Clonal analysis of lineage fate in native haematopoiesis

• Published in: Nature (London) Vol. 553; no. 7687; pp. 212 - 216
• Main Authors: Rodriguez-Fraticelli, Alejo E., Wolock, Samuel L., Weinreb, Caleb S., Panero, Riccardo, Patel, Sachin H., Jankovic, Maja, Sun, Jianlong, Calogero, Raffaele A., Klein, Allon M., Camargo, Fernando D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2018; Nature Publishing Group
• Subjects: 45/100; 45/22; 45/23; 45/77; 49/91; 631/136/232; 631/532/1360; 631/532/1542; 64/60; 96/31; Animals; Cell growth; Cell Lineage; Cells (biology); Clone Cells - cytology; Clone Cells - metabolism; Cloning; Female; Gene sequencing; Genetic aspects; Granulocytes; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hemopoiesis; Humanities and Social Sciences; letter; Male; Megakaryocytes - cytology; Megakaryocytes - metabolism; Mice; multidisciplinary; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Observations; Progenitor cells; Ribonucleic acid; RNA; Science; Sequence Analysis, RNA; Single-Cell Analysis; Stem cells; Transcriptome - genetics; Transplantation; Transplants & implants; Transposons
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature25168

Transposon tagging to clonally trace progenitors and stem cells provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ . New blood lineage Generating new blood, or haematopoiesis, relies on a pool of stem cells that produces multipotent progenitors and differentiated blood and immune cells. Different models have been proposed to explain the hierarchical organization and fate decision of these cells, mainly using transplantation to assess lineage potential. Fernando Camargo and colleagues use transposon tagging to trace progenitors and stem cells clonally in unperturbed haematopoiesis and apply single-cell RNA sequencing to assess the transcriptome of the cells produced. They find the coexistence of unilineage- and oligolineage-producing clones and suggest that the megakaryocyte lineage arises largely independently of other haematopoietic fates, and can do so from long-term haematopoietic stem cells directly. Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top 1 , 2 . Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ .