FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2006771034> ?p ?o ?g. }

• W2006771034 endingPage "985" @default.
• W2006771034 startingPage "976" @default.
• W2006771034 abstract "Signaling downstream from the chemokine receptor CXCR4, the tyrosine kinase receptor c-kit and β1-integrins has been shown to be crucial in the regulation of migration, homing, and engraftment of hematopoietic stem cells and progenitors. Each of these receptors signal through Rac-type Rho guanosine triphosphatases (GTPases). Rac GTPases play a major role in the organization of the actin cytoskeleton and also in the control of gene expression and the activation of proliferation and survival pathways. Here we review the specific roles of the members of the Rac subfamily of the Rho GTPase family in regulating the intracellular signaling of hematopoietic cells responsible for regulation of homing, marrow retention, and peripheral mobilization. Signaling downstream from the chemokine receptor CXCR4, the tyrosine kinase receptor c-kit and β1-integrins has been shown to be crucial in the regulation of migration, homing, and engraftment of hematopoietic stem cells and progenitors. Each of these receptors signal through Rac-type Rho guanosine triphosphatases (GTPases). Rac GTPases play a major role in the organization of the actin cytoskeleton and also in the control of gene expression and the activation of proliferation and survival pathways. Here we review the specific roles of the members of the Rac subfamily of the Rho GTPase family in regulating the intracellular signaling of hematopoietic cells responsible for regulation of homing, marrow retention, and peripheral mobilization. In adults, hematopoietic stem cells and progenitors (HSC/P) reside in the bone marrow (BM) and are largely absent from peripheral blood (PB) [1Morrison S.J. Uchida N. Weissman I.L. The biology of hematopoietic stem cells.Annu Rev Cell Dev Biol. 1995; 11: 35-71Crossref PubMed Google Scholar]. While BM harvests were used to collect transplantable HSC in the past, in the last 20 years, numerous reports have shown that HSC/P can be mobilized from the marrow into the PB in sufficient quantities to be harvested by leukapheresis [2Kessinger A. Sharp J.G. The whys and hows of hematopoietic progenitor and stem cell mobilization.Bone Marrow Transplant. 2003; 31: 319-329Crossref PubMed Scopus (42) Google Scholar]. By the end of the last century, traditional BM transplantation (BMT) had mostly been replaced by PB HSC/P (PBSC) transplantation (PBSCT) [2Kessinger A. Sharp J.G. The whys and hows of hematopoietic progenitor and stem cell mobilization.Bone Marrow Transplant. 2003; 31: 319-329Crossref PubMed Scopus (42) Google Scholar]. In comparison to BM harvest of stem cells, PBSCT has the advantages of not requiring general anesthesia and is typically associated with shorter periods of pancytopenia in the recipient in the posttransplant period [3Sola C. Maroto P. Salazar R. et al.Bone marrow transplantation: prognostic factors of peripheral blood stem cell mobilization with cyclophosphamide and filgrastim (r-metHuG- CSF): The CD34+ cell dose positively affects the time to hematopoietic recovery and supportive requirements after high-dose chemotherapy.Hematology. 1999; 4: 195-209PubMed Google Scholar, 4Salazar R. Sola C. Maroto P. et al.Infectious complications in 126 patients treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.Bone Marrow Transplant. 1999; 23: 27-33Crossref PubMed Google Scholar]. Administration of cytokines, such as granulocyte colony-stimulating factor (G-CSF) [5Cancelas J.A. Hernandez-Jodra M. Zamora C. et al.Circulating stem cell collection in lymphoma and myeloma after mobilization with cyclophosphamide and granulocyte colony-stimulating factor for autologous transplantation.Vox Sang. 1994; 67: 362-367Crossref PubMed Google Scholar] or stem cell factor (SCF) [6Briddell R.A. Hartley C.A. Smith K.A. McNiece I.K. Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential.Blood. 1993; 82: 1720-1723PubMed Google Scholar], chemokine-receptor inhibitors (e.g., AMD3100) [7Devine S.M. Flomenberg N. Vesole D.H. et al.Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.J Clin Oncol. 2004; 22: 1095-1102Crossref PubMed Scopus (262) Google Scholar], and cytotoxic drugs (e.g., cyclophosphamide) [5Cancelas J.A. Hernandez-Jodra M. Zamora C. et al.Circulating stem cell collection in lymphoma and myeloma after mobilization with cyclophosphamide and granulocyte colony-stimulating factor for autologous transplantation.Vox Sang. 1994; 67: 362-367Crossref PubMed Google Scholar, 8Boque C. Petit J. Sarra J. et al.Mobilization of peripheral stem cells with intensive chemotherapy (ICE regimen) and G-CSF in chronic myeloid leukemia.Bone Marrow Transplant. 1996; 18: 879-884PubMed Google Scholar, 9Cancelas J.A. Querol S. Canals C. et al.Peripheral blood CD34+ cell immunomagnetic selection in breast cancer patients: effect on hematopoietic progenitor content and hematologic recovery after high-dose chemotherapy and autotransplantation.Transfusion. 1998; 38: 1063-1070Crossref PubMed Google Scholar, 10Martinez C. Sureda A. Martino R. et al.Efficient peripheral blood stem cell mobilization with low-dose G-CSF (50 microg/m2) after salvage chemotherapy for lymphoma.Bone Marrow Transplant. 1997; 20: 855-858Crossref PubMed Google Scholar, 11Petit J. Boque C. Cancelas J.A. et al.Feasibility of ESHAP + G-CSF as peripheral blood hematopoietic progenitor cell mobilisation regimen in resistant and relapsed lymphoma: a single-center study of 22 patients.Leuk Lymphoma. 1999; 34: 119-127PubMed Google Scholar] have been used clinically to increase the number of circulating HSC/P. A goal of PBSCT for genetic blood and oncological diseases is to optimize the number of HSC to reduce the morbidity and mortality associated with rescue in the myeloablative setting [3Sola C. Maroto P. Salazar R. et al.Bone marrow transplantation: prognostic factors of peripheral blood stem cell mobilization with cyclophosphamide and filgrastim (r-metHuG- CSF): The CD34+ cell dose positively affects the time to hematopoietic recovery and supportive requirements after high-dose chemotherapy.Hematology. 1999; 4: 195-209PubMed Google Scholar, 9Cancelas J.A. Querol S. Canals C. et al.Peripheral blood CD34+ cell immunomagnetic selection in breast cancer patients: effect on hematopoietic progenitor content and hematologic recovery after high-dose chemotherapy and autotransplantation.Transfusion. 1998; 38: 1063-1070Crossref PubMed Google Scholar]. In addition, PBSC are attractive targets for cell and gene therapies [12Graham R.M. Bishopric N.H. Webster K.A. Gene and cell therapy for heart disease.IUBMB Life. 2002; 54: 59-66Crossref PubMed Scopus (13) Google Scholar]. The administration of G-CSF is currently the major method for mobilization of HSC/P for clinical usage. However, over 40% of patients who have previously undergone intensive chemotherapy, and between 10% and 20% of all patients and normal individuals, fail to mobilize sufficient numbers of HSC/P for successful PBSCT [2Kessinger A. Sharp J.G. The whys and hows of hematopoietic progenitor and stem cell mobilization.Bone Marrow Transplant. 2003; 31: 319-329Crossref PubMed Scopus (42) Google Scholar]. In addition, cytokine treatment leads to variability in the efficiency of mobilization [2Kessinger A. Sharp J.G. The whys and hows of hematopoietic progenitor and stem cell mobilization.Bone Marrow Transplant. 2003; 31: 319-329Crossref PubMed Scopus (42) Google Scholar]. HSC homing and engraftment are crucial to successful transplantation, and clinical engraftment is severely compromised when donor-cell numbers are limited. For instance, the number of HSC/P appears to limit the use of umbilical cord blood for transplantation in adult patients, where low cell dose appears to be associated with delayed engraftment and unacceptably high rates of graft failure [13Wagner J.E. Broxmeyer H.E. Byrd R.L. et al.Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment.Blood. 1992; 79: 1874-1881PubMed Google Scholar, 14Wagner J.E. Barker J.N. DeFor T.E. et al.Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.Blood. 2002; 100: 1611-1618Crossref PubMed Scopus (21) Google Scholar, 15Gluckman E. Locatelli F. Umbilical cord blood transplants.Curr Opin Hematol. 2000; 7: 353-357Crossref PubMed Scopus (40) Google Scholar, 16Gluckman E. Rocha V. Chevret S. Results of unrelated umbilical cord blood hematopoietic stem cell transplantation.Rev Clin Exp Hematol. 2001; 5: 87-99Crossref PubMed Scopus (57) Google Scholar, 17Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation.Exp Hematol. 2000; 28: 1197-1205Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar]. Another example is found in the current design of cell/gene therapy protocols, which require large numbers of HSC/P for ex vivo manipulation and subsequent reinfusion. Indeed, the recent successes of gene therapy trials for X-link severe combined immunodeficiency (SCID), adenosine deaminase–deficient SCID, and chronic granulomatous disease are due in part to the large number of transduced CD34 infused into recipients combined with the use of cytoreductive treatment to favor engraftment of these manipulated cells or disease-specific selection of the progeny of transduced cells. The fact that chemotherapy-based protocols may be inadequate or ethically unacceptable to mobilize stem cells in many immunodeficiencies and other nonmalignant genetic hematological diseases makes the search for other methods of mobilization highly desirable. Recently, several studies [18Yeh E.T. Zhang S. Wu H.D. Korbling M. Willerson J.T. Estrov Z. Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo.Circulation. 2003; 108: 2070-2073Crossref PubMed Scopus (304) Google Scholar, 19Korbling M. Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept?.N Engl J Med. 2003; 349: 570-582Crossref PubMed Scopus (464) Google Scholar, 20Hennessy B. Korbling M. Estrov Z. Circulating stem cells and tissue repair.Panminerva Med. 2004; 46: 1-11PubMed Google Scholar] have suggested that mobilized PBSCs may also contribute to the generation of nonlymphohematopoietic tissues. While controversial [21Balsam L.B. Wagers A.J. Christensen J.L. Kofidis T. Weissman I.L. Robbins R.C. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.Nature. 2004; 428: 668-673Crossref PubMed Scopus (1175) Google Scholar, 22Murry C.E. Soonpaa M.H. Reinecke H. et al.Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.Nature. 2004; 428: 664-668Crossref PubMed Scopus (1427) Google Scholar, 23Arai A.E. Sheikh F. Agyeman K.O. et al.Lack of benefit from cytokine mobilized stem cell therapy for acute myocardial infarction in nonhuman primates.J Am Coll Cardiol. 2002; 41: 335Google Scholar], these data suggest additional therapeutic applications of mobilized PBSC. Thus, increasing the HSC/P availability, by improving stem cell mobilization and/or functional modifications of the HSC/P to facilitate their homing and engraftment behavior, might provide an effective approach to cases of absent or poor engraftment after HSC/P transplantation and improve multiple therapeutic uses of stem cells in the future. Bone marrow engraftment is based on the ability of intravenously administered cells to lodge in the medullary cavity and be retained in the appropriate marrow space, a process referred to as homing. It is likely that homing is a multistep process, encompassing a sequence of highly regulated events that mimic the migration of leukocytes to inflammatory sites. In leukocytes, this process includes an initial phase of tethering and rolling of cells to the endothelium via E- and P-selectins, firm adhesion to the vessel wall via integrins that appear to be activated in an “inside-out” fashion, transendothelial migration, and chemotaxis through the extracellular matrix (ECM) to the inflammatory nidus [24Butcher E.C. Picker L.J. Lymphocyte homing and homeostasis.Science. 