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## Hematopoietic Stem Cells

Hematopoietic Stem Cells (HSCs) are the multipotent stem cells, located in the bone marrow, from which originates all diﬀerentiated blood cell lineages (red blood cells, white cells and platelets) through the process of hematopoiesis.

Due to the large number of divisions, and the amount of cells and cytokines involved in hematopoiesis, numerous issues may arise at diﬀerent cellular levels and sometimes lead to disorders aﬀecting blood cells. Among a wide variety of disorders aﬀecting blood cells, myeloproliferative diseases are of great interest. They are characterized by a set of conditions that cause blood cells to grow abnormally. They include chronic myelogenous leukemia, a cancer of the white blood cells that exhibits, in some cases, periodic oscillations in all blood cell counts (see [96]). Myeloproliferative disorders usually originate from the HSC population: an uncontrolled proliferation of HSCs can upset the entire physiological process and result in a much faster or slower proliferation (i.e., the influence of cell cycle duration which is the main focus of Chapter 3).

A low blood cell counts can be associated with many diseases and disorders that cause the body to have fewer blood cells than usual. It can be associated to a bone marrow failure resulting from a disease aﬀecting another organ (liver or kidney, for instance), or to a side aﬀect of a specific treatment (chemotherapy drugs, for instance).

The process of hematopoiesis comprises of multiple complex mechanisms regulated by a wide range of hormone-like molecules called growth factors that respond to stimuli and enable a balance between diﬀerentiation, self-renewal and cell mortality (The main focus of Chapter 2). For instance, in case of a deficiency of oxygen in the blood, mature red blood cells trigger the release of erythropoietin from the kidneys which inhibits apoptosis during hematopoiesis, leading to an increase in red blood cells production [71].

**HSC dynamics : Mathematical modeling**

Mathematical modeling of HSC dynamics has been the focus of a large panel of re-searchers over the last four decades, with attempts to improve the understanding of the complex mechanisms regulating HSC functions, throughout the course of normal and pathological hematopoiesis. One of the earliest mathematical models that shed some light on this process was proposed by Mackey [76] in 1978 inspired by the work of Lajtha [73], and Burns and Tannock [31]. Mackey’s model consists of a system of two delay diﬀerential equations describing the evolution of the HSC population divided into proliferating and quiescent cells (also called resting cells). This model has been studied, analyzed and applied to hematological diseases by many authors (see, for in-stance, [9, 95, 96, 99]). For many years, only systems with discrete delay were proposed to describe HSC dynamics see, for example, [8, 77, 78]. Then, more recently, Adimy and Crauste [3], Adimy, Crauste, and Ruan [9], and Bernard, Bélair, and Mackey [21] proposed and analyzed modified versions of Mackey’s model [76] by considering a dis-tribution of cell cycle durations. In 2005, Adimy and Crauste [4] and Adimy, Crauste, and Pujo-Menjouet [12] proposed a model of HSC dynamics in which the cell cycle duration depends upon the cell maturity.

Mathematical models describing the action of growth factors on the hematopoiesis process have been proposed by Bélair et al in 1995 [18], and Mahaﬀy et al in 1998 [81]. They considered an age-structured model of HSC dynamics, coupled with a dif-ferential equation to describe the action of a growth factor on the reintroduction rate from the resting phase to the proliferating one. In 2006, Adimy et al [10] proposed a system of three delay diﬀerential equations describing the production of blood cells under the action of growth factors assumed to act on the rate of reintroduction into the proliferating phase. Adimy and Crauste considered and analyzed two models of hematopoiesis dynamics with: the influence of growth factors on HSC apoptosis [5], and the action of growth factors on the apoptosis rate as well as on the reintroduction rate into the proliferating phase [6].

Many of the aforementioned mathematical models have subsequent implications to cancer prevention, development and treatment.

### Our contribution to HSC dynamics modeling

The originality of our study regarding the influence of growth factors concentrations on diﬀerentiation, proliferation rate and apoptosis lays in the proposed model itself which, to our knowledge, has never been considered in hematopoiesis dynamics beforehand.

Regarding the originality of our study relating to the influence of the total popula-tion of quiescent cells on the cell cycle duration, it lays in the refinement of the model proposed by Adimy et al. [13].

