The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche.
ABSTRACT The balance between survival and death in many cell types is regulated by small changes in the intracellular content of bioactive sphingolipids. Enzymes that either produce or degrade these sphingolipids control this equilibrium. The findings here described indicate that the lysosomal galactocerebrosidase (GALC) enzyme, defective in globoid cell leukodystrophy, is involved in the maintenance of a functional hematopoietic stem/progenitor cell (HSPC) niche by contributing to the control of the intracellular content of key sphingolipids. Indeed, we show that both insufficient and supraphysiologic GALC activity-by inherited genetic deficiency or forced gene expression in patients' cells and in the disease model-induce alterations of the intracellular content of the bioactive GALC downstream products ceramide and sphingosine, and thus affect HSPC survival and function and the functionality of the stem cell niche. Therefore, GALC and, possibly, other enzymes for the maintenance of niche functionality and health tightly control the concentration of these sphingolipids within HSPCs.
- SourceAvailable from: Daniela Coltrini[Show abstract] [Hide abstract]
ABSTRACT: Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme β-galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post-natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine β-galactosylceramidase complementary DNA. Finally, RNA interference-mediated β-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that β-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy.Brain 09/2013; 136(Pt 9):2859-75. · 10.23 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Blood cell production is maintained by hematopoietic stem cells (HSCs) that reside in specialized niches within bone marrow. Treatment with granulocyte-colony stimulating factor (G-CSF) causes HSC egress from bone marrow niches and trafficking to the peripheral blood, a process termed 'mobilization'. Although the mobilization phenomenon has been known for some time and is utilized clinically to acquire HSC for transplant, the mechanisms mediating HSC release are not completely understood. We discuss recent advances and controversies in defining the mechanisms responsible for G-CSF-induced mobilization. New reports define a role for resident monocytes/macrophages in maintaining niche cells, which is diminished after G-CSF treatment, suggesting a new mechanism for mobilization. Although osteoblasts have been reported to be a primary component of the HSC niche, new results suggest a unique niche composed of innervated mesenchymal stem cells. Modulating bioactive lipid signaling also facilitates mobilization, and may define a future therapeutic strategy. Hematopoietic mobilization by G-CSF is primarily mediated by alterations to the bone marrow niche by both direct and indirect mechanisms, rather than directly altering HSC function. Further understanding of the processes mediating mobilization will advance our understanding on the cellular and molecular components of the HSC niche.Current opinion in hematology 07/2011; 18(4):231-8. · 5.19 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We report a novel role for the lysosomal galactosylceramidase (GALC), which is defective in globoid cell leukodystrophy (GLD), in maintaining a functional post-natal subventricular zone (SVZ) neurogenic niche. We show that proliferation/self-renewal of neural stem cells (NSCs) and survival of their neuronal and oligodendroglial progeny are impaired in GALC-deficient mice. Using drugs to modulate inflammation and gene transfer to rescue GALC expression and activity, we show that lipid accumulation resulting from GALC deficiency acts as a cell-autonomous pathogenic stimulus in enzyme-deficient NSCs and progeny before upregulation of inflammatory markers, which later sustain a non-cell-autonomous dysfunction. Importantly, we provide evidence that supply of functional GALC provided by neonatal intracerebral transplantation of NSCs ameliorates the functional impairment in endogenous SVZ cells. Insights into the mechanism/s underlying GALC-mediated regulation of early post-natal neurogenic niches improve our understanding of the multi-component pathology of GLD. The occurrence of a restricted period of SVZ neurogenesis in infancy supports the implications of our study for the development of therapeutic strategies to treat this severe pediatric neurodegenerative disorder.Human Molecular Genetics 08/2012; 21(21):4732-50. · 7.69 Impact Factor