Age-independent influence of hematopoietic stem and progenitor cell populations during hematopoietic reconstitution

Abstract

Hematopoietic stem cell transplantation (HSCT) following myeloablative conditioning represents the only curative treatment option to overcome numerous hematologic malignancies. Despite the overall clinical success to achieve reconstitution of the blood system in many patients, the length of the aplastic phase until recovery response remains a critical parameter for patient survival. Fatal infections are the major risk factor for immunocompromised individuals and in many cases lead to transplant related morbidity and mortality. Therefore, we hypothesized that transplants from young donors might be beneficial for the spatiotemporal blood reconstitution in comparison to old grafts. Here we report on our multicolor-coded barcode system (BC32) to track hematopoietic stem and progenitor cell (HSPC) populations in a murine model of HSCT. By using different experimental settings of young and aged donor and recipient animals we compared the influence of age on graft composition, leukocyte recovery and more precisely, the contribution of individual HSPC subpopulations to the process. We show that blood reconstitution is substantially driven and maintained by HSCs and MPPs, while the latter accounted for higher output rates than HSCs, confirmed by FACS and NGS analyses. Reconstitution patterns were highly polyclonal and stable in all animals aside from variability between individual animals. This leads to the conclusion that HSPCs home, engraft and differentiate independently of donor and recipient age in our experimental conditions. Our findings add to ongoing efforts to expand the application of HSCT in older individuals while minimizing therapy related risks resulting from intensive myeloablative conditioning or incomplete blood reconstitution.