3005 – AGING ATTENUATES THE HEMATOPOIETIC STEM CELL CONTRIBUTION TO NATIVE HEMATOPOIESIS

While hematopoietic decline is a well-established feature of aging, the in vivo dynamics of such changes remains obscure. Here, using an inducible lineage tracing model, single cell transcriptome and epitope profiling, and an in vitro hematopoietic stem cell (HSC) self-renewal system, we dissected the contribution of HSCs during chronological aging. Age-related attrition in differentiation decreased the HSC output to multipotent progenitors (MPPs), which associated with a pronounced reduction in lymphopoiesis. Combined single-cell molecular profiling and linage tracing revealed that aging associated with a specific depletion of an hitherto uncharacterized early lymphoid-primed progenitor, that we denoted as MPP Ly-I. In native hematopoiesis, MPP Ly-I cells are characterized by a high degree of dormancy and share several phenotypic attributes with HSCs. In a transplantation setting, MPP Ly-I cells generated lymphoid output faster than HSCs and with minimal myeloid differentiation, suggesting that MPP Ly-I cells represent the earliest lymphoid-primed progenitor downstream of HSCs. The apparent reduction of MPP Ly-I cells during aging may underlie defective age-associated lymphopoiesis. Finally, when applying a novel HSC self-renewal promoting cell culture system, we found that while some of the aging phenotypes could be rescued by an in vitro activation approach, most aged HSCs retained a compromised lymphoid differentiation capacity after culture. When increasing the numbers of input HSCs to such cultures, we observed a robust lymphoid output following transplantation, thereby unequivocally demonstrating the existence of rare aged HSC clones fully competent in producing lymphoid offspring. While hematopoietic decline is a well-established feature of aging, the in vivo dynamics of such changes remains obscure. Here, using an inducible lineage tracing model, single cell transcriptome and epitope profiling, and an in vitro hematopoietic stem cell (HSC) self-renewal system, we dissected the contribution of HSCs during chronological aging. Age-related attrition in differentiation decreased the HSC output to multipotent progenitors (MPPs), which associated with a pronounced reduction in lymphopoiesis. Combined single-cell molecular profiling and linage tracing revealed that aging associated with a specific depletion of an hitherto uncharacterized early lymphoid-primed progenitor, that we denoted as MPP Ly-I. In native hematopoiesis, MPP Ly-I cells are characterized by a high degree of dormancy and share several phenotypic attributes with HSCs. In a transplantation setting, MPP Ly-I cells generated lymphoid output faster than HSCs and with minimal myeloid differentiation, suggesting that MPP Ly-I cells represent the earliest lymphoid-primed progenitor downstream of HSCs. The apparent reduction of MPP Ly-I cells during aging may underlie defective age-associated lymphopoiesis. Finally, when applying a novel HSC self-renewal promoting cell culture system, we found that while some of the aging phenotypes could be rescued by an in vitro activation approach, most aged HSCs retained a compromised lymphoid differentiation capacity after culture. When increasing the numbers of input HSCs to such cultures, we observed a robust lymphoid output following transplantation, thereby unequivocally demonstrating the existence of rare aged HSC clones fully competent in producing lymphoid offspring.