Variable Outcomes in Neural Differentiation of Human PSCs Arise from Intrinsic Differences in Developmental Signaling Pathways

Strano, Alessio; Tuck, Eleanor J.; Stubbs, Victoria; Livesey, Frederick J.

doi:10.1016/j.celrep.2020.107732

Cited by 65 publications

(57 citation statements)

References 79 publications

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“…This variation is likely to have a major impact on cell fate decisions, as Wnt signaling is a key regulator of naive pluripotency, germ-layer specification ( Sato et al., 2004 ), and primitive endoderm differentiation ( Anderson et al., 2017 ). Interestingly, variations in Wnt signaling have also been shown to influence the differentiation behavior of human PSCs ( Blauwkamp et al., 2012 ; Strano et al., 2020 ). In agreement with this, we observed that naive hESCs also display different levels of Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation

et al. 2020

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Summary Variability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt pathway, which is modulated by specific genetic variants. Overall, this study shows that genetic background plays a dominant role in driving phenotypic variability of PSCs.

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Section: Discussionmentioning

confidence: 99%

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation

et al. 2020

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“…The low variance within donors suggests aspects of this lineage bias are under genetic control. These findings contribute a novel perspective on a growing body of research that is beginning to reveal the genetic origins of heterogeneity in transcription and differentiation potential of hPSCs (Bonder et al, 2021; Carcamo-Orive et al, 2017; Cuomo et al, 2020; DeBoever et al, 2017; Jerber et al, 2021; Kilpinen et al, 2017; Ortmann et al, 2020; Strano et al, 2020; Vigilante et al, 2019).…”

Section: Discussionmentioning

confidence: 80%

“…Following the discovery of reprogramming factors (Takahashi and Yamanaka, 2006), functional heterogeneity in hiPSC differentiation potential has been a continuing focus of interest (Hu et al, 2010; Kanton et al, 2019; Mariani et al, 2015; Micali et al, 2020; Strano et al, 2020; Wang et al, 2020). Initial studies noted functional consequences of epigenetic memory of parental cell types in reprogrammed cells (Cahan and Daley, 2013; Kim et al, 2010; Kim et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The urgency to answer this question is illustrated by recent work reporting developmental differences between hPSC lines in the generation of neural precursors and their possible implications in the etiology of neurodevelopmental disorders (Burke et al, 2020; Kanton et al, 2019; Mariani et al, 2015; Micali et al, 2020; Strano et al, 2020; Wang et al, 2020). Here we employ cellular and bioinformatic approaches to define functional variation in hPSC lines during in vitro morphogenesis as they traverse the earliest events in forebrain development.…”

Section: Introductionmentioning

confidence: 99%

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Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Kim¹,

Seo

Stein-O’Brien³

et al. 2021

Preprint

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SUMMARYVariability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. We identify differences in the spontaneous self-organization of individual hPSC lines during self-renewal that lie along a fundamental axis of in vivo development. Distinct stable and dynamic transcriptional elements were revealed by decomposition of RNA-seq data in pluripotency and early lineage emergence. Stable differences within pluripotency predicted regional bias in the dynamics of neural differentiation that were also observed in large collections of hPSC lines. Using replicate human induced PSC (hiPSC) lines and paired adult tissue, we demonstrate that cells from individual humans expressed unique transcriptional signatures that were maintained throughout life. In addition, replicate hiPSC lines from one donor showed divergent expression phenotypes driven by distinct chromatin states. These stable transcriptional states are under both genetic and epigenetic control and predict bias in subsequent forebrain and hindbrain neural trajectories. These results define mechanisms controlling transcription in pluripotency to first establish human neural diversity. Data availability: GSE164055; https://nemoanalytics.org/p?l=KimEtAL2021&g=GBX2.Abstract Figure

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“…Not all stem cell lines have similar potency to generate organoids of a particular lineage as observed in the ability to generate retina, inner ear, and skin organoids from ESCs ( Lee et al., 2018 ; Osafune et al., 2008 ; Völkner et al., 2016 ). Analysis of 162 differentiation strategies from 61 PSC lines identified Wnt/β catenin signaling leads to the varied differentiation ability, and its activation could alleviate the outcomes ( Strano et al., 2020 ). Future strategies should focus on empirically investigating the organoid-forming efficiency for each ESC line before initiating functional studies.…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

Sahu

Sharan

2020

iScience

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Summary The astounding capacity of pluripotent stem cells (PSCs) to differentiate and self-organize has revolutionized the development of 3D cell culture models. The major advantage is its ability to mimic in vivo microenvironments and cellular interactions when compared with the classical 2D cell culture models. Recent innovations in generating embryo-like structures (including blastoids and gastruloids) from PSCs have advanced the experimental accessibility to understand embryogenesis with immense potential to model human development. Taking cues on how embryonic development leads to organogenesis, PSCs can also be directly differentiated to form mini-organs or organoids of a particular lineage. Organoids have opened new avenues to augment our understanding of stem cell and regenerative biology, tissue homeostasis, and disease mechanisms. In this review, we provide insights from developmental biology with a comprehensive resource of signaling pathways that in a coordinated manner form embryo-like structures and organoids. Moreover, the advent of assembloids and multilineage organoids from PSCs opens a new dimension to study paracrine function and multi-tissue interactions in vitro . Although this led to an avalanche of enthusiasm to utilize organoids for organ transplantation studies, we examine the current limitations and provide perspectives to improve reproducibility, scalability, functional complexity, and cell-type characterization. Taken together, these 3D in vitro organ-specific and patient-specific models hold great promise for drug discovery, clinical management, and personalized medicine.

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Variable Outcomes in Neural Differentiation of Human PSCs Arise from Intrinsic Differences in Developmental Signaling Pathways

Cited by 65 publications

References 79 publications

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability that Is Driven by Genetic Variation

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

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