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Stem Cell Reports. 2020 Feb 11;14(2):285-299. doi: 10.1016/j.stemcr.2019.12.009. Epub 2020 Jan 16.

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

Author information

1
Department of Pediatrics, Section of Hematology/Oncology/BMT University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
2
Department of Pediatrics, Section of Hematology/Oncology/BMT University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA.
3
Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
4
RNA Biosciences Initiative, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA.
5
Division for Molecular Hematology, Lund Stem Cell Center, Lund University, B10 221 84 Lund, Sweden; Sahlgrenska Cancer Center, University of Gothenburg, 405 30 Gothenburg, Sweden.
6
Department of Pediatrics, Section of Hematology/Oncology/BMT University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: patricia.ernst@cuanschutz.edu.

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.

KEYWORDS:

EMP; KMT2A; embryonic hematopoiesis; hemogenic endothelium; progenitor heterogeneity; single-cell RNA sequencing

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