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Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization
Abstract
The molecular events that regulate engraftment and mobilization of hematopoietic stem cells and progenitors (HSC/Ps) are still incompletely defined. We have examined the role of the Rho GTPases Rac1 and Rac2 in HSC engraftment and mobilization. Rac1, but not the hematopoietic-specific Rac2, is required for the engraftment phase of hematopoietic reconstitution, because Rac1(-/-) HSCs did not rescue in vivo hematopoiesis after transplantation, but deletion of Rac1 after engraftment did not impair steady-state hematopoiesis. Rac1(-/-) HSC/Ps showed impaired spatial localization to the endosteum but near-normal homing to the medullary cavity in vivo. Interaction with the bone marrow microenvironment in vitro was markedly altered. Whereas post-engraftment deletion of Rac1 alone did not impair hematopoiesis, deficiency of both Rac1 and Rac2 led to massive mobilization of HSCs from the marrow associated with ineffective hematopoiesis and intense selection for Rac-expressing HSCs. This mobilization was reversible by re-expression of Rac1. In addition, a rationally designed, reversible small-molecule inhibitor of Rac activation led to transient mobilization of engraftable HSC/Ps. Rac proteins thus differentially regulate engraftment and mobilization phenotypes, suggesting that these biological processes and steady-state hematopoiesis are biochemically separable and that Rac proteins may be important molecular targets for stem cell modification.
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“Several members of the Rho family, including Rac1 and Rac2, can be activated by SDF-1α stimulation and are required for SDF-1α–induced chemotaxis and homing of hematopoietic stem/progenitor cells.5,36”
From Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells (2008) · cites this paper as [36]
In the citing paper
“The Rac subfamily of Rho guanosine triphosphatases (GTPases) plays an essential role in regulating hematopoiesis (Gu et al., 2003;Yang et al., 2001;Cancelas et al., 2005;Cancelas and Williams, 2006).”
From Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease (2007) · cites this paper as Cancelas et al., 2005
In the citing paper
“We have previously shown that both Rac1 and Rac2 are essential for the regulation of multiple HSC functions with unique as well as overlapping roles, including proliferation, apoptosis, homing, and retention (Gu et al., 2003;Cancelas et al., 2005).”
From Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease (2007) · cites this paper as Cancelas et al., 2005
In the citing paper
“Rac1 is required for engraftment of HSC into the stem cell niche and regulates cell-cycle progression (Gu et al., 2003;Cancelas et al., 2005)”
From Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease (2007) · cites this paper as Cancelas et al., 2005
In the citing paper
“Combinatorial expression of both proteins is necessary for normal HSC adhesion and migration and supports long-term hematopoiesis (Gu et al., 2003;Cancelas et al., 2005).”
From Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease (2007) · cites this paper as Cancelas et al., 2005
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Metadata
- Authors
- Cancelas, J. A., Lee, A. W., Prabhakar, R., Stringer, K. F., Zheng, Y., & Williams, D. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Williams, David A
- Venue
- Nature Medicine
- Published
- 2005-07-17
- Volume
- 11
- Issue
- 8
- Pages
- 886-891
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2064771788
- Semantic Scholar
- 3b030828bbdde5a8ef96ecb155d0b62bc0e67dee
- Cited by
- 278
- References
- 30
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 12 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 20 · 2014: 11 · 2013: 20 · 2012: 21
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM060523)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK62752)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Rac1, Rac2, Rho GTPases, hematopoietic stem cells, hematopoietic progenitor cells, engraftment, hematopoietic stem cell mobilization, endosteum, bone marrow microenvironment, hematopoiesis, stem cell targeting
- MeSH terms
- Aminoquinolines, Animals, Cell Movement, Flow Cytometry, Hematopoiesis, Hematopoietic Stem Cells, Neuropeptides, Pyrimidines, Signal Transduction, Bone Marrow Transplantation, Granulocyte Colony-Stimulating Factor, Gene Deletion, Hematopoietic Stem Cell Mobilization, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Cell Proliferation, Mice
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