Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells

Ogura, Tadashi; Sakaguchi, Hidetsugu; Miyamoto, Susumu; Takahashi, Jun

doi:10.1242/dev.162214

Cited by 130 publications

(120 citation statements)

References 47 publications

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“…As shown in the developing spinal cord (Lai et al, 2016), this organization attenuates over time owing to NCC and post-mitotic IN delamination. This may explain why the patterning activity of BMP has not been noticed in previous studies as organoids were analysed solely for terminally differentiated neurons (Andrews et al, 2017;Gupta et al, 2018;Ogura et al, 2018).…”

Section: Concentric Patterns Of Dorsal Neuronal Cell Types Formed Inmentioning

confidence: 95%

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BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids

et al. 2019

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Bone morphogenetic proteins (BMPs) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity in vivo, whether this is sufficient for pattern formation in vitro is unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cell-derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types, and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the speciesspecific tempo of neural differentiation. Together, this study describes efficient methods for generating patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.

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Section: Concentric Patterns Of Dorsal Neuronal Cell Types Formed Inmentioning

confidence: 95%

“…However, recent work based on PSC-derived spinal organoids has questioned the morphogenetic potential of BMP (Andrews et al, 2017;Gupta et al, 2018;Meinhardt et al, 2014;Ogura et al, 2018). Exposure to BMP triggered PNP or NP dorsalization in the organoids.…”

Section: Introductionmentioning

confidence: 99%

BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids

et al. 2019

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“…1E). This organization attenuates overtime due to ncc and post-mitotic IN delamination, which may explain why in previously generated spinal organoids in presence of BMPs and analysed solely for terminally differentiated neurons, the patterning activity of BMPs hasn't been observed (Andrews et al, 2017;Gupta et al, 2018;Ogura et al, 2018).…”

Section: Concentric Patterns Of Dorsal Neuronal Cell Types Formed Inmentioning

confidence: 99%

“…However, recent work based on PSC-derived spinal organoids have questioned the morphogenetic potential of BMPs (Andrews et al, 2017;Gupta et al, 2018;Meinhardt et al, 2014;Ogura et al, 2018). Indeed, although exposure to BMPs triggered the dorsalization of PNP or NP, whatever the concentrations of BMPs used, many dorsal neural tube cellular subtypes were generated together in a non-organized fashion in the organoids.…”

Section: Introductionmentioning

confidence: 99%

BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids

Duval

Vaslin

Barata

et al. 2019

Preprint

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Bone Morphogenetic Proteins (BMP) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity in vivo, whether this is sufficient for pattern formation in vitro is unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cells derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species specific tempo of neural differentiation. Together the study describes efficient methods to generate patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.

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“…HOX genes define the tempo of the induction (Bel-Vialar et al, 2002;Del Corral and Storey, 30 2004;Deschamps and Duboule, 2017;Ebisuya and Briscoe, 2018;Lippmann et al, 2015;31 Mazzoni et al, 2013;Wymeersch et al, 2019). This might result in the current limited control 32 over pluripotent stem cells (PSCs) differentiation into caudal cell types of distinct well-defined 33 rostro-caudal identities (Diaz-Cuadros et al, 2020;Du et al, 2015;Duval et al, 2019;Faustino 34 Martins et al, 2020;Frith et al, 2018;Gouti et al, 2014;Li et al, 2005;Lippmann et al, 2015;35 Matsuda et al, 2020;Maury et al, 2015;Ogura et al, 2018;Peljto et al, 2010;Verrier et al, 36 2018). Indeed, the two models imply different strategies to control in vitro PSC differentiation.…”

Section: Introduction 15mentioning

confidence: 99%

Dynamic extrinsic pacing of theHOXclock in human axial progenitors controls motor neuron subtype specification

Mouilleau

Vaslin

Gribaudo

et al. 2020

Preprint

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Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX 1 genes within axial stem cells that fuel axial embryo elongation. Whether HOX genes sequential 2 activation, the "HOX clock", is paced by intrinsic chromatin-based timing mechanisms or by 3 temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in 4 human pluripotent stem cells differentiating into spinal cord motor neuron subtypes which are 5 progenies of axial progenitors. We show that the progressive activation of caudal HOX genes in 6 axial progenitors is controlled by a dynamic increase in FGF signaling. Blocking FGF pathway 7 stalled induction of HOX genes, while precocious increase in FGF alone, or with GDF11 ligand, 8 accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated 9 appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The 10 HOX clock is thus dynamically paced by exposure parameters to secreted cues. Its manipulation 11 by extrinsic factors alleviates temporal requirements to provide unprecedented synchronized 12 access to human cells of multiple, defined, rostro-caudal identities for basic and translational 13 applications. , et al. (2013). Accelerated highyield generation of limb-innervating motor neurons from human stem cells. J. Neurosci. 33, 574-586. ., et al. (2019). Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons. Elife 8,.

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Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells

Cited by 130 publications

References 47 publications

BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids

BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids

BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids

Dynamic extrinsic pacing of theHOXclock in human axial progenitors controls motor neuron subtype specification

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