Single-cell genomics of mammalian developmental hematopoiesis – towards in vitro modelling of childhood leukemia

Human pluripotent stem cell (hPSC) differentiation is a promising tool to model prenatal events leading to childhood leukemia.

However, developmental hematopoiesis is challenging to model in vitro, as embryonic blood develops through successive waves in multiple anatomical locations.

This proposal aims to define the diversity of blood emergence events during hPSC differentiation and establish a direct correlation with the distinct hematopoietic waves identified in the mouse embryo.The single-cell transcriptional dataset generated in my postdoc work showed multiple transcriptional trajectories leading to blood fates in the mouse embryo, through a heterogeneous endothelial signature.

In the present proposal I will assess whether this transcriptional heterogeneity of embryonic endothelium underlies the functional diversity of hematopoietic repertoires of developmental blood waves.

I will then apply a novel single-cell profiling approach to an hPSCs-based model of human developmental hematopoiesis and assess transcriptional correlation of in vitro blood emergence events with the in vivo mouse embryonic blood waves.

With single-cell profiling of trisomy 21 hPSC I will then establish a blueprint for in vitro identification of developmental precursors vulnerable to transformation.This project will provide a new basis for the establishment of faithful in vitro models of human development to identify mechanisms of prenatal transformation and to produce clinically relevant cell types.