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Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization
Open accessAbstract
Critical to homeostasis of blood cell production by hematopoietic stem/progenitor (HSC/P) cells is the regulation of HSC/P retention within the bone marrow microenvironment and migration between the bone marrow and the blood. Key extracellular regulatory elements for this process have been defined (cell–cell adhesion, growth factors, chemokines), but the mechanism by which HSC/P cells reconcile multiple external signals has not been elucidated. Rac and related small GTPases are candidates for this role and were studied in HSC/P deficient in Rac2, a hematopoietic cell-specific family member. Rac2 appears to be critical for HSC/P adhesion both in vitro and in vivo , whereas a compensatory increase in Cdc42 activation regulates HSC/P migration. This genetic analysis provides physiological evidence of cross-talk between GTPase proteins and suggests that a balance of these two GTPases controls HSC/P adhesion and mobilization in vivo .
Checked 2026-11-12 · 1 reference not checked yet
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TL;DR
Rac2 deficiency in hematopoietic stem/progenitor cells reduces α4β1-mediated adhesion and increases circulating/mobilized HSC/P, while SDF-1-stimulated migration is enhanced via compensatory Cdc42/Rac1 activation. The balance of Rac and Cdc42 GTPase activity controls HSC/P adhesion and mobilization in vivo.
Key findings
- Rac2−/− HSC/P showed defective adhesion to fibronectin fragment H296 via α4β1: WT 50.0 ± 2%, Rac2−/− 17.6 ± 4%, and Rac2−/− transduced with MIEG3-FR2 46.0 ± 7% (P < 0.01 WT vs. Rac2−/−; P > 0.05 Rac2-transduced vs. WT).
- Rac2−/− mice had significantly higher numbers of HSC/P in blood by CFU-C and CFU-S12 assays, and G-CSF mobilized HSC/P into blood in 3- to 4-fold greater numbers than WT mice.
- SDF-1-stimulated Rac2−/− HSC/P were hypermotile: increased responding-cell frequency was 6.7 ± 3.1% vs. 1.1 ± 2.2% (Rac2−/− vs. WT, P = 0.01), with increased velocity in Dunn chamber time-lapse imaging.
- Activated Cdc42 and Rac1 increased after SDF-1: active Cdc42 rose from 0.12% to 0.74% in WT but from 3.12% to 49.26% in Rac2−/− cells; active Rac1 rose from 4.4% to 28.6% in WT but from 21.4% to 49.3% in Rac2−/− cells. Dominant-negative Cdc42 reversed enhanced filopodia and migration but not adhesion.
Methods
- Used 6- to 10-week-old age- and gender-matched 129Sv/C57BL6 or 129Sv mice, with littermates analyzed in parallel where possible; isolated Lin−c-Kit+Sca-1+ bone marrow cells by immunomagnetic depletion and FACS sorting to >90% purity.
- Measured adhesion to fibronectin fragments H-296 and CH-271 or BSA, transwell migration to SDF-1, Dunn chamber time-lapse motility, and in vivo mobilization with G-CSF (250 μg/kg every 12 h) and/or anti-α4β1 antibody (2 mg/kg/day for 3 days), using CFU-C and CFU-S12 assays.
- Analyzed GTP-bound Cdc42/Rac1 by GST-PAK1 p21-binding domain pull-down, receptor expression by real-time PCR, and used retroviral transduction with MIEG3, MIEG-FR2, and T17NCdc42 vectors.
Limitations
- The paper does not include a formal limitations section.
- Stated: the basis for Rac2 functional specificity is unknown, and whether Rac-dependent signaling links adhesion and growth factor stimulation to HSC/P survival remains “yet to be explored.”
- Evident: findings rely on Rac2−/− mice and in vitro assays; some supporting data are reported as “not shown,” and the relative contributions of active migration versus altered adhesion to mobilization are not fully clarified.
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33 Own result · 26 Not checked yet · 24 Own interpretation · 4 Check pending · 3 Own method
In the paper
“adhesion of HSC/P cells derived from Rac2−/− mice to the recombinant FN peptide H296 (4), containing specific ligand sequences, CS1, of the integrin α4β1 was significantly reduced compared with WT cells (Fig. 2B).”
What the sources say
- Not checked yetcites [4] van der Loo J C, Xiao X, McMillin D, Hashino K, Kato I, Williams D A. J Clin Invest. 1998;102:1051–1061. doi: 10.1172/JCI3687. [DOI] [PMC free article] [PubMed] [Google Scholar]
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In the paper
“no augmentation of mobilization is seen in Rac2−/− mice with the combined treatment of G-CSF and anti-α4 antibody, as expected in normal mice (15) and seen here in WT mice (Fig. 2C).”
