Niemann-Pick Type C1 (NPC1) disease is a progressive lysosomal storage disorder caused by mutations of the NPC1 gene. While neurodegeneration is the most severe symptom, a large proportion of NPC1 patients also present with splenomegaly, which has been attributed to cholesterol and glycosphingolipid accumulation in late endosomes and lysosomes. However, recent data also reveal an increase in the inflammatory monocyte subset in the Npc1nih mouse model expressing a Npc1-null allele.
We evaluated the contribution of hematopoietic cells to splenomegaly in NPC1 disease under conditions of hypercholesterolemia. We transplanted Npc1nih (Npc1 null-mutation) or Npc1wt bone marrow into Ldlr- /- mice and fed these mice a cholesterol-rich Western-type diet (WTD). At 9 weeks after bone marrow transplant (BMT), on a chow diet, the Npc1 null-mutation increased plasma granulocyte-colony stimulating factor (G-CSF) by twofold and caused mild neutrophilia. At 18 weeks after BMT, including 9 weeks of WTD feeding, the Npc1 mutation increased G-csf mRNA levels by ~5-fold in splenic monocytes/macrophages accompanied by a ~4-fold increase in splenic neutrophils compared to controls. We also observed ~5-fold increased long-term and short-term hematopoietic stem cells (HSCs) in the spleen, and a ~30-75% decrease of these populations in BM, reflecting HSC mobilization, presumably downstream of elevated G-CSF. In line with these data, four patients with NPC1 disease showed higher plasma G-CSF compared to age- and gender-matched healthy controls.
In conclusion, we show elevated G CSF levels and HSC mobilization in the setting of an Npc1-null mutation, and propose that this contributes to splenomegaly in patients with NPC1 disease
Read the Paper at JLR :https://www.jlr.org/article/S0022-2275(21)00150-4/fulltext
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