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)
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.
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.
↵2Present address: Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
↵3Present address: AI Based Healthcare and Medical Data Analysis Standardization Unit, Medical Sciences Innovation Hub Program, RIKEN, Tokyo 103-0027, Japan.
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.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801480116/-/DCSupplemental.
Published under the PNAS license.
