HLF Expression Defines the Human Haematopoietic Stem Cell State

Haematopoietic stem cells (HSCs) sustain blood cell homeostasis throughout life and are able to regenerate all blood lineages following transplantation. Despite this clear functional definition, the accurate separation of human HSCs from their differentiated progeny can currently only be achieved through combinatorial measurement of multiple surface antigens. Here, we identify the master transcription factor HLF (Hepatic Leukemia Factor) as the most selective and consistently expressed marker gene in HSC-enriched sub-populations of different ontogenetic sources and ex vivo expanded CD34+ cord blood cells. To directly track its expression, we have developed a genomic HLF reporter strategy, capable of selectively labeling the most immature human blood cells on the basis of a single engineered parameter. Most importantly, HLF-expressing cells comprise all of the stem cell activity in culture and in vivo during serial transplantation. Taken together, these results establish HLF as the most defining gene of the human haematopoietic stem cell state and outline a next-generation approach to continuously mark these cells with unmatched fidelity.