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

Yang, Weiwei ; Trahan, G. Devon ; Howell, Elizabeth D. ; Speck, Nancy A. ; Jones, Kenneth L. ; Gillen, Austin E. ; Riemondy, Kent ; Hesselberth, Jay ; Bryder, David LU and Ernst, Patricia (2020) In Stem Cell Reports
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... (More)

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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type
Contribution to journal
publication status
epub
subject
keywords
embryonic hematopoiesis, EMP, hemogenic endothelium, KMT2A, progenitor heterogeneity, single-cell RNA sequencing
in
Stem Cell Reports
publisher
Cell Press
external identifiers
  • pmid:31951812
  • scopus:85078864669
ISSN
2213-6711
DOI
10.1016/j.stemcr.2019.12.009
language
English
LU publication?
yes
id
2c3f7b23-2d98-4ef3-80cb-1301e709be1e
date added to LUP
2020-02-11 13:22:41
date last changed
2020-10-20 01:28:47
@article{2c3f7b23-2d98-4ef3-80cb-1301e709be1e,
  abstract     = {<p>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<sup>+</sup>/Cd41<sup>+</sup> population in the embryoid body and also at sites of hematopoiesis in embryos. Single-cell sequencing analysis illustrates inherent heterogeneity of the c-Kit<sup>+</sup>/Cd41<sup>+</sup> 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.</p>},
  author       = {Yang, Weiwei and Trahan, G. Devon and Howell, Elizabeth D. and Speck, Nancy A. and Jones, Kenneth L. and Gillen, Austin E. and Riemondy, Kent and Hesselberth, Jay and Bryder, David and Ernst, Patricia},
  issn         = {2213-6711},
  language     = {eng},
  month        = {01},
  publisher    = {Cell Press},
  series       = {Stem Cell Reports},
  title        = {Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis},
  url          = {http://dx.doi.org/10.1016/j.stemcr.2019.12.009},
  doi          = {10.1016/j.stemcr.2019.12.009},
  year         = {2020},
}