Expression of Functional P-Selectin Glycoprotein Ligand 1 on Hematopoietic Progenitors Is Developmentally Regulated

Sultana, Dil Afroz; Zhang, Shirley; Todd, Sarah P.; Bhandoola, Avinash

doi:10.4049/jimmunol.1101116

Cited by 33 publications

(27 citation statements)

References 48 publications

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“…This inference was directly confirmed by flow cytometric detection of E-selectin and P-selectin ligands on HPCs and LT-HSCs. These results are consistent with a recent report that also found P-selectin ligands expressed at a low level on HSC [28], and with the BMT data presented above showing that survival of single selectin KO mice is equivalent to that of WT following lethal irradiation and BMT. That report also showed an increase in P-selectin ligands with differentiation, consistent with our finding that LSK cells express higher levels of both E- and P-selectin ligands.…”

Section: Discussionsupporting

confidence: 93%

Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow

Nabors¹,

Wang²,

Wagers³

et al. 2013

Experimental Hematology

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Selectins are carbohydrate-binding adhesion molecules critically involved in leukocyte recognition of endothelium. The endothelial selectins have been implicated in homing of hematopoietic stem/progenitor cell(s) (HSPC) to the bone marrow (BM) during bone marrow transplant (BMT), but the precise role(s) of individual selectins in this process have never been defined. BMT of lethally irradiated mice lacking both endothelial selectins (E/P KO) with limiting numbers of wild-type BM cells rescued significantly fewer E/P KO than WT recipients, but higher numbers of transplanted WT cells rescued E/P KOs in a dose-dependent fashion. Short term homing assays confirmed a substantial defect in HSPC homing to BM in E/P KO mice. In contrast, BMT of E-selectin null (E KO) or P-selectin null (P KO) mice at limiting cell number uniformly rescued >95% of the transplanted animals. Consistent with these functional results, flow cytometric analysis revealed both E-selectin ligands and P-selectin ligands on distinct subsets of HSPC. Taken together, these results demonstrate overlapping functions for the endothelial selectins in HSPC homing to BM in the setting of BMT, and define a novel aspect of HSPC heterogeneity linked to selectin ligand expression.

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Section: Discussionsupporting

confidence: 93%

Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow

Nabors¹,

Wang²,

Wagers³

et al. 2013

Experimental Hematology

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“…These demonstrated abilities of LMPPs and CLPs align with the expression of CCR9 and CCR7 by these progenitor populations 52 and also with their expression of functional PSGL-1. 19 After BMT, homing of progenitors to the thymus was greatly reduced. Progenitors trafficking from the blood to the thymus are thought to use mechanisms analogous to those used by mature lymphocytes to enter lymph nodes in which selectin-mediated rolling is followed by chemokine signals activating integrins on the surface of trafficking cells.…”

Section: Discussionmentioning

confidence: 99%

“…30,36 Only LMPPs and CLPs were each able to home to the thymus within 22 hours (Figure 1C), consistent with the known expression of CCR7, CCR9, and functional PSGL-1 on these progenitors, but not upstream HSCs and MPPs. 12,13,19 To estimate the number of progenitors entering the thymus, we performed a short-term homing assay in which sorted cells were plated on OP9-DL4 at limiting dilution. We found that approximately 7 and 30 progenitors homed to the thymus from 1 3 10 7 and 4 3 10 7 BM cells, respectively (supplemental Figure 1 available on the Blood Web site).…”

Section: Lmpps and Clps Each Settle The Normal Thymusmentioning

confidence: 99%

“…13,16,17 Additionally, functional P-selectin glycoprotein ligand (PSGL-1) and integrins vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 have been shown to be required for efficient thymic homing. [18][19][20] Our understanding of molecules that mediate trafficking of progenitors to the normal thymus derives from unirradiated hosts; the effect of BMT conditioning on progenitor trafficking is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Chemokine treatment rescues profound T-lineage progenitor homing defect after bone marrow transplant conditioning in mice

Zhang

Wang

Manna

et al. 2014

Blood

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Key Points• Homing of T-lineage progenitors to the thymus is reduced after irradiation.• Chemokines limit thymic reconstitution after BMT.Development of T cells in the thymus requires continuous importation of T-lineage progenitors from the bone marrow via the circulation. Following bone marrow transplant, recovery of a normal peripheral T-cell pool depends on production of naïve T cells in the thymus; however, delivery of progenitors to the thymus limits T-lineage reconstitution.Here, we examine homing of intravenously delivered progenitors to the thymus following irradiation and bone marrow reconstitution. Surprisingly, following host conditioning by irradiation, we find that homing of lymphoid-primed multipotent progenitors and common lymphoid progenitors to the thymus decreases more than 10-fold relative to unirradiated mice. The reduction in thymic homing in irradiated mice is accompanied by a significant reduction in CCL25, an important chemokine ligand for thymic homing. We show that pretreatment of bone marrow progenitors with CCL25 and CCL21 corrects the defect in thymic homing after irradiation and promotes thymic reconstitution. These data suggest new therapeutic approaches to promote T-cell regeneration. (Blood. 2014;124(2):296-304)

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“…Although the precise identity of the progenitors that migrate to the thymus from circulation remains elusive, it is known that these progenitors require expression of the P-selectin glycoprotein ligand-1 (PSGL-1) and the chemokine receptors CCR7 and CCR9 to gain entry into the thymus (7)(8)(9)(10)(11). Interactions between P-selectin expressed on vascular endothelium and progenitor PSGL-1 are thought to mediate progenitor rolling along endothelial cells in circulation, whereas signaling through CCR7 and CCR9 is thought to be required for integrin activation and subsequent progenitor transmigration through the thymic endothelium, into the thymus (12,13).…”

mentioning

confidence: 99%

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

Golec

Caviedes

Baldwin

2016

The Journal of Immunology

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T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.

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Expression of Functional P-Selectin Glycoprotein Ligand 1 on Hematopoietic Progenitors Is Developmentally Regulated

Cited by 33 publications

References 48 publications

Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow

Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow

Chemokine treatment rescues profound T-lineage progenitor homing defect after bone marrow transplant conditioning in mice

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

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