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Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

ABSTRACT: The Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Klf5 deficient hematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect was associated with impaired bone marrow (BM) homing and lodging and decreased retention in BM. The Klf5Δ/Δ HSC/P homing defect associated with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo inducible gain-of-function of Klf5 in HSC translated into increased HSC/P adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, was decreased in Klf5Δ/Δ HSC/P. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescued the expression of activated β1/β2-integrins, adhesion and BM homing of Klf5Δ/Δ HSC/P. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/P in the BM through Rab5-dependent post-translational regulation of Beta1/Beta2 integrins.

ORGANISM(S): Mus musculus

PROVIDER: GSE43806 | GEO | 2013/01/30

SECONDARY ACCESSION(S): PRJNA187982

REPOSITORIES: GEO

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Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

Project description:The Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Klf5 deficient hematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect was associated with impaired bone marrow (BM) homing and lodging and decreased retention in BM. The Klf5Δ/Δ HSC/P homing defect associated with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo inducible gain-of-function of Klf5 in HSC translated into increased HSC/P adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, was decreased in Klf5Δ/Δ HSC/P. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescued the expression of activated β1/β2-integrins, adhesion and BM homing of Klf5Δ/Δ HSC/P. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/P in the BM through Rab5-dependent post-translational regulation of Beta1/Beta2 integrins. Differential gene expression analyses was performed with Affymetrix GeneChip Mouse 1.0 ST assay. LSK cells from KLF-/- (n=4) and wt (n=5), bred on a C57BL/6 background, was analyzed for differential gene expression using GeneSpring GX11 using student's T-test.

2013-01-30 | E-GEOD-43806 | biostudies-arrayexpress

CD34+ and Treatment with UTP and CXCL12

Project description:Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and non-peptide molecules. Extracellular nucleotides and their cognate P2 receptors are emerging as key-factors of inflammation and related chemotactic responses. In this study, we investigated the activity of extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) on CXCL12-stimulated CD34+ HSC chemotaxis. In vitro, UTP significantly improved HSC migration, inhibited cell membrane CXCR4 down-regulation of migrating CD34+ cells and increased cell adhesion to fibronectin. In vivo, pre-incubation with UTP significantly enhanced the BM homing efficiency of human CD34+ cells in immunodeficient mice. Pertussis toxin blocked CXCL12- and UTP-dependent chemotactic responses, suggesting that G-protein alpha-subunits (Gαi) may provide a converging signal for CXCR4- and P2Y-activated transduction pathways. In addition, gene expression profiling of UTP-treated CD34+ cells and in vitro inhibition assays demonstrated that Rho guanosine 5’-triphosphatases (GTPase) Rac2 and downstream effectors Rho GTPase–activated kinases 1 and 2 (ROCK1/2) are involved in UTP-promoted/CXCL12-dependent HSC migration. Our data suggest that UTP may physiologically modulate the migration of HSCs and their homing to the BM, in concert with CXCL12, via the activation of converging signaling pathways between CXCR4 and P2Y receptors, involving Gαi proteins and RhoGTPases. Keywords: treatment comparison

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Transcription profiling of human CD34+ cells and treatment with UTP and CXCL12

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2008-06-13 | E-GEOD-5168 | biostudies-arrayexpress

Mus musculus

Project description:Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

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2019-11-12 | PXD011134 | Pride

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2019-11-12 | PXD011135 | Pride

Transcription profiling of multiple mouse myeloma (MM) cells during intra-medullary progression in the 5T2MM mouse model

Project description:Insights into mechanisms involved during intra-medullary myeloma progression could be helpful in the better understanding of this disease and in the development of new therapeutical strategies. Herein gene expression profile of multiple myeloma (MM) cells during intra-medullary progression was investigated using the 5T2MM murine model. MM-cells from 3 subsequent disease stages, quiescent, intermediate and end stage were analyzed using microarrays containing 21,492 Unigene cDNA sequences. ~ 3000 calls of differentially expressed genes were obtained. Most of these genes were silenced during tumor progression. In the early stage the MM-cells had up-regulated genes involved in bone marrow (BM) homing (CCR2, CCR5), motility (tetraspanins, 67kD laminin receptor, paxillin, zyxin, prolactin receptor), invasion (annexin II, cathepsins), adhesion (integrins, ALCAM) and cell adhesion mediated drug resistance (fibronectin). Genes involved in apoptosis (Mcl-1), plasma cell differentiation (XBP-1), angiogenesis (neuropilin-2, angiopoietin-like 4), hypoxia (HIF-1a, carbonic anhydrase 9) and in retention (CXCR4/CXCL12) and anchoring of MM-cells (laminin, collgens) in the BM were up-regulated during progressive stages. Quantative RT-PCR confirmed the trend of expression. These data provide a framework of mechanisms involved in intra-medullary myeloma progression; several genes known to be important in MM-biology are highlighted and novel candidate genes are illuminated as potentially more effective therapeutical targets.

2008-03-27 | E-MEXP-186 | biostudies-arrayexpress

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Project description:Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

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2022-06-17 | GSE206183 | GEO

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