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.
Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Unité de Thérapie Cellulaire et Centre d'Investigation Clinique en Biothérapies CIC-BT501, Paris, France.
Séverine
S
Lecourt
Enguerran
E
Mouly
Delphine
D
Freida
Audrey
A
Cras
Raphaël
R
Ceccaldi
Djazia
D
Heraoui
Christine
C
Chomienne
Jean-Pierre
JP
Marolleau
Bertrand
B
Arnulf
Raphael
R
Porcher
Catherine
C
Caillaud
Valérie
V
Vanneaux
Nadia
N
Belmatoug
Jérôme
J
Larghero
D000328:Adult; D000368:Aged; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology*; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000473:pathology*; D005962:Glucosylceramidase / Q000172:deficiency*; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D011446:Prospective Studies
D005962:Glucosylceramidase