Cell division history determines hematopoietic stem cell potency

Abstract

Loss of stem cell self-renewal may underpin aging. Here, we combined single cell profiling, deep-learning, mathematical modelling and in vivo functional studies to explore how hematopoietic stem cell (HSC) division patterns evolve with age. We trained an artificial neural network (ANN) to accurately identify cell types in the hematopoietic hierarchy and predict their age from their gene expression patterns. We then used this ANN to compare daughter cell identities immediately after HSC divisions, and found that HSC self-renewal declines sharply with age. Furthermore, while HSC cell divisions are deterministic and intrinsically-regulated in young and old age, they become stochastic and niche-sensitive in mid-life. Analysis of evolving division patterns indicated that the self-renewal ability an individual HSC depends upon number times it has divided previously. We propose a model of HSC proliferation that accurately predicts the accumulation of HSCs with age, and reconciles the stochastic and instructive views of fate commitment. Mice and cellsC57BL/6 (B6-Ly5.2), C57BL/6 mice congenic for the Ly5 locus (B6-Ly5.1) were purchased from Sankyo-Lab Service (Tsukuba, Japan). Evi1-GFP knock-in mice were provided by Dr. Kurokawa (The University of Tokyo, Japan). Mice expressing Cre recombinase under the control of the Type I collagen (Col1a1) promoter (Col1a1-Cre) and inducible Angpt1 transgenic 29/45

Heterogeneity and ‘memory’ in stem cell populations

“…Advances in experimental methods that track the mitotic history (or more generally the epigenetic history) of individual cells will help elucidate the mechanisms by which functional memories are formed and propagated. We anticipate that live-cell imaging, genetic barcoding and fluorescent label retention strategies (Kester & van Oudenaarden 2018, Schaniel & Moore 2009, in combination with the advanced mathematical and statistical modelsincluding the latest advances in machine learning (Buggenthin et al 2017, Arai et al 2019) -needed to analyze the resulting data, will be particularly important in this regard.…”

“…In principle there many ways that the interplay with division history and niche instruction could affect cell divisions. Very little is currently known about this interplay except that division history diminishes self-renewal ability (Bernitz et al 2016, Arai et al 2019, Säwén et al 2016. Since a simple model suffices to illustrate our point, we will therefore assume that daughter cells are produced independently of each other (i.e.…”

“…There is emerging evidence that this is the case. A number of recent reports have found that repopulation activity is concentrated in the most quiescent HSC subpopulations (Wilson et al 2008, Foudi et al 2009, Takizawa et al 2011, Qiu et al 2014) and, furthermore, the accumulation of cell divisions is directly associated with loss of stem cell potency both during native hematopoiesis and under conditions of stress (Bernitz et al 2016, Säwén et al 2016, Qiu et al 2014, Wilson et al 2008, Nygren & Bryder 2008, Foudi et al 2009, Arai et al 2019. Although the precise reasons for this association are unclear, it is likely that HSCs are sensitive to the general wear and tear that occurs during cell division (Walter et al 2015).…”