A Prospective Study of Bone Marrow Hematopoietic and Mesenchymal Stem Cells in Type 1 Gaucher Disease Patients

Gaucher disease (GD) is an autosomal recessive disorder characterized by lysosomal glucocerebrosidase (GBA) deficiency leading to hematological and skeletal manifestations. Mechanisms underlying these symptoms have not yet been elucidated. In vivo, bone marrow (BM) mesenchymal stem cells (MSCs) have important role in the regulation of bone mass and in the support of hematopoiesis, thus representing potential candidate that could contribute to the disease. GBA deficiency may also directly impair hematopoietic stem/progenitors cells (HSPCs) intrinsic function and induce hematological defect. In order to evaluate the role of BM stem cells in GD pathophysiology, we prospectively analyzed BM-MSCs and HSPCs properties in a series of 10 patients with type 1 GD. GBA activity was decreased in all tested cell subtypes. GD-MSCs had an impaired growth potential, morphological and cell cycle abnormalities, decreased capacities to differentiate into osteoblasts. Moreover, GD-MSCs secreted soluble factors that stimulated osteoclasts resorbing activities. In vitro and in vivo primitive and mature hematopoiesis were similar between patients and controls. However, GD-MSCs had a lower hematopoietic supportive capacity than those from healthy donors. These data suggest that BM microenvironment is altered in GD and that MSCs are key components of the manifestations observed in GD.

[1]  M. Delpino,et al.  Induction of osteoclastogenesis in an in vitro model of Gaucher disease is mediated by T cells via TNF-α. , 2012, Gene.

[2]  V. Vanneaux,et al.  Bone marrow microenvironment in an in vitro model of Gaucher disease: consequences of glucocerebrosidase deficiency. , 2012, Stem cells and development.

[3]  G. Gould,et al.  Vesicle trafficking and membrane remodelling in cytokinesis. , 2011, The Biochemical journal.

[4]  Hongyu Zhao,et al.  Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage , 2010, Proceedings of the National Academy of Sciences.

[5]  V. Vanneaux,et al.  Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease , 2010, British journal of haematology.

[6]  Jérôme Larghero,et al.  Bone marrow microenvironment in fanconi anemia: a prospective functional study in a cohort of fanconi anemia patients. , 2010, Stem cells and development.

[7]  Philippe M. Campeau,et al.  Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome. , 2009, Blood.

[8]  S. Karlsson,et al.  Successful Low‐Risk Hematopoietic Cell Therapy in a Mouse Model of Type 1 Gaucher Disease , 2009, Stem cells.

[9]  G. Grabowski.  Phenotype, diagnosis, and treatment of Gaucher's disease , 2008, The Lancet.

[10]  J. Hopwood,et al.  Lipid composition of microdomains is altered in a cell model of Gaucher disease** This work was supported by a National Health and Medical Research Council project grant in Australia. Published, JLR Papers in Press, April 21, 2008. , 2008, Journal of Lipid Research.

[11]  B. Barlogie,et al.  Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. , 2008, Bone.

[12]  C. Hollak,et al.  Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature , 2008, Annals of Hematology.

[13]  C. Hollak,et al.  Increased plasma macrophage inflammatory protein (MIP)-1α and MIP-1β levels in type 1 Gaucher disease , 2007 .

[14]  S. Karlsson,et al.  Effective cell and gene therapy in a murine model of Gaucher disease , 2006, Proceedings of the National Academy of Sciences.

[15]  N. Udagawa,et al.  Prostaglandin E2 strongly inhibits human osteoclast formation. , 2005, Endocrinology.

[16]  T. Mizoguchi,et al.  Prostaglandin E2 Receptors EP2 and EP4 Are Down-regulated during Differentiation of Mouse Osteoclasts from Their Precursors* , 2005, Journal of Biological Chemistry.

[17]  M. Kotb,et al.  Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12 , 2004, The Journal of Immunology.

[18]  G. Andria,et al.  Therapeutic goals in the treatment of Gaucher disease. , 2004, Seminars in hematology.

[19]  R. Brady,et al.  Correlation between enzyme activity and substrate storage in a cell culture model system for Gaucher disease , 2004, Journal of Inherited Metabolic Disease.

[20]  F. Zhan,et al.  The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. , 2003, The New England journal of medicine.

[21]  K. Okoń,et al.  Enzyme replacement therapy reduces Gaucher cell burden but may accelerate osteopenia in patients with type I disease – a histological study , 2003, European journal of haematology.

[22]  J. Mosca,et al.  Characterization and functionality of cell surface molecules on human mesenchymal stem cells. , 2003, Journal of biomedical science.

[23]  L. Ronfani,et al.  Bone Marker Alterations in Patients with Type 1 Gaucher Disease , 2003, Calcified Tissue International.

[24]  P. Kaplan,et al.  Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. , 2002, The American journal of medicine.

[25]  M. Noda,et al.  Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. , 2001, The Journal of clinical investigation.

[26]  P. Kaplan,et al.  The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. , 2000, Archives of internal medicine.

[27]  V. Barak,et al.  Cytokines in Gaucher's disease. , 1999, European cytokine network.

[28]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[29]  C. Hollak,et al.  Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. , 1997, Blood cells, molecules & diseases.

[30]  L. Herzenberg,et al.  Detection and isolation of gene-corrected cells in Gaucher disease via a fluorescence-activated cell sorter assay for lysosomal glucocerebrosidase activity. , 1997, Blood.

[31]  S. Michel,et al.  Quantitative correlation between the residual activity of β-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease , 1992, Human Genetics.

[32]  J. Soulier,et al.  Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma , 2007, Leukemia.

[33]  M. V. van Breemen,et al.  Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease. , 2007, Biochimica et biophysica acta.

[34]  D. Raveh,et al.  Fluorescent flow cytometric assay: a new diagnostic tool for measuring beta-glucocerebrosidase activity in Gaucher disease. , 2003, Blood cells, molecules & diseases.

[35]  N. Rushton,et al.  Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10. , 1997, QJM : monthly journal of the Association of Physicians.

[36]  K. Sandhoff,et al.  Partial enzyme deficiencies: residual activities and the development of neurological disorders. , 1983, Developmental Neuroscience.