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2.
Stem Cells ; 33(3): 848-58, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25402778

ABSTRACT

Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes.


Subject(s)
Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Phosphoric Monoester Hydrolases/pharmacology , Animals , Cell Movement/drug effects , Cell Movement/physiology , Granulocyte Colony-Stimulating Factor/biosynthesis , Hematopoietic Stem Cells/metabolism , Inositol Polyphosphate 5-Phosphatases , Male , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
3.
Mucosal Immunol ; 7(6): 1429-1439, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24781051

ABSTRACT

T cells have a critical role in immune surveillance at mucosal surfaces. SHIP1(-/-) mice succumb to mucosal inflammatory disease that afflicts the lung and small intestine (SI). The basis of this condition has not been defined. Here we show that SHIP1 is required for the normal persistence and survival of T cells in mucosal tissues. We find that CD4 and CD8 effector T cells are reduced; however, Treg cells are increased in the SI and lungs of SHIP1(-/-) and CD4CreSHIP(flox/flox) mice. Furthermore, a subset of T cells in the SI of SHIP1(-/-) mice are FasL(+) and are more susceptible to extrinsic cell death. Mechanistic analyses showed that SHIP1 associates with the death receptor CD95/Fas and treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death. Notably, mucosal inflammation in SHIP1(-/-) mice is reduced by treatment with a Caspase 8 inhibitor. We also find that the incidence of Crohn's disease (CD) and pneumonia is significantly increased in mice with dual T and myeloid lineage SHIP1 deletion but not in single lineage-deleted mice. Thus, by promoting survival of protective T cells, thereby preventing an inflammatory myeloid response, SHIP1 maintains an appropriate balance of innate immune function at mucosal surfaces necessary for immune homeostasis.


Subject(s)
Crohn Disease/immunology , Intestinal Mucosa/immunology , Phosphoric Monoester Hydrolases/immunology , Pneumonia/immunology , Respiratory Mucosa/immunology , T-Lymphocytes/immunology , Animals , Caspase 8/genetics , Caspase 8/immunology , Cell Survival/genetics , Cell Survival/immunology , Crohn Disease/genetics , Crohn Disease/pathology , Fas Ligand Protein/genetics , Fas Ligand Protein/immunology , Inositol Polyphosphate 5-Phosphatases , Intestinal Mucosa/pathology , Mice , Mice, Knockout , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphoric Monoester Hydrolases/genetics , Pneumonia/genetics , Respiratory Mucosa/pathology , T-Lymphocytes/pathology , fas Receptor/genetics , fas Receptor/immunology
4.
J Org Chem ; 65(22): 7541-53, 2000 Nov 03.
Article in English | MEDLINE | ID: mdl-11076613

ABSTRACT

The indolo[2,3-a]carbazole glycosides are potent antitumor antibiotics currently undergoing clinical trials for the treatment of numerous types of cancer. AT2433-A1 is the most complex member of this family of compounds possessing a unique disaccharide with a sensitive aminodeoxysugar and an unsymmetric aglycon. The synthesis of this natural product requires a method for glycosylation that sets the stereochemistry of the anomeric center and the regiochemistry of the aglycon. These goals were accomplished by carrying out the Mannich cyclization of a bis-3, 4-(3-indolyl)succinimide to give a key class of indoline intermediates that could be glycosylated stereoselectively with complex carbohydrates without hydroxyl protection or activation. The regiochemistry of the Mannich cyclization was precisely controlled by choosing between kinetic or thermodynamic conditions. This strategy culminated in the first synthesis of the antitumor antibiotic AT2433-A1.


Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemical synthesis , Antibiotics, Antineoplastic/chemical synthesis , Carbazoles , Indoles , Carbohydrate Sequence , Carbohydrates/chemistry , Indicators and Reagents , Mannich Bases
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