Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors

Paul, Franziska; Arkin, Ya'Ara; Giladi, Amir; Jaitin, Diego Adhemar; Kenigsberg, Ephraim; Keren‐Shaul, Hadas; Winter, Deborah R.; Lara‐Astiaso, David; Gury, Meital; Weiner, Assaf; David, Eyal; Cohen, Nadav; Lauridsen, Felicia Kathrine Bratt; Haas, Simon; Schlitzer, Andreas; Mildner, Alexander; Ginhoux, Florent; Jung, Steffen; Trumpp, Andreas; Porse, Bo; Tanay, Amos; Amit, Ido

doi:10.1016/j.cell.2015.12.046

Cited by 305 publications

(556 citation statements)

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“…This non-LR-HSC population, being the product of accumulated divisional history, may be the source of myeloid-repopulating cells described in clonal transplantation experiments (Dykstra et al, 2011;Sudo et al, 2000;Yamamoto et al, 2013). The degree of functional heterogeneity we find within the aging non-LR-HSC population is consistent with evidence from young animals that cell surface marker combinations alone cannot select for functionally homogeneous populations when analyzed at the single-cell level (Paul et al, 2015;Perie et al, 2015;Yamamoto et al, 2013). Additionally, the reduced regenerative capacity of the proliferative non-LR-HSC population is also supported by studies indicating that increasing cell cycle often reduces HSC function (Bowie et al, 2006;Pietras et al, 2011).…”

Section: Divisional History and Heterogeneity Of The Aging Hsc Comparsupporting

confidence: 72%

Hematopoietic stem cells count and remember self-renewal divisions

Bernitz¹,

MacArthur

Sieburg

et al. 2016

Experimental Hematology

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SummaryThe ability of cells to count and remember their divisions could underlie many alterations that occur during development, aging, and disease. We tracked the cumulative divisional history of slow-cycling hematopoietic stem cells (HSCs) throughout adult life. This revealed a fraction of rarely dividing HSCs that contained all the long-term HSC (LT-HSC) activity within the aging HSC compartment. During adult life, this population asynchronously completes four traceable symmetric self-renewal divisions to expand its size before entering a state of dormancy. We show that the mechanism of expansion involves progressively lengthening periods between cell divisions, with long-term regenerative potential lost upon a fifth division. Our data also show that age-related phenotypic changes within the HSC compartment are divisional history dependent. These results suggest that HSCs accumulate discrete memory stages over their divisional history and provide evidence for the role of cellular memory in HSC aging. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Graphical AbstractHSCs count and remember the number of times they have divided to limit the number of cell divisions, a mechanism that may underlie HSC aging.

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Section: Divisional History and Heterogeneity Of The Aging Hsc Comparsupporting

confidence: 72%

Hematopoietic stem cells count and remember self-renewal divisions

Bernitz¹,

MacArthur

Sieburg

et al. 2016

Experimental Hematology

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“…The small branch cell counts (37-380) precluded recursive application of TreeTop (Supp Fig 13, Online Methods). The results from TreeTop are therefore consistent with recent findings in favour of a flat hierarchy [5][6][7] .…”

supporting

confidence: 82%

Tree-ensemble analysis tests for presence of multifurcations in single cell data

Macnair

Roditi

Ganscha

et al. 2017

Preprint

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We introduce TreeTop, an algorithm for single-cell data analysis to identify and assess statistical significance of branch points in biological processes with possibly multi-level branching hierarchies. We demonstrate branch point identification for processes with varying topologies, including T cell maturation, B cell differentiation and hematopoiesis. Our analyses are consistent with recent experimental studies suggesting a shallow hierarchy of differentiation events in hematopoiesis, rather than the classical multi-level hierarchy. MainMany important biological processes, such as differentiation in developmental and immune biology, and clonal evolution in cancer, can be conceived of as bi-or multi-furcated cellular state trajectories. Hematopoiesis is such a process, where hematopoietic stem cells (HSCs) give rise to multiple distinct mature blood cell types via a sequence of lineage commitments. The exact sequence is still debated 1 , either assuming a hierarchical architecture of multiple fate decisions via distinct oligopotent progenitor cell states 2-4 , or a flat hierarchy of hematopoiesis, which does not include oligopotent progenitors, and where HSCs differentiate directly into committed lineages 5-7 .High dimensional single-cell technologies, such as single-cell RNA sequencing 8 and mass cytometry 9 , constitute increasingly widely used tools to investigate such opposing models of differentiation, and other branching processes. These technologies allow the evaluation of the state of single cells, i.e. the transcriptional or proteomic abundance profile in the case of single cell RNA sequencing or mass cytometry, respectively. Biological processes can be conceived of as trajectories through state space: temporal sequences of cellular states that can either be derived from time series or reconstructed from non-time series single-cell data 10 . We define a branch point as the location in state space where three or more distinct . CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/200923 doi: bioRxiv preprint first posted online Oct. 10, 2017; cellular state trajectories meet. Branch points dissect these trajectories into distinct state trajectory branches.Identifying branch points is challenging because for each single cell measurement, both branch membership and ordering within each branch must be learned simultaneously. Existing approaches include pseudotime ordering, which learns a latent time variable along a mean trajectory through state space is limited to non-branching processes [11][12] . SPADE overcomes this limitation by fitting a single minimum spanning tree to non-deterministically clustered data 13 . Monocle 11,14 fits smoothed trees to a low dimensional representation of single cell data, where branch points in the tree are assumed to correspond to branch points in the data. Both Monocle and SPADE by definition impose a tree topology, regardless ...

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“…Instead it appears as though ST-HSC as well as more differentiated progenitors with selfrenewing abilities are the predominant suppliers of new blood cells (11,22), implying that LT-HSC primarily serve as a reservoir in the adult hematopoietic system. In addition, current data suggest that commitment to a specific lineage during the hematopoietic differentiation process, starting with ST-HSC, primarily reflects cell-autonomous features of the relevant cell type (23)(24)(25)(26). The primary role of the LT-HSC niche may thus be to enforce quiescence in order to protect the stem cell pool from proliferative exhaustion and accumulation of DNA damage.…”

Section: Commentarymentioning

confidence: 98%