Abstract
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.
Highlights
Gaucher Disease (GD) is a lysosomal storage disorder due to glucocerebrosidase (GBA, acid-b-glucosidase) deficiency [1]
Pathophysiology of hematological involvement in GD have been related to hypersplenism and hematopoietic impairment due to bone marrow (BM) infiltration by Gaucher cells, but an intrinsic hematopoietic stem/progenitors cells (HSPCs) defect linked with GBA deficiency cannot be ruled out
We hypothesized that GBA deficiency may be responsible for a deregulation of mesenchymal stem cells (MSCs) and/or HSPCs functional properties
Summary
Gaucher Disease (GD) is a lysosomal storage disorder due to glucocerebrosidase (GBA, acid-b-glucosidase) deficiency [1]. In type 1 GD, the accumulation of glucosylceramide in the lysosomal compartment of affected cells results in heterogeneous manifestations including visceral, hematological and skeletal involvement [2]. Skeletal manifestations of GBA deficiency mainly consist in Erlenmeyer flask deformity, bone marrow (BM) infiltration, osteopenia, avascular necrosis, infarction, fractures, lytic lesions and joint replacements. Pathophysiology of these manifestations remains poorly understood and hypotheses include inhibition of osteogenesis and/or stimulation of osteoclastogenesis by cytokines. Pathophysiology of hematological involvement in GD have been related to hypersplenism and hematopoietic impairment due to BM infiltration by Gaucher cells, but an intrinsic hematopoietic stem/progenitors cells (HSPCs) defect linked with GBA deficiency cannot be ruled out
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
