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Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis

Journal article
Authors W. Yang
G. D. Trahan
E. D. Howell
N. A. Speck
K. L. Jones
A. E. Gillen
K. Riemondy
J. Hesselberth
David Bryder
P. Ernst
Published in Stem Cell Reports
Volume 14
Issue 2
Pages 285-299
ISSN 2213-6711
Publication year 2020
Published at Sahlgrenska Cancer Center
Pages 285-299
Language en
Links dx.doi.org/10.1016/j.stemcr.2019.12...
Keywords hemogenic endothelium, definitive hematopoiesis, yolk-sac, progenitor, cells, blood-cells, in-vivo, mll, differentiation, expression, hemangioblast, Cell Biology
Subject categories Cancer and Oncology, Cell biology

Abstract

The Mixed Lineage Leukemia (MLL1, KMT2A) gene is critical for development and maintenance of hematopoietic stem cells (HSCs), however, whether this protein is limiting for HSC development is unknown due to lack of physiologic model systems. Here, we develop an MLL1-inducible embryonic stem cell (ESC) system and show that induction of wild-type MLL1 during ESC differentiation selectively increases hematopoietic potential from a transitional c-Kit(+)/Cd41(+) population in the embryoid body and also at sites of hematopoiesis in embryos. Single-cell sequencing analysis illustrates inherent heterogeneity of the c-Kit(+)/Cd41(+) population and demonstrates that MLL1 induction shifts its composition toward multilineage hematopoietic identities. Surprisingly, this does not occur through increasing Hox or other canonical MLL1 targets but through an enhanced Rac/Rho/integrin signaling state, which increases responsiveness to Vla4 ligands and enhances hematopoietic commitment. Together, our data implicate a Rac/Rho/integrin signaling axis in the endothelial to hematopoietic transition and demonstrate that MLL1 actives this axis.

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