Computational modeling of stem and progenitor cell kinetics identifies plausible hematopoietic lineage hierarchies

Abstract

Summary Classically, hematopoietic stem cell (HSC) differentiation is assumed to occur via progenitor compartments of decreasing plasticity and increasing maturity in a specific, hierarchical manner. The classical hierarchy has been challenged in the past by alternative differentiation pathways. We abstracted experimental evidence into 10 differentiation hierarchies, each comprising 7 cell type compartments. By fitting ordinary differential equation models with realistic waiting time distributions to time-resolved data of differentiating HSCs from 10 healthy human donors, we identified plausible lineage hierarchies and rejected others. We found that, for most donors, the classical model of hematopoiesis is preferred. Surprisingly, multipotent lymphoid progenitor differentiation into granulocyte-monocyte progenitors is plausible in 90% of samples. An in silico analysis confirmed that, even for strong noise, the classical model can be identified robustly. Our computational approach infers differentiation hierarchies in a personalized fashion and can be used to gain insights into kinetic alterations of diseased hematopoiesis.

Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS

“…We complemented our cohort with 8 BM samples from healthy age-matched individuals without mutations ( Table 1 ) that were partly reported in our previous study. 18 …”

“…We assessed the abundance and fraction of HSC (lin-CD34 + CD38 − CD90 + CD45RA-), MPP (lin-CD34 + CD38 − CD90 − CD45RA-), MLP (lin-CD34 + CD38 − CD90 + CD45RA+) CMP (lin-CD34 + CD38 + CD45RA-CD123+), GMP (lin-CD34 + CD38 + CD45RA + CD123+), MEP (lin-CD34 + CD38 + CD45RA-CD123-), and CD34 − compartments following the gating strategy presented in Figure 1 A. By normalizing cell counts to the lineage negative (lin-) compartment, 18 we observed a significant reduction of HSPC proportions in MDS compared to healthy BM (p = 0.038, Kruskal-Wallis test followed by Dunn’s multiple comparison test, Figure 1 B). This difference was driven by significantly decreased CMP and GMP fractions in MDS ( Figure 1 C).…”

“…By comparing these competing hierarchies quantitatively to HSPC kinetics, we recently showed that the classical model of hematopoiesis describes human healthy hematopoiesis best. 18 However, in CHIP and MDS, the plasticity of HSPC and transitions between cellular compartments may shift.…”

“…Our in vitro approach allows us to observe cell type-specific abundances and division distributions at several time points. Equipped with a computational multi-compartment model with realistic waiting time distributions, 18 we are able to infer division, differentiation, and death rates for every observed progenitor cell type, allowing us to compare competing models of hematopoietic hierarchies and deconvolute kinetic alterations in CHIP and MDS. We show that alterations in kinetics and differentiation transitions can be readily detected in individuals with CHIP before any hematopoietic disorder becomes evident and that the hematopoietic architecture becomes progressively disrupted in the transition from CHIP to MDS.…”

Altered expression response upon repeated gene repression in single yeast cells

“…We then determined whether the model accounting for repression was required to explain a total GFP trace using the Bayesian information criterion (BIC). A BIC difference of ten between the model accounting for and not accounting for repression (BIC repression < BIC no repression − 10) was considered an appropriate threshold to reject the model not accounting for repression with fewer model parameters (see Materials and Methods and Fig 3B and 3C), as commonly done in model selection using BIC as selection criterion [23][24][25]. GFP traces of cells requiring the model accounting for repression are henceforth referred to as "cells with repression kinetics".…”