Article

The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche

San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
Blood (Impact Factor: 10.45). 09/2010; 116(11):1857-66. DOI: 10.1182/blood-2009-12-256461
Source: PubMed

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.

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Available from: Sabata Martino, Sep 03, 2015
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    • "In this regard we have developed the hematopoietic stem cell (HSC)-based gene therapy for Krabbe disease, fatal LSD caused by mutations in the galactocerebrosidase (GALC) gene [125,126]. To be effective, this therapy needs the modulation of the transgene expression to avoid forced GALC toxicity [127]. The rationale of this approach was the inhibition of GALC toxicity in the HSCs used for GLD treatment in order to protect differentiated cells that could be able to carry efficiently their function. "
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    • "Galactosylceramidase catalyzes hydrolytic removal of galactose from galactosylceramide or galactosylsphingosine , yielding ceramide or sphingosine, respectively. It was reported that galactosylceramidase was involved in maintaining a functional hematopoietic stem cell niche by control of the intracellular ceramide and sphingosine levels (Visigalli et al. 2010). Direct evidence of GSLs modulating stem cell character comes from the study of a GCS-knockout mouse (Yamashita et al. 1999). "

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    ABSTRACT: Globoid cell leukodystrophy (GLD; also known as Krabbe disease) is an invariably fatal lysosomal storage disorder caused by mutations in the galactocerebrosidase (GALC) gene. Hematopoietic stem cell (HSC)-based gene therapy is being explored for GLD; however, we found that forced GALC expression was toxic to HSCs and early progenitors, highlighting the need for improved regulation of vector expression. We used a genetic reporter strategy based on lentiviral vectors to detect microRNA activity in hematopoietic cells at single-cell resolution. We report that miR-126 and miR-130a were expressed in HSCs and early progenitors from both mice and humans, but not in differentiated progeny. Moreover, repopulating HSCs could be purified solely on the basis of miRNA expression, providing a new method relevant for human HSC isolation. By incorporating miR-126 target sequences into a GALC-expressing vector, we suppressed GALC expression in HSCs while maintaining robust expression in mature hematopoietic cells. This approach protected HSCs from GALC toxicity and allowed successful treatment of a mouse GLD model, providing a rationale to explore HSC-based gene therapy for GLD.
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