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

While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the end...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 4; pp. 1447 - 1456
Main Authors:	Lu, Rong, Czechowicz, Agnieszka, Seita, Jun, Jiang, Du, Weissman, Irving L.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 22-01-2019
Series:	PNAS Plus
Subjects:	Animals Bias Biological Sciences Blood Cell Differentiation - physiology Cell Lineage Cell self-renewal Clone Cells Hematology Hematopoiesis Hematopoiesis - physiology Hematopoietic stem cells Hematopoietic Stem Cells - physiology Hematopoietic system Homeostasis Homeostasis - physiology Hyperglycemia Irradiation Medical research Mice Mice, Inbred C57BL PNAS Plus Population studies Radiation Stem cells Transplantation hematopoietic stem cell lineage commitment transplantation preconditioning radiation clonal tracking
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Summary:	While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 3Present address: AI Based Healthcare and Medical Data Analysis Standardization Unit, Medical Sciences Innovation Hub Program, RIKEN, Tokyo 103-0027, Japan. 2Present address: Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305. Contributed by Irving L. Weissman, December 3, 2018 (sent for review January 26, 2018; reviewed by Iannis Aifantis, Craig T. Jordan, and Amy J. Wagers) Author contributions: R.L., A.C., and I.L.W. designed research; R.L., A.C., and D.J. performed research; R.L., A.C., and J.S. contributed new reagents/analytic tools; R.L. and A.C. analyzed data; and R.L. wrote the paper. Reviewers: I.A., New York University School of Medicine; C.T.J., University of Colorado; and A.J.W., Harvard University.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1801480116