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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Weiwei Yang
  • G. Devon Trahan
  • Elizabeth D. Howell
  • Nancy A. Speck
  • Kenneth L. Jones
  • Austin E. Gillen
  • Kent Riemondy
  • Jay Hesselberth
  • David Bryder
  • Patricia Ernst
Enheter & grupper
Externa organisationer
  • University of Colorado
  • Dartmouth College
  • Göteborgs universitet
  • University of Pennsylvania
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
  • Hematologi

Nyckelord

Originalspråkengelska
TidskriftStem Cell Reports
StatusE-pub ahead of print - 2020 jan 16
PublikationskategoriForskning
Peer review utfördJa