Rac2-Deficient Hematopoietic Stem Cells Show Defective Interaction with the Hematopoietic Microenvironment and Long-Term Engraftment Failure

Jansen, Michael; Yang, Feng-Chun; Cancelas, José A.; Bailey, Jeff; Williams, David A.

doi:10.1634/stemcells.2004-0216

Cited by 57 publications

(42 citation statements)

References 63 publications

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“…Similar findings were reported in Rac2-deficient HSC/P cells: the proliferation of Rac2 À/À HSC/P cells in high proliferative potential colonyforming assays was not different from their wild-type counterparts; however, in vivo studies demonstrated that Rac2 À/À HSC/P ability of long-term engraftment was impaired, suggesting that Rac2 plays an important role in HSC/P microenvironmental localization during the engraftment process. 51 In summary, the current studies provide evidence for the importance of FAK signaling in chemotactic and pro-adhesive responses of hematopoietic cells. We conclude that in vivo studies employing FAK-targeted mouse model systems are needed to provide insight into the function of FAK in various aspects of hematopoiesis, including HSC/P homing, engraftment and lineage development.…”

Section: Fak Deletion Significantly Reduces Cxcl12-mediated Migrationmentioning

confidence: 67%

Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells

Glodek

Dykxhoorn

et al. 2007

Leukemia

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Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell-cell and cell-matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK flox/flox hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.

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Section: Fak Deletion Significantly Reduces Cxcl12-mediated Migrationmentioning

confidence: 67%

Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells

Glodek

Dykxhoorn

et al. 2007

Leukemia

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“…Other alternative conditioning regimens have been reported that involve mobilization using AMD3100, 44 which was sufficient for chimerism at levels of 5% overall chimerism using 4 ϫ 10 7 BM cells. Rac2 Ϫ/Ϫ mice could be modestly engrafted 45 at less than 5% overall using 2.5 ϫ 10 7 cells, but this was associated with mobilization that was most profound when both Rac1/2 were deleted. 46 An important observation of these studies is that STAT5 dosage regulates HSC competition.…”

Section: Discussionmentioning

confidence: 99%

Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement

Wang

Tse

et al. 2009

Blood

104

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IntroductionThe hematopoietic stem cell (HSC) niche has a direct role in supporting hematopoietic engraftment and the potential for maintenance of normal hematopoiesis. Because of the critical nature of the hematopoietic microenvironment for the long-term HSC (LT-HSC) activity in the host, the ability to get HSCs into the niche efficiently has been the goal of clinical bone marrow (BM) transplantation since its first inception. With the aim of lifelong disease correction, this has classically been achieved through general nonspecific destruction of the BM cells and, along with them, some of the niche components, including stroma and vasculature. Common approaches rely on high-dose radiation or DNA alkylating agents, both of which are stem cell toxic because they target dividing and nondividing cells and have nonhematopoietic toxicities, especially of the gastrointestinal tract. The DNA damage ultimately kills quiescent host HSCs when they reenter the cell cycle and allows for donor engraftment. Defects in the repair of DNA damage by nonhomologous end joining in DNA ligase IV-deficient mice permits high levels of donor HSC engraftment in nonablated hosts 1 by mimicking the effects of traditional conditioning. In contrast, drugs, such as 5-fluorouracil, which spare quiescent HSCs, 2 do not effectively promote donor engraftment.Murine preclinical studies as early as 1968 demonstrated that engraftment could be achieved without myeloablation using large cell doses. 3,4 A series of studies using single or cumulative doses up to 2 ϫ 10 8 cells in wild-type adult Balb/c recipients showed significant donor chimerism without ablation. [5][6][7][8][9][10] Other groups also reported similar levels of engraftment. 11 Studies in nonablated newborn mice with intravenous injections with a cumulative dose of 3 ϫ 10 7 adult BM cells were able to show donor engraftment. 12 However, fetal and newborn mice are generally more receptive to engraftment than adults. In adult mice, either local irradiation 13 or intrafemoral injection 14 of donor BM cells improved engraftment in the entire BM space and showed that homing was essentially independent of irradiation.Although increasing the cell dose can overcome some barriers to HSC engraftment in experimental models, in the clinical setting repeated injections with large numbers of stem cells might not be feasible without safe and efficient methods for HSC expansion ex vivo. Although myeloablative conditioning is generally required for donor engraftment of BM HSCs, some genetically altered mice provide clues toward targeted approaches with less DNA damaging treatment. Mice with mutations at the W locus are very receptive to donor engraftment without the need for myeloablative conditioning. Recent studies have shown important roles for the cell surface receptor tyrosine kinases stem cell factor/c-Kit 15 or thrombopoietin (TPO)/c-Mpl 16,17 in maintaining HSC quiescence. Furthermore, proof of principle has been obtained that targeting these receptors can be manipulated to support donor HSC en...

