Browsing by Subject "hematopoietic stem and progenitor cells"

Now showing 1 - 3 of 3
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    DEK, a nuclear protein, is chemotactic for hematopoietic stem/progenitor cells acting through CXCR2 and Gαi signaling
    (Wiley, 2022) Capitano, Maegan L.; Sammour, Yasser; Ropa, James; Legendre, Maureen; Mor-Vaknin, Nirit; Markovitz, David M.; Microbiology and Immunology, School of Medicine
    Few cytokines/growth modulating proteins are known to be chemoattractants for hematopoietic stem (HSC) and progenitor cells (HPC); stromal cell-derived factor 1α (SDF1α/CXCL12) being the most potent known such protein. DEK, a nuclear DNA-binding chromatin protein with hematopoietic cytokine-like activity, is a chemotactic factor attracting mature immune cells. Transwell migration assays were performed to test whether DEK serves as a chemotactic agent for HSC/HPC. DEK induced dose- and time-dependent directed migration of lineage negative (Lin–) Sca-1+ c-Kit+ (LSK) bone marrow (BM) cells, HSCs and HPCs. Checkerboard assays demonstrated that DEK's activity was chemotactic (directed), not chemokinetic (random migration), in nature. DEK and SDF1α compete for HSC/HPC chemotaxis. Blocking CXCR2 with neutralizing antibodies or inhibiting Gαi protein signaling with Pertussis toxin pretreatment inhibited migration of LSK cells toward DEK. Thus, DEK is a novel and rare chemotactic agent for HSC/HPC acting in a direct or indirect CXCR2 and Gαi protein-coupled signaling-dependent manner.
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    Putative Mechanisms Underlying Cardiovascular Disease Associated with Clonal Hematopoiesis of Indeterminate Potential
    (Elsevier, 2020-08-11) Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of Medicine
    Characterized by the expansion of somatic mutations in the hematopoietic lineages of aging individuals, clonal hematopoiesis of indeterminate potential (CHIP) is a common condition that increases the risk of developing hematological malignancies and cardiovascular disease (CVD). The presence of CHIP-associated mutations in hematopoietic stem and progenitor cells (HSPCs) suggests that these mutations may alter the functions of the diverse hematopoietic lineages, many of which influence the pathogenesis of CVD. Inflammation may be a potential pathogenic mechanism, linking both CVD and hematological malignancy. However, it remains unknown whether CHIP-associated CVD and hematological malignancy are features of a common disease spectrum. The contributions of CHIP-associated mutations to both CVD and hematological malignancy underscore the importance of stem cell biology in pathogenesis and treatment. This review discusses possible mechanisms underlying the contributions of multiple hematopoietic lineages to CHIP-associated CVD and the putative pathogenic links between CHIP-associated CVD and hematological malignancy.
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    Rap1 is a Potential Therapeutic Target for Non-myeloablative Conditioning
    (Office of the Vice Chancellor for Research, 2013-04-05) Ghosh, Joydeep; Ramdas, Baskar; Quilliam, Lawrence; Kapur, Reuben
    various side effects including gastrointestinal mucositis. Identification of therapeutic targets and determining their role in HSC development and function is important to determine a regimen for nonmyeloablative conditioning. Previous studies have shown that GTPases play a critical role in self-renewal, engraftment and retention of HSCs. Rap1, a GTPase, is necessary for migration, adhesion as well as function of mature hematopoietic cells. To study the role of Rap1 in hematopoietic stem and progenitor cells (HSC/Ps), we have generated a mouse model in which the Rap1a and Rap1b isoforms of Rap1 are conditionally deleted in HSC/Ps (Rap1a/b -/-). Deficiency of Rap1a/b results in increased peripheral blood count as well as increase in HSCs in bone marrow along with a decrease in bone marrow cellularity. Rap1a/b deficient bone marrow HSC/Ps also have reduced adhesion capability in vitro. The self-renewal property of HSCs, in conjunction with their ability of multi-lineage reconstitution is important to repopulate the hematopoietic system of irradiated recipients of bone marrow transplant. Rap1a/b -/- HSCs show a defect in engraftment as well as multi-lineage reconstitution when they are transplanted into lethally irradiated hosts. Rap1 deficient HSCs show decreased homing into bone marrow of lethally irradiated recipients. To determine whether Rap1 can be used as a potential target for nonmyeloablative conditioning, we performed bone marrow transplant into WT and Rap1a/b -/- mice without prior irradiation. Deficiency of Rap1a/b in HSCs resulted in availability of bone marrow niche for exogenously transplanted HSCs to engraft along with subsequent multi-lineage reconstitution. Overall, our study reveals that Rap1a/b are important for homing and retention of hematopoietic cells in bone marrow and deletion of Rap1a/b in HSCs result in engraftment of exogenous HSCs within the bone marrow of non-irradiated recipients.