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Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure

ABSTRACT: Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure

PROVIDER: PRJNA1174126 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR31029418.fastq.gz	Fastqsanger.gz
	SRR31029419.fastq.gz	Fastqsanger.gz
	SRR31029424.fastq.gz	Fastqsanger.gz
	SRR31029425.fastq.gz	Fastqsanger.gz

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Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure

Project description:Pluripotent stem cells provide a scalable approach to analyse molecular regulation of cell differentiation across multiple any developmental lineage trajectories. In this study, we engineered barcoded iPSCs to generate an atlas of multilineage differentiation from pluripotency, encompassing a time-course of WNT-induced differentiation perturbed using modulators of WNT, BMP, and VEGF signalling. Computational mapping of in vitro cell types to in vivo developmental lineages revealed a diversity of iPSC-derived cell types comprising mesendoderm lineage cell types including lateral plate and paraxial mesoderm, neural crest, and primitive gut. Coupling this atlas of in vitro differentiation with Summary data-based Mendelian Randomisation analysis of human complex traits, we identify the WNT-inhibitor protein TMEM88 as a putative regulator of mesendodermal cell types governing development of diverse cardiovascular and anthropometric traits. Using genetic loss of function models, we show that TMEM88 is required for differentiation of diverse endoderm and mesoderm cell lineages in vitro and that TMEM88 knockout in vivo results in a significant dysregulation of arterial blood pressure. This study provides an atlas of multilineage iPSC differentiation coupled with new molecular, computational, and statistical genetic tools to dissect genetic determinants of mammalian developmental physiology.

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Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure.

Project description:Pluripotent stem cells provide a scalable approach to analyse molecular regulation of cell differentiation across developmental lineages. Here, we engineer barcoded induced pluripotent stem cells to generate an atlas of multilineage differentiation from pluripotency, encompassing an eight-day time course with modulation of WNT, BMP, and VEGF signalling pathways. Annotation of in vitro cell types with reference to in vivo development reveals diverse mesendoderm lineage cell types including lateral plate and paraxial mesoderm, neural crest, and primitive gut. Interrogation of temporal and signalling-specific gene expression in this atlas, evaluated against cell type-specific gene expression in human complex trait data highlights the WNT-inhibitor gene TMEM88 as a regulator of mesendodermal lineages influencing cardiovascular and anthropometric traits. Genetic TMEM88 loss of function models show impaired differentiation of endodermal and mesodermal derivatives in vitro and dysregulated arterial blood pressure in vivo. Together, this study provides an atlas of multilineage stem cell differentiation and analysis pipelines to dissect genetic determinants of mammalian developmental physiology.

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