Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1(ext-IgG), consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG(1), promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1(ext-IgG) increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7Ralpha, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1(ext-IgG)-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.
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PMID:Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. 1721 87

In this study, we use competitive repopulation to compare the quality and frequency of stem cells isolated from mobilized blood with stem cells isolated from bone marrow (BM) in a mouse model. Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were harvested from control BM and peripheral blood of mice following granulocyte colony-stimulating factor (G-CSF) administration. LSK cells were used because of their resemblance to human CD34(+) cells. We confirmed that transplantation of phenotypically defined mobilized peripheral blood (MPB) stem cells results in rapid recovery of blood counts. However, in vitro results indicated that LSK cells purified from MPB had lower cobblestone area-forming cell day 35 activity compared to BM. Additionally, evaluation of chimerism after co-transplantation of LSK cells purified from blood and BM revealed that MPB stem cells contained 25-fold less repopulation potential compared to BM stem cells. Competitive repopulating unit frequency analysis showed that freshly isolated MPB LSK cells have 8.8-fold fewer cells with long-term repopulating ability compared to BM LSK cells. Secondary transplantation showed no further decline in contribution of hematopoiesis relative to BM. We conclude that the reduced frequency of stem cells within the LSK population of MPB, rather than poorer quality, causes the reduced repopulation potential.Bone Marrow Transplantation (2007) 39, 401-409. doi:10.1038/sj.bmt.1705601; published online 12 February 2007.
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PMID:Mobilized peripheral blood stem cells provide rapid reconstitution but impaired long-term engraftment in a mouse model. 1729 81

It is now evident that hemopoietic stem cells (HSC) are located in close proximity to bone lining cells within the endosteum. Accordingly, it is unlikely that the traditional method for harvesting bone marrow (BM) from mice by simply flushing long bones would result in optimal recovery of HSC. With this in mind, we have developed improved methodologies based on sequential grinding and enzymatic digestion of murine bone tissue to harvest higher numbers of BM cells and HSC from the endosteal and central marrow regions. This methodology resulted in up to a sixfold greater recovery of primitive hemopoietic cells (lineage(-)Sca(+)Kit(+) [LSK] cells) and HSC as shown by transplant studies. HSC from different anatomical regions of the marrow exhibited important functional differences. Compared with their central marrow counterparts, HSC isolated from the endosteal region (a) had 1.8-fold greater proliferative potential, (b) exhibited almost twofold greater ability to home to the BM following tail vein injection and to lodge in the endosteal region, and (c) demonstrated significantly greater long-term hemopoietic reconstitution potential as shown using limiting dilution competitive transplant assays.
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PMID:Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. 1742 Feb 30

Studies from our and other laboratories have over the last 2 years implicated the existence of multipotent progenitors (MPPs) with combined granulocyte-macrophage, B cell, and T cell potential, but little or no megakaryocyte-erythroid (MkE) potential in the adult bone marrow Lineage(-)SCA-1(+)KIT(+) (LSK) compartment of multipotent stem and progenitor cells. The evidence for the existence of LSKCD34(+)FLT3(hi) lymphoid-primed MPPs (LMPPs) implicates that a strict separation into common myeloid and lymphoid pathways might not be the first lineage commitment step of hematopoietic stem cells (HSCs). Together with the evidence for existence of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively), the identification of LMPPs also suggests that at least the granulocyte-macrophage lineage can be generated through alternative pathways. However, the existence of LMPPs has recently been questioned, as there is evidence that at least a fraction of LSKCD34(+)FLT3(hi) cells sustains MkE potential. Thus, in more recent studies we have in more detail compared the molecular signature of adult LMPPs to populations of LSK cells enriched for cells with pluripotent HSC activity. Notably, we have found at the global as well as single-cell level that LMPPs when compared with pluripotent HSCs downregulate the transcriptional priming of genes typically expressed in cells of the MkE lineage, while upregulating early lymphoid genes. Although other studies have suggested that the earliest HSC commitment steps might differ in fetal and adult hematopoiesis, we have also obtained evidence suggesting that the LMPP is defined already during fetal development.
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PMID:Biological and molecular evidence for existence of lymphoid-primed multipotent progenitors. 1744 77

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)-deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor alpha (IL-7Ralpha) signaling. Fl-/-Il-7r-/- mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Ralpha-independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Ralpha, in regulation of the earliest lineage-negative (Lin(-)) Lin(-)SCA1+KIT+ (LSK) FLT3(hi) lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
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PMID:Critical role of FLT3 ligand in IL-7 receptor independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors. 1754 Aug 45