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“…43,44 Small Rho GTPases, including Rac1, Rac2, and Cdc42, are involved in the regulation of adhesion in various mammalian cell types, including hematopoietic cells. 40,[45][46][47] They act as molecular switches by cycling between an active GTP-bound form and an inactive GDP-bound form. Upon activation by distinct signals originating from these "environment sensing" receptors, active GTP-bound GTPases ultimately regulate actin polymerization, integrin clustering, and adhesion receptor-mediated adhesion.…”

Section: Increased Level Of Activation Of Cdc42 In Aged Primitive Hemmentioning

confidence: 99%

Increased hematopoietic stem cell mobilization in aged mice

Xing

Ryan

Daria

et al. 2006

Blood

149

111

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IntroductionHematopoietic stem and progenitor cells (HSPCs) are located in the bone marrow (BM) in close association with a highly organized 3-dimensional structure formed by stroma cells, referred to as the niche. 1,2 It has been demonstrated that these cell-cell interactions are vital for the biology of HSPCs. Systemic administration of cytokines and chemokines or cytotoxic agents mobilize HSPCs from the BM into peripheral blood (PB), where they are collected in clinically useful quantities for stem cell therapies. 3,4 Mobilization of HSPCs in response to these factors requires the de-adhesion of HSPCs from the niche. 5,6 Evidence accumulating over the past decade has proven that there is a measurable and successive functional decline in hematopoietic, intestinal, and muscle stem cell function. 7,8 Given that stem cell activity is necessary to replenish lost differentiated cells, it has been hypothesized that aging of hematopoietic stem cells (HSCs) leads to reduced stem cell renewal and thus reduced tissue homeostasis in aged animals, [7][8][9][10][11] which is emphasized by ageassociated anemia and a decline in function of immune cells in elderly persons. 12-19 HSC aging is intrinsic to the aged cell and cannot be reverted by exposing HSCs from aged animals to a young microenvironment. [18][19][20] The ability of healthy, older patients to undergo stem cell mobilization in response to granulocyte colony-stimulating factor (G-CSF), the standard regimen used for clinical HSPC mobilization, has thus far not been investigated in detail because autologous hematopoietic stem cell transplantation is most often administered to adults younger than 50 years and rarely to patients older than 60 years. 21,22 The limited available information is not conclusive in terms of efficiency of mobilization because it is based primarily on the analysis of mobilization of elderly patients after severe chemotherapy 23,24 and possibly also because 2 different methods of determining mobilization efficiency are used (colony-forming cell [CFC] frequency vs CD34 ϩ cell frequency in PB). Combining general clinical wisdom and these published reports, it is anticipated that the ability to mobilize HSPCs in response to G-CSF may be reduced in elderly patients, [23][24][25][26] hampering the efficient collection of HSPCs for subsequent hematopoietic stem cell therapies. Whether a negative correlation exists between age and mobilization is still under debate. 24,25 The mouse has been used in a wide variety of studies to model human G-CSF-induced mobilization of HSCs, with an overall good correlation between results obtained from murine studies and subsequent results obtained in humans. By investigating mobilization proficiency in aged mice, we report here that aged mice show not only decreased but increased efficiency in mobilizing hematopoietic progenitor cells (HPCs) and HSCs to PB. Materials and methods AnimalsYoung C57BL/6J mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were subsequently housed in the animal barrier ...

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Rac2-Deficient Hematopoietic Stem Cells Show Defective Interaction with the Hematopoietic Microenvironment and Long-Term Engraftment Failure

Cited by 57 publications

References 63 publications

Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells

Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells

Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement

Increased hematopoietic stem cell mobilization in aged mice

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