Anna Marciniak-Czochra

Modeling of asymmetric cell division in hematopoietic stem cells--regulation of self-renewal is essential for efficient repopulation.

Hematopoietic stem cells (HSCs) are characterized by their ability of self-renewal to replenish the stem cell pool and differentiation to more mature cells. The subsequent stages of progenitor cells also share some of this dual ability. It is yet unknown whether external signals modulate proliferation rate or rather the fraction of self-renewal. We propose three multicompartment models, which rely on a single external feedback mechanism. In Model 1 the signal enhances proliferation, whereas the self-renewal rates in all compartments are fixed. In Model 2 the signal regulates the rate of self-renewal, whereas the proliferation rate is unchanged. In Model 3, the signal regulates both proliferation and self-renewal rates. This study demonstrates that a unique strictly positive stable steady state can only be achieved by regulation of the rate of self-renewal. Furthermore, it requires a lower number of effective cell doublings. In order to maintain the stem cell pool, the self-renewal ratio of the HSC has to be > or =50% and it has to be higher than the self-renewal ratios of all downstream compartments. Interestingly, the equilibrium level of mature cells depends only on the parameters of self-renewal of HSC and it is independent of the parameters of dynamics of all upstream compartments. The model is compatible with the increase of leukocyte numbers following HSC transplantation. This study demonstrates that extrinsic regulation of the self-renewal rate of HSC is most essential in the process of hematopoiesis.

Expansion of Adipose Mesenchymal Stromal Cells is Affected by Human Platelet Lysate and Plating Density

The composition of mesenchymal stromal cells (MSCs) changes in the course of in vitro culture expansion. Little is known how these cell preparations are influenced by culture media, plating density, or passaging. In this study, we have isolated MSCs from human adipose tissue in culture medium supplemented with either fetal calf serum (FCS) or human platelet lysate (HPL). In addition, culture expansion was simultaneously performed at plating densities of 10 or 10,000 cells/cm2. The use of FCS resulted in larger cells, whereas HPL significantly enhanced proliferation. Notably, HPL also facilitated expansion for more population doublings than FCS (43 ± 3 vs. 22 ± 4 population doubling; p < 0.001), while plating density did not have a significant effect on long-term growth curves. To gain further insight into population dynamics, we conceived a cellular automaton model to simulate expansion of MSCS. It is based on the assumptions that the number of cell divisions is limited and that due to contact inhibition proliferation occurs only at the rim of colonies. The model predicts that low plating densities result in more heterogeneity with regard to cell division history, and favor subpopulations of higher migratory activity. In summary, HPL is a suitable serum supplement for isolation of MSC from adipose tissue and facilitates more population doublings than FCS. Cellular automaton computer simulations provided additional insights into how complex population dynamics during long-term expansion are affected by plating density and migration.

Characterization of stem cells using mathematical models of multistage cell lineages

Stem cells dynamics is an important field of research with promising clinical impacts. Due to the revolutionary new technologies of biological data collection, an enormous amount of information on specific factors and genes responsible for cell differentiation is available. However, the mechanisms controlling stem cell self-renewal, maintenance and differentiation are still poorly understood and there exists no general characterization of stem cells based on observable cell properties. We address these problems with the help of mathematical models. Stem cells are described as the cell type that is most responsive to certain environmental signals. This results in a dynamic characterization of stemness that depends on environmental conditions and is not necessarily linked to a unique cell population.

DERIVATION OF A MACROSCOPIC RECEPTOR-BASED MODEL USING HOMOGENIZATION TECHNIQUES

We study the problem of diffusive transport of biomolecules in the intercellular space, modeled as porous medium, and of their binding to the receptors located on the surface membranes of the cells. Cells are distributed periodically in a bounded domain. To describe this process we introduce a reaction-diffusion equation coupled with nonlinear ordinary differential equations on the boundary. We prove existence and uniqueness of the solution of this problem. We consider the limit, when the number of cells tends to infinity and at the same time their size tends to zero, while the volume fraction of the cells remains fixed. Using the homogenization technique of two-scale convergence, we show that the sequence of solutions of the original problem converges to the solution of the so-called macroscopic problem. To show the convergence of the nonlinear terms on the surfaces we use the unfolding method (periodic modulation). We discuss applicability of the result to mathematical description of membrane receptors ...

Enabling multiscale modeling in systems medicine.

CITATION: Wolkenhauer, O. et al. 2014. Enabling multiscale modeling in systems medicine. Genome Medicine, 6:21, doi:10.1186/gm538.

