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

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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; Ernst, Patricia.

I: Stem Cell Reports, 16.01.2020.

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Yang, Weiwei ; Trahan, G. Devon ; Howell, Elizabeth D. ; Speck, Nancy A. ; Jones, Kenneth L. ; Gillen, Austin E. ; Riemondy, Kent ; Hesselberth, Jay ; Bryder, David ; Ernst, Patricia. / Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis. I: Stem Cell Reports. 2020.

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TY - JOUR

T1 - Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis

AU - Yang, Weiwei

AU - Trahan, G. Devon

AU - Howell, Elizabeth D.

AU - Speck, Nancy A.

AU - Jones, Kenneth L.

AU - Gillen, Austin E.

AU - Riemondy, Kent

AU - Hesselberth, Jay

AU - Bryder, David

AU - Ernst, Patricia

PY - 2020/1/16

Y1 - 2020/1/16

N2 - 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.

AB - 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.

KW - embryonic hematopoiesis

KW - EMP

KW - hemogenic endothelium

KW - KMT2A

KW - progenitor heterogeneity

KW - single-cell RNA sequencing

U2 - 10.1016/j.stemcr.2019.12.009

DO - 10.1016/j.stemcr.2019.12.009

M3 - Article

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

ER -