Enhancing Hematopoiesis from Murine Embryonic Stem Cells through MLL1-Induced Activation of a Rac/Rho/Integrin Signaling Axis
(2020) In Stem Cell Reports 14(2). p.285-299- 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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- author
- 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
- organization
- publishing date
- 2020-02-11
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- embryonic hematopoiesis, EMP, hemogenic endothelium, KMT2A, progenitor heterogeneity, single-cell RNA sequencing
- in
- Stem Cell Reports
- volume
- 14
- issue
- 2
- pages
- 15 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:85078864669
- pmid:31951812
- 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
- 2024-08-21 15:53:30
@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}}, keywords = {{embryonic hematopoiesis; EMP; hemogenic endothelium; KMT2A; progenitor heterogeneity; single-cell RNA sequencing}}, language = {{eng}}, month = {{02}}, number = {{2}}, pages = {{285--299}}, 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}}, volume = {{14}}, year = {{2020}}, }