Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells

Current in vitro models of developmental blood formation lack spatiotemporal coherence and weakly replicate the hematopoietic microenvironment. Developmentally-appropriate models can enhance understanding of infant acute myeloid leukemia (infAML), which putatively originates in utero and has 50% age-unique genetic events, suggesting unique biology. The commonest genetic abnormality unique to infants involves homeobox gene MNX1, whose leukemogenic mechanisms remain unknown. Recently, 3D self-organising embryonic stem cell (SC)-based gastruloids have shown promise in recapitulating embryonic events with time/space precision. Herein, we report a hemogenic gastruloid (haemGx) system that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and approximates generation of hematopoietic SC precursors. Enforced MNX1 expression in haemGx promotes HE formation, perturbs endothelial-to-hemogenic transition, and critically achieves transformation, generating myeloid colonies which display MNX1 AML signatures. By combining functional assays with single-cell transcriptomics, we establish the haemGx as a new model of normal and leukemic embryonic hematopoiesis amenable to mechanistic exploration.

show abstract

Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells

Cited by 4 publications

References 209 publications

Tracing embryonic hematopoiesis guides induction of pluripotent stem cells to hematopoietic progenitors

Tracing embryonic hematopoiesis guides induction of pluripotent stem cells to hematopoietic progenitors

The molecular and cellular hematopoietic stem cell specification niche

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Contact Info

Product

Resources

About