Glycan-Mediated Mechanosensing Regulates Megakaryocyte-Biased Hematopoietic Stem Cell Subsets.

Definitive hematopoietic stem and progenitor cells (HSPCs) development relies on intrinsic and extrinsic programs to meet homeostatic and stress-related demands. The comprehensive mechanisms governing HSPCs fate remain poorly understood. Our study identifies B4GALT1, a glycosyltransferase essential for N-glycosylation, as a key modulator of HSPC lineage decisions. We demonstrate that B4GALT1 deficiency disrupts glycosylation patterns within the bone marrow (BM) niche, resulting in oncogenic glycan signatures and altered expression of Mucin13 in HSPCs. Loss of B4GALT1 expands HSPC pools and promotes megakaryocyte priming in HSPCs through transcriptional and chromatin modifications, enhancing the Wnt-Mucin13 axis. Mucin13, an oncogene characterized by aberrant glycosylation, underscores the critical role of B4GALT1 in sustaining BM glycosylation and mechanosensing, thereby regulating HSPC fate through functional, transcriptional, and chromatin dynamics. These observations provide insights into the impact of glycan structures on HSPC function, lineage reprogramming, and malignant transformation.