Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrow

Adams, Gregor B.; Alley, Ian R.; Chung, Ung-il; Chabner, Karissa T.; Jeanson, Nathaniel T.; Celso, Cristina Lo; Marsters, Emily S.; Chen, Min; Weinstein, Lee S.; Lin, Charles P.; Kronenberg, Henry M.; Scadden, David T.

doi:10.1038/nature07859

Cited by 66 publications

(63 citation statements)

References 21 publications

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“…Global Gαs deficiency is embryonically lethal; therefore, we generated mice with a T cell-selective deletion of Gαs (8,23,24). Gnas ΔCD4 CD4-Cre mice developed normally, but their CD4 + T cells did not accumulate cAMP; had reduced Ca 2+ influx; secreted lower levels of IL-17, IL-22, and IFN-γ (but normal IL-4) compared with WT CD4 + T cells; and did not mount an antigen-specific Th17 response upon CT/OVA immunization ( Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Li¹,

Murray²,

Koide³

et al. 2012

J. Clin. Invest.

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cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engineered mice in which the stimulatory Gα subunit of Gs (Gαs) could be deleted in T cells using CD4-Cre (Gnas ΔCD4 ). Gnas ΔCD4 CD4 + T cells had reduced cAMP accumulation and Ca 2+ influx. In vitro and in vivo, Gnas ΔCD4 CD4 + T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas ΔCD4 CD4 + T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas ΔCD4

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Section: Discussionmentioning

confidence: 99%

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Li¹,

Murray²,

Koide³

et al. 2012

J. Clin. Invest.

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“…1 Other molecules more recently described to be involved in the trafficking and homing of CD34 + cells include β3-adrenergic receptor (ADRB3) and guaninenucleotide-binding protein stimulatory alpha subunit (GNAS). 9,10 An increasing number of studies have found evidence that genetic factors known as single nucleotide polymorphisms (SNP) explain, in part, the significant inter-individual variability in responses to drug administration. 11 Identifying SNP predictive of a poor or good response to G-CSF, in terms of number of CD34 + cells mobilized, might be useful when discussing the possibility of using a different mobilizing agent or a different source of CD34 + cells for allogeneic HSCT.…”

Section: Introductionmentioning

confidence: 99%

Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors

Martín-Antonio¹,

Carmona²,

Falantes³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe number of CD34 + cells mobilized from bone marrow to peripheral blood after administration of granulocyte colony-stimulating factor varies greatly among healthy donors. This fact might be explained, at least in part, by constitutional differences in genes involved in the interactions tethering CD34 + cells to the bone marrow. Design and MethodsWe analyzed genetic characteristics associated with CD34 + cell mobilization in 112 healthy individuals receiving granulocyte colony-stimulating factor (filgrastim; 10 μg/kg; 5 days). ResultsGenetic variants in VCAM1 and in CD44 were associated with the number of CD34 + cells in peripheral blood after granulocyte colony-stimulating factor administration (P=0.02 and P=0.04, respectively), with the quantity of CD34 + cells ¥10 6 /kg of donor (4.6 versus 6.3; P<0.001 and 7 versus 5.6; P=0.025, respectively), and with total CD34 + cells ¥10 6 (355 versus 495; P=0.002 and 522 versus 422; P=0.012, respectively) in the first apheresis. Of note, granulocyte colonystimulating factor administration was associated with complete disappearance of VCAM1 mRNA expression in peripheral blood. Moreover, genetic variants in granulocyte colony-stimulating factor receptor (CSF3R) and in CXCL12 were associated with a lower and higher number of granulocyte colony-stimulating factor-mobilized CD34 + cells/μL in peripheral blood (81 versus 106; P=0.002 and 165 versus 98; P=0.02, respectively) and a genetic variant in CXCR4 was associated with a lower quantity of CD34 + cells ¥10 6 /kg of donor and total CD34 + cells ¥10 6 (5.3 versus 6.7; P=0.02 and 399 versus 533; P=0.01, respectively). ConclusionsIn conclusion, genetic variability in molecules involved in migration and homing of CD34 + cells influences the degree of mobilization of these cells.

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“…The supportive cells in the niches produce growth factors and extracellular matrix components and provide other intercellular signals that promote self-renewal rather than differentiation of HSCs. In the endosteal HSC niche osteoblasts are the main supportive cell type for maintenance of hematopoiesis [31][32][33][34][35]. The vascular HSC niche is mainly composed of perivascular stromal cells and endothelial cells including reticular cells that express stromal cell derived factor 1 (SDF-1) [36], CD146-expressing subendothelial stromal cells [37], Nestin + mesenchymal stem cells (MSCs) [38], NG2 + periarteriolar cells [39], and perisinusoidal LEPR + cells [40,41].…”

Section: Bone Marrow Niche Of Hscsmentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. ex vivo expansion, hematopoietic stem cells, niche, signal transduction, cord blood, transplantation, SCID-repopulating cell, genome editing, CRISPR/Cas9 Citation:Xie JJ, Zhang CC. Ex vivo expansion of hematopoietic stem cells.

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Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrow

Cited by 66 publications

References 21 publications

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets

Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors

Ex vivo expansion of hematopoietic stem cells

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