Abstract
Krabbe disease (KD) is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase β-galactosylceramidase (GALC). Oligodendroglia degeneration and demyelination of the nervous system lead to neurological dysfunctions which are usually lethal by two years of age. At present, the only clinical treatment with any proven efficacy is hematopoietic stem-cell transplantation, which is more effective when administered in the neonatal period to presymptomatic recipients. Bone marrow (BM) sinusoidal endothelial cells (SECs) play a pivotal role in stem cell engraftment and reconstitution of hematopoiesis. Previous observations had shown significant alterations of microvascular endothelial cells in the brain of KD patients and in Galc mutant twitcher mice, an authentic model of the disease. In the present study, we investigated the vascular component of the BM in the femurs of symptomatic homozygous twitcher mice at postnatal day P36. Histological, immunohistochemical, and two-photon microscopy imaging analyses revealed the presence of significant alterations of the diaphyseal BM vasculature, characterized by enlarged, discontinuous, and hemorrhagic SECs that express the endothelial marker vascular endothelial growth factor receptor-2 (VEGFR2) but lack platelet/endothelial cell adhesion molecule-1 (CD31) expression. In addition, computer-aided image analysis indicates that twitcher CD31−/VEGFR2+ SECs show a significant increase in lumen size and in the number and size of endothelial gaps compared to BM SECs of wild type littermates. These results suggest that morphofunctional defects in the BM vascular niche may contribute to the limited therapeutic efficacy of hematopoietic stem-cell transplantation in KD patients at symptomatic stages of the disease.
Highlights
Lysosomal storage disorders are characterized by the accumulation of disease-specific metabolic intermediates within the lysosomes [1]
Krabbe disease (KD), or globoid cell leukodystrophy, is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase β-galactosylceramidase (GALC) (EC 3.2.1.46) [2]
The results reveal the presence of significant alterations in bone marrow (BM) sinusoidal endothelial cells (SECs), in keeping with the hypothesis that defects in the vascular niche may contribute to the limited therapeutic efficacy of hematopoietic stem cell transplantation (HSCT) in KD patients at symptomatic stages of the disease
Summary
Lysosomal storage disorders are characterized by the accumulation of disease-specific metabolic intermediates within the lysosomes [1]. GALC deficiency in twitcher mice is responsible for postnatal bone growth retardation [22], liver damage [23], and lymphoid organ atrophy [24], supporting the notion that KD is a generalized psychosine storage disease [20]. In keeping with this hypothesis, significant vascular permeability defects occur in different visceral organs of twitcher mice, including kidney, lung, and liver [19]. The results reveal the presence of significant alterations in BM SECs, in keeping with the hypothesis that defects in the vascular niche may contribute to the limited therapeutic efficacy of HSCT in KD patients at symptomatic stages of the disease
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