Abstract:Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions for the rapid differentiation of hPSCs into peripheral sensory neurons. Here we generalize the approac… Show more
“…Several protocols have now established an accelerated differentiation of iPSC into neurons, and for the direct conversion (transdifferentiation) of fibroblasts into neurons, which may promote retention of biological signatures of aging (31,40,57). It is interesting to speculate whether these accelerated neuronal differentiation paradigms will also accelerate the acquisition of mature tau isoforms.…”
Tau pathology is a defining characteristic of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) with tau pathology. There is strong evidence from genetics and experimental models to support a central role for tau dysfunction in neuronal death, suggesting tau is a promising therapeutic target for AD and FTD. However, the development of tau pathology can precede symptom onset by several years, so understanding the earliest molecular events in tauopathy is a priority area of research. Induced pluripotent stem cells (iPSC) derived from patients with genetic causes of tauopathy provide an opportunity to derive limitless numbers of human neurons with physiologically appropriate expression levels of mutated genes for in vitro studies into disease mechanisms. This review discusses the progress made to date using this approach and highlights some of the challenges and unanswered questions this technology has the potential to address.
“…Several protocols have now established an accelerated differentiation of iPSC into neurons, and for the direct conversion (transdifferentiation) of fibroblasts into neurons, which may promote retention of biological signatures of aging (31,40,57). It is interesting to speculate whether these accelerated neuronal differentiation paradigms will also accelerate the acquisition of mature tau isoforms.…”
Tau pathology is a defining characteristic of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) with tau pathology. There is strong evidence from genetics and experimental models to support a central role for tau dysfunction in neuronal death, suggesting tau is a promising therapeutic target for AD and FTD. However, the development of tau pathology can precede symptom onset by several years, so understanding the earliest molecular events in tauopathy is a priority area of research. Induced pluripotent stem cells (iPSC) derived from patients with genetic causes of tauopathy provide an opportunity to derive limitless numbers of human neurons with physiologically appropriate expression levels of mutated genes for in vitro studies into disease mechanisms. This review discusses the progress made to date using this approach and highlights some of the challenges and unanswered questions this technology has the potential to address.
“…While sample sizes in these iPSC studies tend to be small (ranging from 3 in Deshpande et al, 2017 to 8 autistic subjects with macrocephaly in Marchetto et al, 2017 andSchafer et al, 2019), these studies nonetheless highlight that iPSCs can be used to model brain overgrowth in autism and gain insight on underlying mechanisms. To begin to model gray matter using human iPSCs, we differentiated the iPSCs into NPCs using an established NPC differentiation protocol that gives rise to cortical neurons 29,30 . Following 12 days of directed differentiation ( Figure 1C), NPCs express Pax6 mRNA at comparable and high levels of >1000-fold relative to undifferentiated iPSCs ( Figure 1D).…”
Section: Upregulation Of Cd47 In 16p112 Deletion Npcs Suppresses Phamentioning
confidence: 99%
“…Control and 16p11.2 CNV iPSCs were differentiated into cortical neural progenitor cells (NPCs) as previously described 29,30 . The iPSC cultures were plated at a high-density monolayer onto GelTrex (ThermoFisher) coated wells.…”
Section: Generation Of Neural Progenitor Cells (Npcs)mentioning
One of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a 'don't eat me' signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic 'eat me' signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.
“…The differentiation of iPSCs to neuron‐like cells in a dish is very time‐consuming and often results in heterogeneous cultures with batch‐to‐batch variability . Recent studies indicate that it may be possible to substantially shorten the derivation of neurons of the central nervous system even in the absence of glia coculture . However, even if iPSC‐derived neurons show signs of electrophysiological activity, their gene expression pattern may still be immature in comparison to neurons of the human brain .…”
Section: Ipsc‐derived Neural Cell Models For Mitochondrial Disease Drmentioning
High attrition rates and loss of capital plague the drug discovery process. This is particularly evident for mitochondrial disease that typically involves neurological manifestations and is caused by nuclear or mitochondrial DNA defects. This group of heterogeneous disorders is difficult to target because of the variability of the symptoms among individual patients and the lack of viable modeling systems. The use of induced pluripotent stem cells (iPSCs) might significantly improve the search for effective therapies for mitochondrial disease. iPSCs can be used to generate patientspecific neural cell models in which innovative compounds can be identified or validated. Here we discuss the promises and challenges of iPSC-based drug discovery for mitochondrial disease with a specific focus on neurological conditions. We anticipate that a proper use of the potent iPSC technology will provide critical support for the development of innovative therapies against these untreatable and detrimental disorders. STEM CELLS 2017;35:1655-1662
SIGNIFICANCE STATEMENTMitochondrial disease is an untreatable condition caused by mutations in nuclear or mitochondrial DNA. This review describes the application of patient-derived induced pluripotent stem cells (iPSCs) in the drug discovery process of mitochondrial disease. iPSCs allow the development of innovative and effective cellular model systems in a personalized approach. Their use may significantly benefit the search for treatments against debilitating mitochondrial disease.
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