Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

Significance Hematopoietic stem cells (HSCs) are the key therapeutic component of bone marrow transplantation, the first and most prevalent clinical stem cell therapy. HSCs sustain daily and life-long blood and immune production through a complex stepwise lineage commitment process. In this work, we analyzed HSC lineage commitment at the clonal level and identified HSC regulatory mechanisms that are undetectable by conventional population-level studies. We uncovered distinct HSC clonal pathways that lead to differential blood production and imbalances. Furthermore, we showed that regulation of HSCs transplanted into unconditioned hosts is strikingly different from that after irradiation and after an antagonistic antibody treatment, which has important implications for understanding, interpreting, and optimizing HSC transplantation.