Bone marrow-inspired DLL1-presenting microparticles enhance asymmetric division and maintenance of mouse hematopoietic stem and progenitor cells.

Understanding the regulation of hematopoietic stem and progenitor cell (HSPC) fate and translating it into effective culture strategies remains a significant challenge. Asymmetric lysosomal inheritance during HSPC division has been shown to predict variations in daughter cell activity and fate, yet the underlying regulators remain unclear. Through cell-cell communication analysis of bone marrow single-cell sequencing data, we identified the Notch ligand Delta-like protein 1 (DLL1) as a potential regulator in HSPC asymmetric division (ACD). Interactions between DLL1-presenting microparticles (MP-Ds) and HSPCs were observed in addressable microwell arrays, simulating cellular responses to localized niche signals. Long-term single-cell tracking revealed that MP-D interactions polarized HSPC lysosomes toward the contact site, directing division orientation and consequent asymmetric lysosomal inheritance in paired daughter cells. Furthermore, this co-culture system enhanced long-term hematopoietic reconstitution capacity of HSPCs in serial transplantations. Our findings support an association between HSPC ACD and the presentation mode of DLL1 signals, which enhances the ex vivo maintenance of HSPCs.