SHIP is required for a functional hematopoietic stem cell niche

Hazen, Amy L.; Smith, Michelle J.; Desponts, Caroline; Winter, Oliver; Moser, Katrin; Kerr, William G.

doi:10.1182/blood-2008-02-138008

Cited by 68 publications

(114 citation statements)

References 46 publications

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“…However, this defect was not observed when HSC were rendered SHIP-deficient in adult hosts where the BM milieu or niche remained SHIP-competent. These findings suggested that defective HSC function in germline SHIP-deficient hosts might arise from disruption of niche cell components [22]. Consistent with this hypothesis, primary OB were found to express the SH2 domain containing 145 and 150 kDa isoforms encoded by the SHIP1 locus [22].…”

Section: Introductionsupporting

confidence: 56%

“…These findings suggested that defective HSC function in germline SHIP-deficient hosts might arise from disruption of niche cell components [22]. Consistent with this hypothesis, primary OB were found to express the SH2 domain containing 145 and 150 kDa isoforms encoded by the SHIP1 locus [22]. In addition, BM-derived SHIP1 -/ -OBs have less alkaline phosphatase (ALP) activity required for bone formation indicating impaired OB development and function [22].…”

Section: Introductionmentioning

confidence: 73%

“…Consistent with this hypothesis, primary OB were found to express the SH2 domain containing 145 and 150 kDa isoforms encoded by the SHIP1 locus [22]. In addition, BM-derived SHIP1 -/ -OBs have less alkaline phosphatase (ALP) activity required for bone formation indicating impaired OB development and function [22]. SHIP -/ -mutant mice have previously been reported to be osteoporotic [23].…”

Section: Introductionmentioning

confidence: 73%

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SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Iyer

Viernes

Chisholm³

et al. 2014

Stem Cells and Development

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Here, we show that Src homology 2-domain-containing inositol 5¢-phosphatase 1 (SHIP1) is required for the efficient development of osteoblasts from mesenchymal stem cells (MSCs) such that bone growth and density are reduced in mice that lack SHIP1 expression in MSCs. We find that SHIP1 promotes the osteogenic output of MSCs by limiting activation of the PI3K/Akt/b-catenin pathway required for induction of the MSC stemness factor Id2. In parallel, we demonstrate that mice with myeloid-restricted ablation of SHIP1, including osteoclasts (OCs), show no reduction in bone mass or density. Hence, diminished bone mass and density in the SHIP1-deficient mice results from SHIP deficiency in MSC and osteolineage progenitors. Intriguingly, mice with a SHIP-deficient MSC compartment also exhibit decreased OC numbers. In agreement with our genetic findings we also show that treatment of mice with an SHIP1 inhibitor (SHIPi) significantly reduces bone mass. These findings demonstrate a novel role for SHIP1 in MSC fate determination and bone growth. Further, SHIPi may represent a novel therapeutic approach to limit bone development in osteopetrotic and sclerotic bone diseases.

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Section: Introductionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 73%

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SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Iyer

Viernes

Chisholm³

et al. 2014

Stem Cells and Development

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“…SHIP-1 deficiency might explain other characteristics of MDS. Loss of SHIP-1 reduces the expression of CXCR4, the receptor for the stroma cell-derived factor-1, which modifies the interactions between the bone marrow niche and hematopoietic stem cells (Hazen et al, 2009). Human CD34 þ cells from MDS patients do not respond to stroma cell-derived factor-1 effectively even though MDS patients have higher plasma stroma cell-derived factor-1 levels than healthy volunteers (Matsuda et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

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The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3 0 kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.

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“…SHIP is expressed predominantly by cells in the hematopoietic compartment (Kerr 2011). SHIP it is also found to be present in osteoblasts, mature granulocytes, monocyte/macrophages, mast cells, platelets and NK cells (Cox et al 2001;Geier et al 1997;Giuriato et al 1997;Hazen et al 2009;Maresco et al 1999;Trotta et al 2005).…”

Section: Inpp5dmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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SHIP is required for a functional hematopoietic stem cell niche

Cited by 68 publications

References 46 publications

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

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