1996; 272: 60-66Crossref PubMed Google Scholar, 25Springer T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.Cell. 1994; 76: 301-314Abstract Full Text PDF PubMed Scopus (5267) Google Scholar, 26Peled A. Grabovsky V. Habler L. et al.The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow.J Clin Invest. 1999; 104: 1199-1211Crossref PubMed Google Scholar]. For HSC/P, the cells appear to migrate to the endosteal space [27Gong J.K. Endosteal marrow: a rich source of hematopoietic stem cells.Science. 1978; 199: 1443-1445Crossref PubMed Google Scholar, 28Nilsson S.K. Johnston H.M. Coverdale J.A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches.Blood. 2001; 97: 2293-2299Crossref PubMed Scopus (321) Google Scholar, 29Driessen R.L. Johnston H.M. Nilsson S.K. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region.Exp Hematol. 2003; 31: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. A second phase involves the subsequent interaction of specific HSC/P surface receptors, such as α4β1-integrin receptor with vascular cell adhesion molecule-1 (VCAM-1) and fibronectin in the ECM, and interactions with growth factors that are soluble, membrane- or matrix-bound [30Williams D.A. Rios M. Stephens C. Patel V.P. Fibronectin and VLA-4 in haematopoietic stem cell–microenvironment interactions.Nature. 1991; 352: 438-441Crossref PubMed Google Scholar, 31Williams D.E. Fletcher F.A. Lyman S.D. de Vries P. Cytokine regulation of hematopoietic stem cells.Semin Immunol. 1991; 3: 391-396PubMed Google Scholar]. HSC/P can be temporarily detected in other organs such as liver, lung, and kidneys after intravenous infusion but disappear from these sites within 48 hours after transplantation. In contrast, the retention of HSC/P in BM is sustained and appears specific [32Papayannopoulou T. Priestley G.V. Nakamoto B. Zafiropoulos V. Scott L.M. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins.Blood. 2001; 98: 2403-2411Crossref PubMed Scopus (123) Google Scholar]. The factors that influence the specific retention of HSC/P in the BM have only recently been defined and appear to involve the interplay between chemokines, growth factors, proteolytic enzymes, and adhesion molecules [33Papayannopoulou T. Bone marrow homing: the players, the playfield, and their evolving roles.Curr Opin Hematol. 2003; 10: 214-219Crossref PubMed Scopus (66) Google Scholar]. Among the chemokines, stromal derived factor-1α (SDF-1α) and its receptor, the G-protein-coupled seven-span transmembrane receptor CXCR4, play key roles in human HSC trafficking and repopulation [34Lapidot T. Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice.Leukemia. 2002; 16: 1992-2003Crossref PubMed Scopus (218) Google Scholar]. SDF-1α is expressed by both human and murine BM endothelium and stroma [26Peled A. Grabovsky V. Habler L. et al.The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow.J Clin Invest. 1999; 104: 1199-1211Crossref PubMed Google Scholar, 35Nagasawa T. Tachibana K. Kishimoto T. A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection.Semin Immunol. 1998; 10: 179-185Crossref PubMed Scopus (150) Google Scholar] and acts as a powerful chemoattractant of HSC/P [36Wright D.E. Bowman E.P. Wagers A.J. Butcher E.C. Weissman I.L. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines.J Exp Med. 2002; 195: 1145-1154Crossref PubMed Scopus (299) Google Scholar, 37Aiuti A. Webb I.J. Bleul C. Springer T. Gutierrez-Ramos J.C. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood.J Exp Med. 1997; 185: 111-120Crossref PubMed Scopus (944) Google Scholar]. SDF-1α may also regulate the survival of HSC/P [38Lataillade J.J. Clay D. Dupuy C. et al.Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival.Blood. 