engleski

CXCL12/SDF-1 Stimulates Megakaryocyte beta-1, 4- Galactosyltransferase 1 Activity to Enhance Platelet Production in Vivo

Platelet recovery following bone marrow (BM) transplant and chemotherapy is crucial to prevent bleeding complications. The chemokine SDF-1 promotes megakaryocyte (MK) migration towards BM sinusoids increasing platelet production. Here we show that SDF-1 upregulates expression of the glycan structure Type-2- Lactosaminoglycan (LacNAc), synthesized by β4Galactosyltransferase1 (β4galt1). We hypothesized that SDF-1 increases LacNAc synthesis promoting platelet production. Supporting this hypothesis, β4galt1–/– mice had severe macrothrombocytopenia (80% reduction) with increased BMMK numbers (35%), which localized poorly with BM sinusoids (50%), compared to WT MKs (72%). β4galt1–/– hematopoietic stem cells (HSCs) transplanted into lethally irradiated WT mice restored BMMKs, which failed to migrate to sinusoids and produce circulating platelets. We next treated WT and β4galt1–/– mice with the myeloablative chemotherapeutic agent 5-Fluorouracil (5-FU), which decreased platelet counts by 50% in both phenotypes. SDF-1 injections increased platelet counts by 70% in 5-FU treated WT mice but not in β4galt1–/– mice. Importantly, WT but not β4galt1–/– platelets had increased LacNAc expression after SDF-1 injections.β4galt1–/– BMMKs had increased β1 integrin expression. Expression of laminin, β1 integrin ligand, was upregulated in β4galt1–/– MKs and sinusoids. Our results suggest that SDF-1 upregulates β4GalT1-dependentLacNAc expression promoting MK interaction with BM sinusoids, likely regulating β1 integrin expression and interaction with components of the extracellular matrix, specifically laminin.

SDF-1, thrombopoiesis, Galactosyltransferase 1

nije evidentirano