Causes and Consequences of Hematopoietic Stem Cell Heterogeneity Simon Haas, Andreas Trumpp, Michael D. Milsom  Cell Stem Cell  Volume 22, Issue 5, Pages 627-638 (May 2018) DOI: 10.1016/j.stem.2018.04.003 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 Models of HSC Lineage Commitment (A) Classical model of hematopoiesis. HSCs undergo lineage commitment by passing through a series of discrete intermediate progenitor stages in a stepwise manner. Lineage decisions are made on subsequent binary branching points, resulting in a tree-like model. The first lineage separation occurs between common myeloid versus lymphoid progenitors (Akashi et al., 2000; Kondo et al., 1997; Seita and Weissman, 2010). A direct shortcut into the megakaryocytic lineage has been suggested (dashed lines) (Haas et al., 2015; Notta et al., 2016; Yamamoto et al., 2013). (B) Early split model. Lineage separation appears earlier compared with previous models (Mercier and Scadden, 2015; Notta et al., 2016; Paul et al., 2015; Perié et al., 2015; Velten et al., 2017). (C) Continuous Waddington-like model. HSCs do not pass through stable, discrete intermediate states but gradually acquire lineage-committed transcriptomic states in a continuous manner. In such a model, developmental stages downstream of HSCs, such as MPPs or CMPs, do not represent discrete cell types but should rather be considered transitory states within the HSPC continuum (Macaulay et al., 2016; Nestorowa et al., 2016; Pina et al., 2012; Velten et al., 2017). Cell Stem Cell 2018 22, 627-638DOI: (10.1016/j.stem.2018.04.003) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 2 HSC Lineage Biases and Transcriptional Lineage Priming HSC lineage biases and transcriptional lineage-priming are illustrated in a continuous Waddington-like model (adapted from Velten et al., 2017). Balanced HSCs show a roughly equivalent contribution toward the production of all mature blood cells (center). Lineage-biased HSCs show a skewed production of certain cell types while retaining multi-lineage potential. Functional lineage biases are typically associated with transcriptional lineage priming (left and right). Cell Stem Cell 2018 22, 627-638DOI: (10.1016/j.stem.2018.04.003) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 3 Causes of HSC Heterogeneity Distinct sources shape the heterogeneity within the HSC compartment. (A) HSCs can localize to distinct bone marrow niches associated with exposure to distinct biochemical and biophysical environments. (B) Mutations of HSCs and their progeny can result in genetic mosaics that have altered functional properties. (C) Differential modification of epigenetic marks across individual HSCs will result in epigenetic heterogeneity. (D) HSCs can differ in their cellular state, such as cell cycle or metabolism. This is associated with biomolecular heterogeneity. (E) During cell division, asymmetric segregation of cell components can contribute to heterogeneity within the HSC pool. (F) Stochastic processes within the cell are drivers of cellular variability. Cell Stem Cell 2018 22, 627-638DOI: (10.1016/j.stem.2018.04.003) Copyright © 2018 Elsevier Inc. Terms and Conditions