Homing of hematopoietic stem cells (HSCs) into the bone marrow (BM) is a prerequisite for establishment of hematopoiesis during development and following transplantation. However, the molecular interactions that control homing of HSCs, in particular, of fetal HSCs, are not well understood. Herein, we studied the role of the alpha6 and alpha4 integrin receptors for homing and engraftment of fetal liver (FL) HSCs and hematopoietic progenitor cells (HPCs) to adult BM by using integrin alpha6 gene-deleted mice and function-blocking antibodies. Both integrins were ubiquitously expressed in FL Lin(-)Sca-1(+)Kit(+) (LSK) cells. Deletion of integrin alpha6 receptor or inhibition by a function-blocking antibody inhibited FL LSK cell adhesion to its extracellular ligands, laminins-411 and -511 in vitro, and significantly reduced homing of HPCs to BM. In contrast, the anti-integrin alpha6 antibody did not inhibit BM homing of HSCs. In agreement with this, integrin alpha6 gene-deleted FL HSCs did not display any homing or engraftment defect compared with wild-type littermates. In contrast, inhibition of integrin alpha4 receptor by a function-blocking antibody virtually abrogated homing of both FL HSCs and HPCs to BM, indicating distinct functions for integrin alpha6 and alpha4 receptors during homing of fetal HSCs and HPCs.
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PMID:Distinct roles of integrins alpha6 and alpha4 in homing of fetal liver hematopoietic stem and progenitor cells. 1758 25

CD8(+) tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3 zeta is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLC gamma-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56(lck) is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting "switch". Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56(lck) ( approximately 10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56(lck) in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56(lck) in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56(lck) activation motif (Y394), thus inhibiting effector phase functions.
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PMID:Suppression of proximal T cell receptor signaling and lytic function in CD8+ tumor-infiltrating T cells. 1805 73

Hematopoietic stem cell (HSC) numbers are tightly regulated and maintained in postnatal hematopoiesis. Extensive studies have supported a role of the cytokine tyrosine kinase receptor Kit in sustaining cycling HSCs when competing with wild-type HSCs posttransplantation, but not in maintenance of quiescent HSCs in steady state adult bone marrow. In this study, we investigated HSC regulation in White Spotting 41 (Kit(W41/W41)) mice, with a partial loss of function of Kit. Although the extensive fetal HSC expansion was Kit-independent, adult Kit(W41/W41) mice had an almost 2-fold reduction in long-term HSCs, reflecting a loss of roughly 10,000 Lin(-)Sca-1(+)Kit(high) (LSK)CD34(-)Flt3(-) long-term HSCs by 12 wk of age, whereas LSKCD34(+)Flt3(-) short-term HSCs and LSKCD34(+)Flt3(+) multipotent progenitors were less affected. Whereas homing and initial reconstitution of Kit(W41/W41) bone marrow cells in myeloablated recipients were close to normal, self-renewing Kit(W41/W41) HSCs were progressively depleted in not only competitive but also noncompetitive transplantation assays. Overexpression of the anti-apoptotic regulator BCL-2 partially rescued the posttransplantation Kit(W41/W41) HSC deficiency, suggesting that Kit might at least in the posttransplantation setting in part sustain HSC numbers by promoting HSC survival. Most notably, accelerated in vivo BrdU incorporation and cell cycle kinetics implicated a previously unrecognized role of Kit in maintaining quiescent HSCs in steady state adult hematopoiesis.
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PMID:Kit regulates maintenance of quiescent hematopoietic stem cells. 1825 Apr 9

Immunosuppressive therapy has relied on tailoring combinations of relatively nonselective drugs to individual patient tolerance. The next steps in the development of small molecule agents are to define and to develop selective inhibitors of cascades unique to T cells. This selectivity would minimize the inherent toxicity associated with drug therapy. Two targets identified at present are lymphoid cell kinase (lck; Signal 1) and Janus kinase 3 (Jak3; Signal 3). Although preliminary data support the immunosuppressive efficacy of putative antagonists, it is not clear that they are sufficiently selective for the target molecule as opposed to other kinases. Another novel approach to immunosuppression seeks to promote lymphoid cell sequestration in nodes through agonistic effects on sphingosine-1-phosphate receptors. Due to the availability of specific assays and high through put analysis of molecular candidates, the next decade should witness a panoply of new agents.
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PMID:Frontiers in immunosuppression. 1826 36

It was recently discovered that a subset of osteoblasts functions as a key component of the hematopoietic stem cells (HSC) niche in vivo, controlling HSC self-renewal and multi-lineage differentiation. Disruption of Smad4 gene specifically in osteoblasts leads to a remarkable decrease of osteoblast number and endosteal surface area. In order to elucidate if the osteoblast loss has any effect on hematopoietic activity, the bone marrow (BM) and extramedullary hematopoiesis in the osteoblast-specific Smad4 knockout mice were systematically analyzed, the proportions of mature hematocytes in BM, liver and spleen were detected by flow cytometry, the hematopoietic progenitor number in different stages was measured by colong-forming assay, CFU-S and analysis of LSK cells. The results indicated that the conditional mutant mice demonstrated normal BM hematopoiesis without sign of extramedullary hematopoiesis. Furthermore, the proportion of hematopoietic progenitor cells was normal, while cell number/body weight of the conditional knockout mice increased. It is concluded that hematopoiesis is normally maintained in osteoblast-specific Smad4 knockout mice, and osteoblast loss does not of necessity result in the decrease in BM hematopoiesis.
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PMID:[Hematopoiesis is normally maintained in osteoblast-specific Smad4 gene knockout mice]. 1831 22


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