The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche.
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.
Visigalli
Ilaria
I
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
Ungari
Silvia
S
Martino
Sabata
S
Park
Hyejung
H
Cesani
Martina
M
Gentner
Bernhard
B
Sergi Sergi
Lucia
L
Orlacchio
Aldo
A
Naldini
Luigi
L
Biffi
Alessandra
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000201:enzymology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D005698:Galactosylceramidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013107:Sphingolipids / Q000378:metabolism; D055153:Stem Cell Niche / Q000201:enzymology* / Q000378:metabolism; D014162:Transfection; D020298:U937 Cells
D013107:Sphingolipids; D007334:Insulin-Like Growth Factor I; D005698:Galactosylceramidase