Browsing by Subject "Bone marrow cells"

Now showing 1 - 4 of 4
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    CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation
    (Oxford University Press, 2020-07) Singh, Pratibha; Mohammad, Khalid S.; Pelus, Louis M.; Microbiology and Immunology, School of Medicine
    The bone marrow (BM) microenvironment/niche plays a key role in regulating hematopoietic stem and progenitor cell (HSPC) activities; however, mechanisms regulating niche cell function are not well understood. In this study, we show that niche intrinsic expression of the CXCR4 chemokine receptor critically regulates HSPC maintenance during steady state, and promotes early hematopoietic regeneration after myeloablative irradiation. At steady state, chimeric mice with wild-type (WT) HSPC and marrow stroma that lack CXCR4 show decreased HSPC quiescence, and their repopulation capacity was markedly reduced. Mesenchymal stromal cells (MSC) were significantly reduced in the BM of CXCR4 deficient mice, which was accompanied by decreased levels of the HSPC supporting factors stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF). CXCR4 also plays a crucial role in survival and restoration of BM stromal cells after myeloablative irradiation, where the loss of BM stromal cells was more severe in CXCR4-deficient mice compared to WT mice. In addition, transplantation of WT donor HSPC into CXCR4-deficient recipient mice demonstrated reduced HSPC homing and early hematopoietic reconstitution. We found that CXCR4 signaling attenuates irradiation-induced BM stromal cell loss by upregulating the expression of the antiapoptotic protein Survivin via the PI3K pathway. Our study suggests that SDF-1-CXCR4 signaling in the stromal microenvironment cells plays a crucial role in maintenance of HSPCs during homeostasis, and promotes niche regeneration and early hematopoietic reconstitution after transplantation. Modulation of CXCR4 signaling in the HSPC microenvironment could be a means to enhance hematopoietic recovery after clinical hematopoietic cell transplantation.
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    Impact of ALCAM (CD166) on homing of hematopoietic stem and progenitor cells
    (2012-12-18) Aleksandrova, Mariya Aleksandrova; Goebl, Mark G.; Srour, Edward F.; Hurley, Thomas D., 1961-
    The potential of hematopoietic stem cells (HSC) to home and to anchor within the bone marrow (BM) microenvironment controls the ability of transplanted HSCs to establish normal hematopoiesis. Activated Leukocyte Cell Adhesion Molecule (ALCAM; also identified as CD166), which participates in homophilic interactions, is expressed on a group of osteoblasts in the hematopoietic niche capable of sustaining functional HSC in vitro. Since we could also detect ALCAM expression on HSC, we suspect that ALCAM may play a role in anchoring primitive hematopoietic cells to ALCAM expressing components of the hematopoietic niche via dimerization. We investigated the role of ALCAM on the homing abilities of hematopoietic stem and progenitor cells (HSPC) by calculating recovery frequency of Sca-1+ALCAM+ cells in an in vivo murine bone marrow transplantation model. Our data supports the notion that ALCAM promotes improved homing potential of hematopoietic Sca-1+ cells. Recovery of BM-homed Sca-1+ cells from the endosteal region was 1.8-fold higher than that of total donor cells. However, a 3.0-fold higher number of Sca-1+ALCAM+ cells homed to the endosteal region compared to total donor cells. Similarly, homed Sca-1+ALCAM+ cells were recovered from the vascular region at 2.1-fold greater frequency than total homed donor cells from that region, compared to only a 1.3-fold increase in the recovery frequency of Sca-1+ cells. In vitro quantitation of clonogenic BM-homed hematopoietic progenitors corroborate the results from the homing assay. The frequency of in vitro clonogenic progenitors was significantly higher among endosteal-homed Sca-1+ALCAM+ cells compared to other fractions of donor cells. Collectively, these data demonstrate that engrafting HSC expressing ALCAM home more efficiently to the BM and within the BM microenvironment, these cells preferentially seed the endosteal niche.
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    Prostaglandin E₂ promotes recovery of hematopoietic stem and progenitor cells after radiation exposure
    (2014-07-11) Stilger, Kayla N.; Broxmeyer, Hal E.; Kacena, Melissa A.; Srour, Edward F.; Pelus, Louis
    The hematopoietic system is highly proliferative, making hematopoietic stem and progenitor cells (HSPC) sensitive to radiation damage. Total body irradiation and chemotherapy, as well as the risk of radiation accident, create a need for countermeasures that promote recovery of hematopoiesis. Substantive damage to the bone marrow from radiation exposure results in the hematopoietic syndrome of the acute radiation syndrome (HS-ARS), which includes life-threatening neutropenia, lymphocytopenia, thrombocytopenia, and possible death due to infection and/or hemorrhage. Given adequate time to recover, expand, and appropriately differentiate, bone marrow HSPC may overcome HS-ARS and restore homeostasis of the hematopoietic system. Prostaglandin E2 (PGE2) is known to have pleiotropic effects on hematopoiesis, inhibiting apoptosis and promoting self-renewal of hematopoietic stem cells (HSC), while inhibiting hematopoietic progenitor cell (HPC) proliferation. We assessed the radiomitigation potential of modulating PGE2 signaling in a mouse model of HS-ARS. Treatment with the PGE2 analog 16,16 dimethyl PGE2 (dmPGE2) at 24 hours post-irradiation resulted in increased survival of irradiated mice compared to vehicle control, with greater recovery in HPC number and colony-forming potential measured at 30 days post-irradiation. In a sublethal mouse model of irradiation, dmPGE2-treatment at 24 hours post-irradiation is associated with enhanced recovery of HSPC populations compared to vehicle-treated mice. Furthermore, dmPGE2-treatment may also act to promote recovery of the HSC niche through enhancement of osteoblast-supporting megakaryocyte (MK) migration to the endosteal surface of bone. A 2-fold increase in MKs within 40 um of the endosteum of cortical bone was seen at 48 hours post-irradiation in mice treated with dmPGE2 compared to mice treated with vehicle control. Treatment with the non-steroidal anti-inflammatory drug (NSAID) meloxicam abrogated this effect, suggesting an important role for PGE2 signaling in MK migration. In vitro assays support this data, showing that treatment with dmPGE2 increases MK expression of the chemokine receptor CXCR4 and enhances migration to its ligand SDF-1, which is produced by osteoblasts. Our results demonstrate the ability of dmPGE2 to act as an effective radiomitigative agent, promoting recovery of HSPC number and enhancing migration of MKs to the endosteum where they play a valuable role in niche restoration.
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    RARα supports the development of Langerhans cells and langerin-expressing conventional dendritic cells
    (Springer Nature, 2018-09-25) Hashimoto-Hill, Seika; Friesen, Leon; Park, Sungtae; Im, Suji; Kaplan, Mark H.; Kim, Chang H.; Pediatrics, School of Medicine
    Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside specifically in the epidermis, but langerin-expressing conventional DCs also reside in the dermis and other tissues, yet the factors that regulate their development are unclear. Because retinoic acid receptor alpha (RARα) is highly expressed by LCs, we investigate the functions of RARα and retinoic acid (RA) in regulating the langerin-expressing DCs. Here we show that the development of LCs from embryonic and bone marrow-derived progenitors and langerin+ conventional DCs is profoundly regulated by the RARα-RA axis. During LC differentiation, RARα is required for the expression of a LC-promoting transcription factor Runx3, but suppresses that of LC-inhibiting C/EBPβ. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. Our findings identify positive and negative regulatory mechanisms to tightly regulate the development of the specialized DC populations.