**Immunosenescence, Cancer and Stem Cells**

The immune system is not permanently fully eﬃcient. Indeed, immunosenescence is a process that reflects a gradual decrease of immune system activity with age mainly through a decreased capacity of immunosurveillance [49]. The beginning of immunose-nescence is assumed to be associated with the beginning of thymopoiesis decline. In-deed, the thymus play a crucial role in the development of T cells but also in main-taining immune eﬃciency [102]. Maximal activity is reached at puberty (from 10 to 19 years old according to the World Health Organization) and decrease progressively in adults [108]. The elderly (more than 65 years old (WHO)) usually have i) a depleted population of naive T cells (the set of T lymphocytes that can respond to novel anti-gens) [92, 93], ii) a shrinking repertoire of T cell clones [55, 83, 93], iii) an increased number of naturally occurring regulatory T cells that down-regulate T cell responses [46, 98], iv) a low grade, pro-inflammatory status [92], and v) increased numbers of myeloid-derived suppressor cells, which are associated with impaired T-cell functioning and produce high amounts of reactive oxygen species [24]. All these immune-associated changes can potentially promote tumor proliferation [55].

**The Link Between Aging and Cancer : Mathematical modeling**

Mathematical models have been used, since 1954, to investigate the link between aging and cancer by correlating increasing incidences of cancer with advancing age to muta-tion accumulation [16]. More recently, genetic and epigenetic changes in stem cells have been associated with both normal aging processes and cancer risk [23, 36, 106, 111]. Normal aging is linked with lymphocytes immunosenescence leading to increased se-cretion of cytokines such as IL − 6 and T N F − α [90]. This state of chronic immune activation has been associated with DNA-modifying events that lead to an increased risk of malignancy [28]. Inflammatory cytokines are also important regulators of stem cell states [70]. Mathematical models have proven useful in the study the eﬀects of stress and hormesis [86] on lifespan and the relationship between accelerated aging and carcinogenesis [32–34]. Stochastic models have been used to study the balance between damaged and repaired states in stressed worms. Predictions of lifespan us-ing this model matched the experimental observations [33]. Further stochastic models have been used to examine levels of free radicals and cumulative damage to DNA, lipid structures, and proteins, leading to genetic instability and malignant transformation [32]. Predictions from these models matched both experimental data of survival and fertility curves in Mediterranean fruit flies, and cancer incidence in rats exposed to bromode-oxyuridine [33, 34].

**Our contribution to the modeling of the interactions between aging and cancer**

The originality of our study lays in the ability of our model to predict that acute immunosuppressive infections could also impact cancer risk and in a larger extent than persistent infections. Empirical evidences of such situation are obviously harder to identify, but the impact of “common” diseases on immune system and their relation with cancer risk are worthy of investigation. Our results suggest a stronger impact of acute and repeated immune challenges after the beginning of immunosencence.

**Organization of the thesis**

The thesis is structured in two parts besides this introductory chapter. The first part consists of two chapters dedicated to mathematical modeling and analysis of hematopoietic stem cell dynamics.

In chapter 2, we propose and analyze the following age-structured partial diﬀeren-tial model for hematopoietic stem cell dynamics, in which proliferation, diﬀerentiation and apoptosis are regulated by growth factor concentrations, where we denote respectively by n(t, a), p(t, a) and m(t, a) the cell population densities of quiescent HSCs, proliferating HSCs and mature cells, with age a ≥ 0 at time t ≥ 0. The age represents the time spent by a cell in one of the three compartments. Quiescent cells are assumed to die with a constant rate 0 ≤ δ ≤ 1, and they can be introduced into the proliferating phase with a rate β in order to divide. We suppose that β depends upon a growth factor concentration E1. We assume that the duration of the proliferating phase is the same for all cells, so τ is constant, and describes an average duration of the cell cycle. The population of proliferating cells is controlled by apoptosis γ ≥ 0. We assume that the apoptosis rate γ depends upon the concentration of growth factor E2. The portion of quiescent cells that diﬀerentiate to mature cells is denoted by KN ≥ 0 which, we assume, depends upon a growth factor concentration denoted E3, whereas the portion of daughter cells entering the mature phase is denoted The asymptotic stability of the positive steady state, the most biologically mean-ingful one, is analyzed using the characteristic equation. This study may be helpful in understanding the uncontrolled proliferation of blood cells in some hematological disorders.