2000; 95: 756-768Crossref PubMed Google Scholar, 39Broxmeyer H.E. Kohli L. Kim C.H. et al.Stromal cell–derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and Gαi proteins and enhances engraftment of competitive, repopulating stem cells.J Leukoc Biol. 2003; 73: 630-638Crossref PubMed Scopus (112) Google Scholar]. SDF-1α induces the integrin-mediated firm adhesion of human HSC/P, facilitates their transendothelial migration [26Peled A. Grabovsky V. Habler L. et al.The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow.J Clin Invest. 1999; 104: 1199-1211Crossref PubMed Google Scholar, 40Peled A. Kollet O. Ponomaryov T. et al.The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice.Blood. 2000; 95: 3289-3296Crossref PubMed Google Scholar], and regulates homing [41Kollet O. Spiegel A. Peled A. et al.Rapid and efficient homing of human CD34+CD38−/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice.Blood. 2001; 97: 3283-3291Crossref PubMed Scopus (201) Google Scholar] and BM engraftment [42Peled A. Petit I. Kollet O. et al.Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.Science. 1999; 283: 845-848Crossref PubMed Scopus (1058) Google Scholar]. Furthermore, SDF-1α is also required for the retention of murine HSC/P within the BM [43Ma Q. Jones D. Springer T.A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment.Immunity. 1999; 10: 463-471Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 44Nagasawa T. Hirota S. Tachibana K. et al.Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.Nature. 1996; 382: 635-638Crossref PubMed Scopus (1491) Google Scholar]. Among growth factors, a critical factor for HSC/P survival and engraftment is stem cell factor (SCF). SCF is expressed by BM stromal cells and is the ligand for the receptor tyrosine kinase, c-kit. A transmembrane isoform of SCF, membrane-bound SCF (m-SCF), has recently been shown to be critical in the lodgment and retention of HSC within the hematopoietic microenvironment, although it does not appear to play a role in the homing of transplanted cells to BM [29Driessen R.L. Johnston H.M. Nilsson S.K. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region.Exp Hematol. 2003; 31: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. In addition, it appears that c-kit activation is differentially affected by soluble vs m-SCF [45Miyazawa K. Williams D.A. Gotoh A. Nishimaki J. Broxmeyer H.E. Toyama K. Membrane-bound Steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form.Blood. 1995; 85: 641-649Crossref PubMed Google Scholar] and SCF induces overexpression of CXCR4 [41Kollet O. Spiegel A. Peled A. et al.Rapid and efficient homing of human CD34+CD38−/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice.Blood. 2001; 97: 3283-3291Crossref PubMed Scopus (201) Google Scholar, 42Peled A. Petit I. Kollet O. et al.Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.Science. 1999; 283: 845-848Crossref PubMed Scopus (1058) Google Scholar]. A third important factor in stem cell retention is the integrin-mediated adhesion molecules. Among them, α4β1-integrin is probably the best characterized [32Papayannopoulou T. Priestley G.V. Nakamoto B. Zafiropoulos V. Scott L.M. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins.Blood. 2001; 98: 2403-2411Crossref PubMed Scopus (123) Google Scholar, 46Papayannopoulou T. Craddock C. Nakamoto B. Priestley G.V. Wolf N.S. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen.Proc Natl Acad Sci U S A. 1995; 92: 9647-9651Crossref PubMed Scopus (329) Google Scholar, 47Papayannopoulou T. Craddock C. Homing and trafficking of hemopoietic progenitor cells.Acta Haematol. 1997; 97: 97-104Crossref PubMed Google Scholar, 48Scott L.M. Priestley G.V. Papayannopoulou T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing.Mol Cell Biol. 2003; 23: 9349-9360Crossref PubMed Scopus (159) Google Scholar] and is discussed below. HSC/P mobilization is also a dynamic and complex process [49Thomas J. Liu F. Link D.C. Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor.Curr Opin Hematol. 2002; 9: 183-189Crossref PubMed Scopus (91) Google Scholar, 50Rafii S. Heissig B. Hattori K. Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors.Gene Ther. 2002; 9: 631-641Crossref PubMed Google Scholar, 51Kronenwett R. Martin S. Haas R. The role of cytokines and adhesion molecules for mobilization of peripheral blood stem cells.Stem Cells. 2000; 18: 320-330Crossref PubMed Google Scholar]. HSC/P must presumably exit the stem cell niche in the BM, migrate through the marrow sinusoidal endothelium, and gain access to the blood. Circulating HSC/P and BM-adherent HSC/P appear to be interchangeable. Studies utilizing parabiotic mice have demonstrated that HSC/P can leave their niche without induction, traffic through the bloodstream, and finally migrate into BM of the conjoined animal [52Wang J. Kimura T. Asada R. et al.SCID-repopulating cell activity of human cord blood–derived CD34− cells assured by intra–bone marrow injection.Blood. 2003; 101: 2924-2931Crossref PubMed Scopus (132) Google Scholar, 53Wright D.E. Wagers A.J. Gulati A.P. Johnson F.L. Weissman I.L. Physiological migration of hematopoietic stem and progenitor cells.Science. 2001; 294: 1933-1936Crossref PubMed Scopus (465) Google Scholar, 54Warren S. Chute R.N. Farrington E.M. Protection of the hematopoietic system by parabiosis.Lab Invest. 1960; 9: 191-198PubMed Google Scholar, 55Abkowitz J.L. Robinson A.E. Kale S. Long M.W. Chen J. The mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure.Blood. 2003; 102: 1249-1253Crossref PubMed Scopus (141) Google Scholar]. This suggests that HSC/P trafficking is a physiological process. If so, circulating HSC/P would be predicted to move into the BM microenvironment through transendothelial migration directed by chemoattractants, and ultimately anchor within the extravascular BM space where proliferation and differentiation occur. In this process, adhesion molecules, chemokine receptors, and integrin signaling require signal integration that drives cytoskeleton rearrangements, gene transcription activation, cell survival, and cell cycle activation pathways. At the molecular level, the interaction between SDF-1α and the chemokine receptor CXCR4 has been recognized as pivotal in stem cell mobilization. As HSC/P are known to migrate towards a SDF-1α gradient [56Sweeney E.A. Papayannopoulou T. Increase in circulating SDF-1 after treatment with sulfated glycans. The role of SDF-1 in mobilization.Ann N Y Acad Sci. 2001; 938: 48-52Crossref PubMed Google Scholar], it has been suggested that treatment with G-CSF, cyclophosphamide, or interleukin (IL)-8 leads to a reduction of SDF-1α in BM, resulting in a positive gradient towards PB and induction of HSC/P migration into the blood. Raising the plasma levels of SDF-1α by intravenous injection of SDF-1α-expressing adenovirus [57Hattori K. Heissig B. Tashiro K. et al.Plasma elevation of stromal cell–derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells.Blood. 2001; 97: 3354-3360Crossref PubMed Scopus (341) Google Scholar] or sulfated polysaccharides [58Sweeney E.A. Lortat-Jacob H. Priestley G.V. Nakamoto B. Papayannopoulou T. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells.Blood. 2002; 99: 44-51Crossref PubMed Scopus (148) Google Scholar], or by inhibition of the CXCR4 receptor [7Devine S.M. Flomenberg N. Vesole D.H. et al.Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.J Clin Oncol. 2004; 22: 1095-1102Crossref PubMed Scopus (262) Google Scholar, 59Tavor S. Petit I. Porozov S. et al.CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice.Cancer Res. 2004; 64: 2817-2824Crossref PubMed Scopus (149) Google Scholar, 60Liles W.C. Broxmeyer H.E. Rodger E. et al.Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist.Blood. 2003; 102: 2728-2730Crossref PubMed Scopus (406) Google Scholar], leads to mobilization of HSC/P. G-protein inhibition by pertussis toxin [61Papayannopoulou T. Priestley G.V. Bonig H. Nakamoto B. The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization.Blood. 