Monocytes in allo-HSCT with aged donors secrete IL-1/IL-6/TNF to increase the risk of GVHD and damage the aged HSCs

Aging is considered a critical factor of poor prognosis in allogenic hemopoietic stem cell transplantation (allo-HSCT). To elucidate the underlying mechanisms, we comprehensively reintegrated our clinical data from patients after allo-HSCT and public single-cell transcriptomic profile from post-allo-HSCT and healthy individuals, demonstrating that old donors were more prone to acute GVHD (aGVHD) with pronounced inflammation accumulation and worse overall survival (OS). We also found the presence of inflammation-related CXCL2+ HSC subpopulation during aging with significantly enriched pro-inflammatory pathways. Shifting attention to the HSC microenvironment, we deciphered that IL-1/IL-6 and TRAIL (i.e., TNFSF10) ligand‒receptor pair serves as the crucial bridge between CD14/CD16 monocytes and hematopoietic stem/progenitor cells (HSPCs). The profound upregulation of these signaling pathways during aging finally causes HSC dysfunction and lineage-biased differentiation. Our findings provide the theoretical basis for achieving tailored GVHD management and enhancing allo-HSCT regimens efficacy for aged donors.