Thomas Stiehl

Thomas Stiehl
Universität Heidelberg ·  Interdisciplinary Center for Scientific Computing

About

56
Publications
4,340
Reads
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1,382
Citations
Education
April 2010 - December 2014
Universität Heidelberg
Field of study
  • Mathematics
October 2007 - July 2016
Universität Heidelberg
Field of study
  • Medicine
October 2003 - April 2010
Universität Heidelberg
Field of study
  • Mathematics

Publications

Publications (56)
Preprint
Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to t...
Article
Full-text available
Acute myeloid leukemia is an aggressive cancer of the blood forming system. The malignant cell population is composed of multiple clones that evolve over time. Clonal data reflect the mechanisms governing treatment response and relapse. Single cell sequencing provides most direct insights into the clonal composition of the leukemic cells, however i...
Article
Full-text available
The adult mammalian brain entails a reservoir of neural stem cells (NSCs) generating glial cells and neurons¹. However, NSCs become increasingly quiescent with age, which hampers their regenerative capacity². New means are therefore required to genetically modify adult NSCs for re-enabling endogenous brain repair. Recombinant adeno-associated virus...
Preprint
The adult mammalian brain entails a reservoir of neural stem cells (NSCs) generating glial cells and neurons. However, NSCs become increasingly quiescent with age, which hampers their regenerative capacity. New means are therefore required to genetically modify adult NSCs for re-enabling endogenous brain repair. Recombinant adeno-associated viruses...
Article
Haematopoiesis is the process of generation of blood cells. Lymphopoiesis generates lymphocytes, the cells in charge of the adaptive immune response. Disruptions of this process are associated with diseases like leukaemia, which is especially incident in children. The characteristics of self-regulation of this process make them suitable for a mathe...
Article
Full-text available
Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilize during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this stabilization of stem cell numbers in young adults is the result of coordinated changes in stem cell behavior. Although proliferating neural stem cells in juveniles differentiate rap...
Preprint
Acute myeloid leukemia is an aggressive cancer of the blood forming system. The malignant cell population is composed of multiple clones that evolve over time. Clonal data reflect the mechanisms governing treatment response and relapse. Single cell sequencing provides most direct insights into the clonal composition of the leukemic cells, however i...
Article
Full-text available
Coordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to elucidate the impact of hormonal...
Article
h3> Acute myeloid leukemia (AML) is a stem cell–driven malignant disease. There is evidence that leukemic stem cells (LSC) interact with stem cell niches and outcompete hematopoietic stem cells (HSC). The impact of this interaction on the clinical course of the disease remains poorly understood. We developed and validated a mathematical model of s...
Preprint
Full-text available
Haematopoiesis is the process of generation of blood cells. Lymphopoiesis generates lymphocytes, the cells in charge of the adaptive immune response. Disruptions of this process are associated with diseases like leukaemia, which is especially incident in children. The characteristics of self-regulation of this process make them suitable for a mathe...
Preprint
Full-text available
Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilise during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this reduction in stem cell depletion rate is the result of multiple coordinated changes in stem cell behaviour. In particular, while active neural stem cells divide only once or twice be...
Article
Full-text available
In this work we prove occurrence of a super-critical Hopf bifurcation in a model of white blood cell formation structured by three maturation stages. We provide an explicit analytical expression for the bifurcation point depending on model parameters. The Hopf bifurcation is a unique feature of the multi-compartment structure as it does not exist i...
Article
We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structu...
Preprint
Full-text available
p, li { white-space: pre-wrap; } Coordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to...
Article
Full-text available