2003; 101: 4739-4747Crossref PubMed Google Scholar] induces a similar mobilization effect, probably by interfering with the CXCR4 signaling pathway. Functional blocking of α4β1-integrin (receptor for VCAM-1 and fibronectin) alone or together with αlβ2-integrin or the functional blocking of the β2 integrin LFA-1 (leukocyte function–associated antigen-1) by antibodies results in mobilization of HSC/P [62Papayannopoulou T. Priestley G.V. Nakamoto B. Zafiropoulos V. Scott L.M. Harlan J.M. Synergistic mobilization of hemopoietic progenitor cells using concurrent β1 and β2 integrin blockade or β2-deficient mice.Blood. 2001; 97: 1282-1288Crossref PubMed Scopus (50) Google Scholar, 63Craddock C.F. Nakamoto B. Andrews R.G. Priestley G.V. Papayannopoulou T. Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice.Blood. 1997; 90: 4779-4788PubMed Google Scholar]. HSC/P accumulate in the PB soon after gene deletion in inducible α4β1-integrin-deficient mice. Although their numbers gradually stabilize at a lower level, progenitor cell influx into the circulation continues at above-normal levels for more than 50 weeks with a concomitant progressive accumulation of spleen HSC/P [48Scott L.M. Priestley G.V. Papayannopoulou T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing.Mol Cell Biol. 2003; 23: 9349-9360Crossref PubMed Scopus (159) Google Scholar]. The interaction between SCF and its receptor c-kit plays an important and independent role in HSC/P mobilization. SCF/c-kit interaction plays a critical role in G-CSF-mediated mobilization [64Heissig B. Hattori K. Dias S. et al.Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.Cell. 2002; 109: 625-637Abstract Full Text Full Text PDF PubMed Scopus (1027) Google Scholar, 65Levesque J.P. Hendy J. Winkler I.G. Takamatsu Y. Simmons P.J. Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-kit receptor (CD117) from the surface of hematopoietic progenitor cells.Exp Hematol. 2003; 31: 109-117Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar], and SCF in combination with G-CSF has been shown to enhance HSC/P mobilization [66McNiece I.K. Briddell R.A. Stem cell factor.J Leukoc Biol. 1995; 58: 14-22PubMed Google Scholar]. As mentioned above, m-SCF has been shown to be critical in retaining HSC/P in BM [29Driessen R.L. Johnston H.M. Nilsson S.K. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region.Exp Hematol. 2003; 31: 1284-1291Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. The signals involved in engraftment and mobilization also drive cytoskeleton rearrangements, gene transcription activation, cell survival, and cell cycle activation. In 1992, Ridley and Hall [67Ridley A.J. Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors.Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (2847) Google Scholar, 68Ridley A.J. Paterson H.F. Johnston C.L. Diekmann D. Hall A. The small GTP-binding protein rac regulates growth factor–induced membrane ruffling.Cell. 1992; 70: 401-410Abstract Full Text PDF PubMed Scopus (2332) Google Scholar] reported that cytoskeleton rearrangements are controlled by members of th" @default.
• W2006771034 created "2016-06-24" @default.
• W2006771034 creator A5056346259 @default.
• W2006771034 creator A5058501688 @default.
• W2006771034 creator A5073333838 @default.
• W2006771034 date "2006-08-01" @default.
• W2006771034 modified "2023-10-07" @default.
• W2006771034 title "The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization" @default.
• W2006771034 cites W1485136427 @default.
• W2006771034 cites W1532087698 @default.
• W2006771034 cites W1539448360 @default.
• W2006771034 cites W1548908535 @default.
• W2006771034 cites W1568345151 @default.
• W2006771034 cites W1577314069 @default.
• W2006771034 cites W1845171218 @default.
• W2006771034 cites W1964015260 @default.
