Reconciling Flux Experiments for Quantitative Modeling of Normal and Malignant Hematopoietic Stem/Progenitor Dynamics

Abstract

Summary Hematopoiesis serves as a paradigm for how homeostasis is maintained within hierarchically organized cell populations. However, important questions remain as to the contribution of hematopoietic stem cells (HSCs) toward maintaining steady state hematopoiesis. A number of in vivo lineage labeling and propagation studies have given rise to contradictory interpretations, leaving key properties of stem cell function unresolved. Using processed flow cytometry data coupled with a biology-driven modeling approach, we show that in vivo flux experiments that come from different laboratories can all be reconciled into a single unifying model, even though they had previously been interpreted as being contradictory. We infer from comparative analysis that different transgenic models display distinct labeling efficiencies across a heterogeneous HSC pool, which we validate by marker gene expression associated with HSC function. Finally, we show how the unified model of HSC differentiation can be used to simulate clonal expansion in the early stages of leukemogenesis.

A time and single-cell resolved model of hematopoiesis

“…Self-renewal and differentiation capacities are particularly relevant to leukemia research, which, in most cases, struggles with identifying cell types of cancer origin. As we show here and supported by previous studies (Busch et al, 2015; Takahashi et al, 2021), progenitors can also operate close to self- renewal and a small proliferative advantage may be sufficient to immortalize them. Finally, population dynamic models are universally applicable across biological fields, as adult tissues are commonly replenished from their own stem cell pools (Goodell et al, 2015).…”

“…The reason for this choice lays in 2 observed characteristics in the data: cluster 0 ratio of labelled to unlabeled cells (labelling frequency) grows over time, and some downstream clusters’ labelling frequency overshoots the one in cluster 0. Based on (Barile et al, 2020) and (Takahashi et al, 2021), this implies that the progenitor cluster must be heterogeneous. Indeed, the most immature HSCs occupy only the tip of cluster 0 (Figure 2C).…”

Mast Cell Repopulating Ability Is Lost During the Transition From Pre-HSC to FL HSC

“…However, finding a specific marking of HSC is also challenging. Currently, the iFgd5 is thought to be the best model regarding specificity and recombination efficiency compared to Tie2, Pdzk1ip1, or KRT18 (19,27,(40)(41)(42). Additionally, intrauterine labeling is less efficient than postnatal p2 marking as Figure S3D.…”

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

“…Both a study of somatic mutations in a 115-yr-old woman and a recent longitudinal study following the evolution of clones in an individual from age 103 to 110 (3 time points) found that likely benign clones achieved VAFs of up to 0.3 (van den Akker et al, 2020; Holstege et al, 2014)-suggesting a very small pool of stem cells. Another possible explanation is that the observed variants arose in cells with faster rates of self-renewing symmetric divisions λ , either due to natural selection of faster dividing HSPCs or because the observed variants in the LBC arose in different HSPC compartments, such as multipotent progenitor cells (Barile et al, 2020; Morcos et al, 2020; Takahashi et al, 2021). Since we can only directly measure θ , it is possible that both a depletion of the pool of HSPCs at old age and heterogeneity in the self-renewal rate λ have enabled neutral events to reach high VAFs.…”