Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease

Abstract

Summary One of the cardinal symptoms of type 1 Gaucher Disease (GD) is cytopenia, usually explained by bone marrow (BM) infiltration by Gaucher cells and hypersplenism. However, some cases of cytopenia in splenectomized or treated patients suggest possible other mechanisms. To evaluate intra‐cellular glucocerebrosidase (GlcC) activity in immature progenitors and to prove the conduritol B epoxide (CBE)‐induced inhibition of the enzyme, we used an adapted flow cytometric technique before assessing the direct effect of GlcC deficiency in functional assays. Among haematopoietic cells from healthy donors, monocytes showed the highest GlcC activity but immature CD34+ and mesenchymal cells also had significant GlcC activity. CBE greatly inhibited the enzyme activity of all cell categories. GlcC‐deficient CD34+ cells showed impaired ability to proliferate and differentiate in the expansion assay and had lower frequency of erythroid burst‐forming units, granulocyte colony‐forming units (CFU) and macrophage CFU progenitors, but the effect of GlcC deficiency on megakaryocyte CFU lineage was not significant. GlcC deficiency strongly impaired primitive haematopoiesis in long‐term culture. Furthermore, GlcC deficiency progressively impaired proliferation of mesenchymal progenitors. These data suggest an intrinsic effect of GlcC deficiency on BM immature cells that supplements the pathophysiology of GD and opens new perspectives of therapeutic approach.

Gaucher disease geneGBAfunctions in immune regulation

“…It requires the recruitment of progenitors from bone marrow (37). Most notably, biochemical inhibition of acid β-glucosidase in vitro impairs marrow hematopoiesis (38). Here, we show that the two accumulated GCase substrates, GL1 and Lyso-GL1, inhibit proliferation of HSC derived by GBA KO mice, although it seems that the progenitor population within bone marrow is unchanged in early stages of the disease.…”

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

“…Nelly Reihani, 1 Jean-Benoit Arlet, 2 Michael Dussiot, 3 Thierry Billette de Villemeur, 4 Nadia Belmatoug, 5 Christian Rose, 6 Yves Colin-Aronovicz, 1 Olivier Hermine, 7 Caroline Le Van Kim 1* and Melanie Franco 1*…”

“…However, a growing number of studies performed on murine and in vitro models as well as those using cells from GD patients, indicate that the pathophysiology of GD may involve a wider array of cell types, including hematopoietic and mesenchymal cells, thymic T cells and progenitors, dendritic cells and osteoblasts. [5][6][7][8][9][10] We have previously shown that the red blood cells (RBCs) of GD patients exhibit abnormal morphological, rheological and functional properties, and could be considered additional factors in the GD pathophysiology on the basis that they can trigger ischemic events. 11 Importantly, a study of a large cohort revealed that anemia was the only risk factor for avascular osteonecrosis, the most debilitating skeletal complication for GD type 1 patients.…”

Gaucher Disease

“…Cytopenias are secondary to hypersplenism, bone marrow infiltration by Gaucher cells and an intrinsic haemopoietic defect cells. 19 The increased bleeding tendency in patients with type 1 GD is related to thrombocytopenia, coagulation abnormalities, and defective platelet function. 20 The organomegaly can reach massive proportions and the splenomegaly is often the first presentation and the spleen is much more enlarged (median 15.2 times, up to 75 times) than the liver (up to 3 times).…”