What the sources say
- Not checked yetcites [15] Craddock C F, Nakamoto B, Andrews R G, Priestley G V, Papayannopoulou T. Blood. 1997;90:4779–4788. [PubMed] [Google Scholar]
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“SDF-1-stimulated primitive cells (c-kit+Sca-1+Lin−) from Rac2−/− mice demonstrated increased migration in transwell chambers (16) across multiple concentrations (Fig. 3A).”
What the sources say
- Not checked yetcites [16] Aiuti A, Webb I J, Bleul C, Springer T, Gutierrez-Ramos J C. J Exp Med. 1997;185:111–120. doi: 10.1084/jem.185.1.111. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper
“Rac2−/− mice injected with G-CSF mobilized HSC/P into the blood in 3- to 4-fold greater numbers than similarly treated WT mice (Fig. 1B).”
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In the paper
“Both increased velocity of migration (Fig. 3B) and increased frequency of responding cells (6.7 ± 3.1% vs. 1.1 ± 2.2%, Rac2−/− vs. WT, P = 0.01) were further documented in Rac2-deficient cells by analysis with time-lapsed video microscopy in Dunn chambers.”
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- Probably not a substantial claim. 22
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Rac subfamily members, Rac1 and Rac2, are essential for cortical filamentous-actin (F-actin) assembly and chemotaxis in hematopoietic stem/progenitor cells.4,5”
From Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells (2008) · cites this paper as [4]
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 Yang et al., 2001
In the citing paper
“whereas Rac2 is important for retention of HSC/P within the hematopoietic microenvironment (Yang et al., 2001) and regulates survival (Gu et al., 2003).”
From Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease (2007) · cites this paper as Yang et al., 2001
In the citing paper
“The main function of RAC GTPases is traditionally associated with cytoskeleton rearrangements and thus processes such as regulation of cell shape, migration and adhesion [27,28,48].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [27]
In the citing paper
“Consequently, RAC proteins have a critical role for the biology of HSCs, as they have been implicated in such processes as migration, homing and retention of HSCs in the bone marrow [20,26,27].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [27]
Self-check
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Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Results
“whereas expression of the dominant negative Cdc42 bearing Thr→Asp at position 17 is associated with reversal of the enhanced filopodia in Rac2−/− cells”
§ Materials and Methods
“The cells were infected with MIEG3, MIEG-FR2, and T17NCdc42 virus supernatant on FN CH-296-coated plates.”
Citations
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Rac Downregulates Rho Activity
Sander, E. E., ten Klooster, J. P., van Delft, S., van der Kammen, R. A., & Collard, J. G. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.147.5.1009 · Cited by 826
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Episomal Vectors Rapidly and Stably Produce High-Titer Recombinant Retrovirus
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Endomembrane Trafficking of Ras
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Cited by
Bissell, M. J., & Radisky, D. (2001) · Nature Reviews Cancer · doi:10.1038/35094059 · Cited by 2,180
Mammalian Rho GTPases: new insights into their functions from in vivo studies
Heasman, S. J., & Ridley, A. J. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2476 · Cited by 1,871
Yin, T. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28568 · Cited by 810
Kucia, M., Reca, R., Miękus, K., Wanzeck, J., Wojakowski, W., Janowska‐Wieczorek, A., Ratajczak, J., & Ratajczak, M. Z. (2005) · Stem Cells · doi:10.1634/stemcells.2004-0342 · Cited by 774
Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia
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Metadata
- Authors
- Yang, F.-C., Atkinson, S. J., Gu, Y., Borneo, J. B., Roberts, A. W., Zheng, Y., Pennington, J., & Williams, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-04-24
- Volume
- 98
- Issue
- 10
- Pages
- 5614-5618
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC33261
- OpenAlex
- W2122152063
- Semantic Scholar
- 10b658434496f0ef237ecf32ac8b7937ecf77f9c
- Cited by
- 201
- References
- 38
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 6 · 2018: 6 · 2017: 7 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 9 · 2012: 16
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Colorado State University
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (P50DK049218, P30DK049218)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- hematopoietic stem cells, hematopoietic stem and progenitor cells, Rac2, Cdc42, small GTPases, cell adhesion, cell migration, hematopoietic stem cell mobilization, bone marrow microenvironment
- MeSH terms
- Animals, Base Sequence, Cell Adhesion, Cell Movement, Hematopoietic Stem Cells, Mice, Inbred Strains, DNA Primers, rac GTP-Binding Proteins, cdc42 GTP-Binding Protein, Cell Size, Mice
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