The work presented in Chapter 2 has been published in a peer-reviewed journal and is reproduced in extenso.

In chapter 3, we propose and analyze a mathematical model describing the dynam-ics of a hematopoietic stem cell population, in which the duration of the cell cycle τ depends upon the total population of quiescent cells. The function τ : R+ → [0, τmax] is supposed to be bounded, positive, continuously diﬀerentiable (C2) and increasing. The method of characteristics reduces the age-structured model to a system of diﬀer-ential equations with a state-dependent delay. We perform a detailed stability analysis of the following delay diﬀerential equation Furthermore, it is shown that a unique non-trivial steady state can appear through a transcritical bifurcation of the trivial steady state. The analysis of the positive steady state’s behavior concludes to the existence of a Hopf bifurcation and gives criteria for stability switches. Moreover, we have confirmed the analytical results by numerical simulations.

The work presented in Chapter 3 is soon to be submitted for publication.

The second part of the thesis is comprised of a single chapter where we focus on the interactions between the immune system and cancer cells proliferation. Particularly, in Chapter 4, we consider the compartment of invisible cells in order to deepen our analysis of the aforementioned interactions. We propose the following ODE system

where H represents healthy cells, P precancerous cells, C cancerous cells, I can-cerous cells that are invisible to the immune system and N the total number of cells (i.e., N = H + P + C + I). Precancerous cells become cancerous at rate µ2, and finally invisible at rate µ3. We consider that invisible cancerous cells have acquired the capacity to avoid destruction by immune system whatever the mechanism implied. Healthy and precancerous cells replicate at rate β1 while cancerous and invisible cells replicate at rate β2 (greater than β1) with a maximal total number of cells K (i.e., car-rying capacity) in order to induce competition between diﬀerent kinds of cells. Each precancerous and cancerous cells can be eliminated from the organism through the function ω(t).

Afterwords, we show that the frequency, the duration and the action (positive or negative) of immune challenges may significantly impact tumor proliferation. First, we observe that a long immunosuppressive challenge increases accumulation of cancerous cells. However, short immune challenges result in an even greater accumulation of cancerous cells for the same total duration of immunosuppression. Finally, we show that short challenges of immune activation could lead to a slightly decrease in cancerous cell accumulation compared to a long one.

The work presented in Chapter 4 has been published in a peer-reviewed journal and is reproduced in extenso.

**Table of contents :**

**1 General Introduction **

Motivation

1.1 Hematopoietic Stem Cells

1.1.1 HSC dynamics : Mathematical modeling

1.1.2 Our contribution to HSC dynamics modeling

1.2 Immunosenescence, Cancer and Stem Cells

1.2.1 The Link Between Aging and Cancer : Mathematical modeling

1.2.2 Our contribution to the modeling of the interactions between aging and cancer

Organization of the thesis

**I Hematopoietic Stem Cell Dynamics **

**2 Age-structured model of hematopoiesis dynamics with growth factordependent coefficients **

Abstract

2.1 Introduction

2.2 Age-structured partial differential model

2.3 Reduction to a delay differential system

2.4 Positivity and boundedness of solutions

2.5 Existence of steady states

2.6 Global asymptotic stability of trivial steady state

2.7 Local asymptotic stability of the positive steady state

2.8 Numerical illustrations

**3 Hematopoietic Stem Cells dynamics model with state dependant delay**

Abstract

3.1 Age-structured partial differential model

3.2 Properties of the model and existence of steady states

3.3 Linearization and Characteristic Equation

3.4 Global Asymptotic Stability of the Trivial Steady State

3.5 Transcritical Bifurcation and Hopf Bifurcation

3.6 Numerical illustrations

3.6.1 Discussion

**II Cancer cells Proliferation: Immune System Response **

**4 Interactions between immune challenges and cancer cells proliferation: timing does matter! **

Abstract

4.1 Introduction

4.2 Materials and Methods

4.3 Results

Influence of timing and duration of a single immunosuppressive challenge

Combined effect of duration and the number of immunosuppressive challenges

Influence of immune activation challenges combined with immunosenescence

4.4 Discussion

**Conclusion and Perspectives **

Appendix A Supplementary data to Chapter 4

**Bibliography**