BOUNDEDNESS OF SOLUTIONS OF A HAPTOTAXIS MODEL

In this paper we prove the existence of global solutions of the haptotaxis model of cancer invasion for arbitrary non-negative initial conditions. Uniform boundedness of the solutions is shown using the method of bounded invariant rectangles applied to the reformulated system of reaction-diffusion equations in divergence form with a diagonal diffusion matrix. Moreover, the analysis of the model shows how the structure of kinetics of the model is related to the growth properties of the solutions and how this growth depends on the ratio of the sensitivity function (describing the size of haptotaxis) and the diffusion coefficient. One of the implications of our analysis is that in the haptotaxis model with a logistic growth term, cell density may exceed the carrying capacity, which is impossible in the classical logistic equation and its reaction-diffusion extension.

Clonal selection and therapy resistance in acute leukaemias: mathematical modelling explains different proliferation patterns at diagnosis and relapse

Recent experimental evidence suggests that acute myeloid leukaemias may originate from multiple clones of malignant cells. Nevertheless, it is not known how the observed clones may differ with respect to cell properties, such as proliferation and self-renewal. There are scarcely any data on how these cell properties change due to chemotherapy and relapse. We propose a new mathematical model to investigate the impact of cell properties on the multi-clonal composition of leukaemias. Model results imply that enhanced self-renewal may be a key mechanism in the clonal selection process. Simulations suggest that fast proliferating and highly self-renewing cells dominate at primary diagnosis, while relapse following therapy-induced remission is triggered mostly by highly self-renewing but slowly proliferating cells. Comparison of simulation results to patient data demonstrates that the proposed model is consistent with clinically observed dynamics based on a clonal selection process.

MODELLING OF EARLY LUNG CANCER PROGRESSION: INFLUENCE OF GROWTH FACTOR PRODUCTION AND COOPERATION BETWEEN PARTIALLY TRANSFORMED CELLS

The generally accepted Moolgavkars theory of carcinogenesis assumes that all cancers are clonal, i.e. that they arise from progressive genetic deregulation in a cell pedigree originating from a single ancestral cell.18 However, recently the clonal theory has been challenged by the field theory of carcinogenesis, which admits the possibility of simultaneous changes in tissue subject to carcinogenic agents, such as tobacco smoke in lung cancer. Axelrod et al.1 formulated a more detailed framework, in which partially transformed cells depend in a mutualistic way on growth factors they produce, in this way enabling these cells to proliferate and undergo further transformations. On the other hand, the field theory assumes spatial distribution of precancerous cells and indeed there exists evidence that early-stage precancerous lesions in lung cancer progress along linear, tubular, or irregular surface structures. This seems to be the case for the atypical adenomatous hyperplasia (AAH),10 a likely precursor of adenocarcinoma of the lung. In this paper we explore the consequences of linking the model of spatial growth of precancerous cells,12 with the mutualistic hypothesis. We investigate the solutions of the model using analytical and computational techniques. The picture emerging from our modelling indicates that production of growth factors by cells considered may lead to diffusion-driven instability, which in turn may lead either to decay of both population, or to emergence of local growth foci, represented by spike-like solutions. Mutualism may, in some situations, increase the stability of solutions. One important conclusion is that models of field carcinogenesis, which include spatial effects, generally have very different behaviour compared to ODE models.

Stability analysis of multi-compartment models for cell production systems

We study two- and three-compartment models of a hierarchical cell production system with cell division regulated by the level of mature cells. We investigate the structure of equilibria with respect to parameters as well as local stability properties for the equilibria. To interpret the results we adapt the concept of reproduction numbers, which is well known in ecology, to stem cell population dynamics. In the two-compartment model, the positive equilibrium is stable wherever it exists. In the three-compartment model, we find that the intermediate stage of differentiation is responsible for the emergence of an instability region in the parameter plane. Moreover, we prove that this region shrinks as the mortality rate for mature cells increases and discuss this result.

Cell division patterns in acute myeloid leukemia stem-like cells determine clinical course: a model to predict patient survival

Acute myeloid leukemia (AML) is a heterogeneous disease in which a variety of distinct genetic alterations might occur. Recent attempts to identify the leukemia stem-like cells (LSC) have also indicated heterogeneity of these cells. On the basis of mathematical modeling and computer simulations, we have provided evidence that proliferation and self-renewal rates of the LSC population have greater impact on the course of disease than proliferation and self-renewal rates of leukemia blast populations, that is, leukemia progenitor cells. The modeling approach has enabled us to estimate the LSC properties of 31 individuals with relapsed AML and to link them to patient survival. On the basis of the estimated LSC properties, the patients can be divided into two prognostic groups that differ significantly with respect to overall survival after first relapse. The results suggest that high LSC self-renewal and proliferation rates are indicators of poor prognosis. Nevertheless, high LSC self-renewal rate may partially compensate for slow LSC proliferation and vice versa. Thus, model-based interpretation of clinical data allows estimation of prognostic factors that cannot be measured directly. This may have clinical implications for designing treatment strategies.