Hematopoietic stem cell heterogeneity is determined at the clonal level

Abstract

Recent studies suggest that hematopoietic stem cells (HSCs) heterogeneously supply blood cells after transplantation. Little is known about how this heterogeneity is regulated. Here, we used a genetic barcode system to track the blood production of individual HSC clones during serial transplantation in mice. HSC clones were marked with unique genetic barcodes prior to their transplantation into primary recipient mice. Four months later, we recovered HSCs from each primary recipient and transplanted them into multiple secondary recipient mice. Blood cells were sampled and analyzed four months after each transplantation. We found that fewer HSC clones supplied blood cells in the secondary recipients than in the primary recipients but that their clonal expansion had significantly increased. Surprisingly, many clones found in the peripheral blood of the secondary recipients were not present in the peripheral blood of the primary recipients. Most of these clones were activated in multiple secondary recipients and were biased towards myeloid lineages. Strikingly, HSCs derived from the same clone exhibited consistent clonal expansion and lineage bias characteristics across different secondary recipients. However, these differentiation characteristics changed between the primary and secondary recipients. For example, lineage-balanced HSC clones in the primary recipients mostly converted to lymphoid bias in the secondary recipients, and myeloid-biased clones in the primary recipients were more likely to become lineage balanced in the secondary recipients. Overall, our data suggest that HSCs derived from the same clone exhibit similar blood production characteristics, which are altered in a predictable way upon transplantation. These findings suggest that the clonal-level characteristics of HSC blood production may be exploited in bone marrow transplantation therapy. For example, select HSC clones can be transplanted to improve the efficacy of this treatment. Better therapeutic outcomes may also be achieved by matching donor HSC clones to patient specific requirements.