• W2006771034 cites W1964825686 @default.
• W2006771034 cites W1966760616 @default.
• W2006771034 cites W1969814333 @default.
• W2006771034 cites W1970170695 @default.
• W2006771034 cites W1970590098 @default.
• W2006771034 cites W1971119286 @default.
• W2006771034 cites W1973318395 @default.
• W2006771034 cites W1974896636 @default.
• W2006771034 cites W1982627832 @default.
• W2006771034 cites W1985128235 @default.
• W2006771034 cites W1985753831 @default.
• W2006771034 cites W1985965995 @default.
• W2006771034 cites W1986013003 @default.
• W2006771034 cites W1989550450 @default.
• W2006771034 cites W2000894772 @default.
• W2006771034 cites W2002248235 @default.
• W2006771034 cites W2006777514 @default.
• W2006771034 cites W2007660746 @default.
• W2006771034 cites W2010401334 @default.
• W2006771034 cites W2010630254 @default.
• W2006771034 cites W2011874994 @default.
• W2006771034 cites W2013789757 @default.
• W2006771034 cites W2017802236 @default.
• W2006771034 cites W2018750173 @default.
• W2006771034 cites W2021889129 @default.
• W2006771034 cites W20228888 @default.
• W2006771034 cites W2023873491 @default.
• W2006771034 cites W2024207983 @default.
• W2006771034 cites W2027927113 @default.
• W2006771034 cites W2029434537 @default.
• W2006771034 cites W2039638385 @default.
• W2006771034 cites W2040443947 @default.
• W2006771034 cites W2042626190 @default.
• W2006771034 cites W2047870699 @default.
• W2006771034 cites W2048148938 @default.
• W2006771034 cites W2049788084 @default.
• W2006771034 cites W2050154239 @default.
• W2006771034 cites W2058402992 @default.
• W2006771034 cites W2061285112 @default.
• W2006771034 cites W2061913305 @default.
• W2006771034 cites W2064068411 @default.
• W2006771034 cites W2064771788 @default.
• W2006771034 cites W2066723778 @default.
• W2006771034 cites W2068380542 @default.
• W2006771034 cites W2071294208 @default.
• W2006771034 cites W2074356513 @default.
• W2006771034 cites W2075109573 @default.
• W2006771034 cites W2075831592 @default.
• W2006771034 cites W2081769332 @default.
• W2006771034 cites W2083643468 @default.
• W2006771034 cites W2090041902 @default.
• W2006771034 cites W2091076807 @default.
• W2006771034 cites W2091153543 @default.
• W2006771034 cites W2093139913 @default.
• W2006771034 cites W2093226717 @default.
• W2006771034 cites W2093715533 @default.
• W2006771034 cites W2095535774 @default.
• W2006771034 cites W2097925286 @default.
• W2006771034 cites W2098301486 @default.
• W2006771034 cites W2098658264 @default.
• W2006771034 cites W2099186644 @default.
• W2006771034 cites W2099675490 @default.
• W2006771034 cites W2101129972 @default.
• W2006771034 cites W2101163518 @default.
• W2006771034 cites W2103188253 @default.
• W2006771034 cites W2111061323 @default.
• W2006771034 cites W2112668385 @default.
• W2006771034 cites W2114736117 @default.
• W2006771034 cites W2114741924 @default.
• W2006771034 cites W2118060829 @default.
• W2006771034 cites W2118573723 @default.
• W2006771034 cites W2122152063 @default.
• W2006771034 cites W2124090816 @default.
• W2006771034 cites W2124514001 @default.
• W2006771034 cites W2125768358 @default.
• W2006771034 cites W2126229173 @default.
• W2006771034 cites W2128797396 @default.
• W2006771034 cites W2135776652 @default.
• W2006771034 cites W2136864957 @default.
• W2006771034 cites W2141569720 @default.
• W2006771034 cites W2141837666 @default.
• W2006771034 cites W2142207476 @default.

• next