Atlas of Multilineage Stem Cell Differentiation Reveals TMEM88 As a Developmental Regulator of Blood Pressure

Overview

Journal Nat Commun

Date 2025 Feb 5

PMID 39904980

Authors

Sophie Shen

Tessa Werner

Samuel W Lukowski

Stacey Andersen

Yuliangzi Sun

Woo Jun Shim

Dalia Mizikovsky

Sakurako Kobayashi

Jennifer Outhwaite

Han Sheng Chiu

Xiaoli Chen

Gavin Chapman

Ella M M A Martin

Di Xia

Duy Pham

Zezhuo Su

Daniel Kim

Pengyi Yang

Men Chee Tan

Enakshi Sinniah

Qiongyi Zhao

Sumedha Negi

Meredith A Redd

Joseph E Powell

Sally L Dunwoodie

Patrick P L Tam

Mikael Boden

Joshua W K Ho

Quan Nguyen

Nathan J Palpant

Affiliations

Soon will be listed here.

Abstract

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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