pluripotency markers and gene expression analysis (Mattis et al, 2015), and removal of reprogramming plasmids was confirmed by genomic polymerase chain reaction (PCR) and southern blotting (Mattis et al, 2015).…”

Section: Mouse Striatal Western Blotmentioning

confidence: 99%

The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

Machiela

Jeloka

Caron

et al. 2019

Preprint

Self Cite

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Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress. Figure 1. Oxidative stressors increase ROS in immature control and mature HD primary neurons. Primary Hu97/18 and Hu18/18 control neurons were treated with stressors for 24h and ROS was measured by live-imaging of CM-H2DCFDA florescence. Immature neurons were treated with (A) NBC or H2O2 at the indicated doses. (B) PBS or 5µM menadione. (C) DMSO or 500nM staurosporine. (D) Mature neurons were treated with 100µM H2O2

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Innovations in 3D Tissue Models of Human Brain Physiology and Diseases

Lovett

Nieland

Dingle

et al. 2020

Adv Funct Materials

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3D laboratory tissue cultures have emerged as an alternative to traditional 2D culture systems that do not recapitulate native cell behavior. The discrepancy between in vivo and in vitro tissue-cell-molecular responses impedes understanding of human physiology in general and creates roadblocks for the discovery of therapeutic solutions. Two parallel approaches have emerged for the design of 3D culture systems. The first is biomedical engineering methodology, including bioengineered materials, bioprinting, microfluidics, and bioreactors, used alone or in combination, to mimic the microenvironments of native tissues. The second approach is organoid technology, in which stem cells are exposed to chemical and/or biological cues to activate differentiation programs that are reminiscent of human (prenatal) development. This review article describes recent technological advances in engineering 3D cultures that more closely resemble the human brain. The contributions of in vitro 3D tissue culture systems to new insights in neurophysiology, neurological diseases, and regenerative medicine are highlighted. Perspectives on designing improved tissue models of the human brain are offered, focusing on an integrative approach merging biomedical engineering tools with organoid biology.

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Human Huntington’s Disease iPSC-Derived Cortical Neurons Display Altered Transcriptomics, Morphology, and Maturation

Abstract: Highlights d Differentiated HD and non-diseased iPSCs into functional cortical neurons d HD iPSC-derived cortical neurons display altered transcriptomics d HD iPSC-derived cortical neurons display altered morphology d HD iPSC-derived cortical neurons display altered functional phenotypes

Cited by 83 publications

References 69 publications

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons

Innovations in 3D Tissue Models of Human Brain Physiology and Diseases

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