Recent progress in genetic techniques has shed light on the complex co-evolution of malignant cell clones in leukemias. However, several aspects of clonal selection still remain unclear. In this paper, we present a multi-compartmental continuously structured population model of selection dynamics in acute leukemias, which consists of a system of co...
Preprint
Recent progress in genetic techniques has shed light on the complex co-evolution of malignant cell clones in leukemias. However, several aspects of clonal selection still remain unclear. In this paper, we present a multi-compartmental continuously structured population model of selection dynamics in acute leukemias, which consists of a system of co...
Article
Full-text available
Purpose of Review Adult stem cells play a key role in tissue regeneration and cancer. To translate findings from stem cell biology into clinics, we require a quantitative characterization of stem cell dynamics in vivo. This review explores how mathematical models can help to characterize stem cell behavior in health and disease. Recent Findings Ma...
Article
The function of somatic stem cells declines with age. Understanding the molecular underpinnings of this decline is key to counteract age-related disease. Here, we report a dramatic drop in the neural stem cells (NSCs) number in the aging murine brain. We find that this smaller stem cell reservoir is protected from full depletion by an increase in q...
Preprint
In this work we prove occurrence of a super-critical Hopf bifurcation in a model of white blood cell formation structured by three maturation stages. We provide an explicit analytical expression for the bifurcation point depending on model parameters. The Hopf bifurcation is a unique feature of the multi-compartment structure as it does not exist i...
Article
We consider a 2 time scale nonlinear system of ordinary differential equations. The small parameter of the system is the ratio ϵ of the time scales. We search for an approximation involving only the slow time unknowns and valid uniformly for all times at order O(ϵ2). A classical approach to study these problems is Tikhonov's singular perturbation t...
Article
Full-text available
Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine-independent leukemic cell prolifer...
Preprint
Acute myeloid leukemia (AML) is a heterogeneous disease. One reason for the heterogeneity may originate from inter-individual differences in the responses of leukemic cells to endogenous cytokines. On the basis of mathematical modeling, computer simulations and patient data, we have provided evidence that cytokine-independent leukemic cell prolifer...
Data
SAM size quantification (panel C); SAM cell number quantification (panel D); Quantification silique number (panel G); Mean plastochron quantification (panel H).
Data
Intensity plot profiles: pWUS:3xYFP-NLS (panel C). Intensity plot profiles: pCLV3:mCherry-NLS (panel D); CLV3 cell number quantification (panel G); Ratio CLV3/SAM cells: pCLV3:HEC1-linker-GR (Figure 2H); Mitotic index CZ quantification (panel K); Mitotic index PZ quantification (panel L).
Data
SAM size measurement pCLV3:HEC1-linker-GR (Figure 2—figure supplement 2A); SAM cell number quantification (Figure 2—figure supplement 6B); Mitotic index quantification (Figure 2—figure supplement 6C).
Data
Intensity plot profiles pTCSn:erGFP (panel C); TCS quantification plot profile (panel F); Source data also included for panels G and H.
Data
Quantification number of auxin maxima (Figure 6—figure supplement 2C); Root Expression data Li et al., 2016 (Figure 6—figure supplement 3A); RAM size measurement p16:HEC1-linker-GR (Figure 6—figure supplement 3G); Quantification cortex cell number p16:HEC1-linker-GR (Figure 6—figure supplement 3H); Cortex cell lenght measurement p16:HEC1-linker-GR...
Data
Source data provided for panel E and intensity plot profiles pTCSn:erGFP under different light regimes (panel J).
Data
Cell surface area MorphographX (Figure 10—figure supplement 1E); Cell surface area: MorphoGraphX individual plants (Figure 10—figure supplement 1F).
Data
Quantification auxin maxima pDR5v2:3xYFP-NLS (panel E).
Data
Calculation ARE_G-box enrichments (Figure 7—figure supplement 1G–I).
Data
qRT-PCR (panel 9A and B); Quantification primordia number for pCUC2:HEC1-linker-GR (panel I); Quantification primordia number for p16:HEC1-linker-GR (panel J).
Article
Self-renewal is the process by which stem cells give rise to stem cells. Recent insights from experimental and theoretical models suggest that self-renewal not only influences the stem cell population but has a crucial impact on dynamics of non-stem cells. Efficient production of mature cells in tissue regeneration requires up-regulation of stem ce...
Article
Full-text available
ELife digest Unlike animals, plants continuously generate new organs that make up their body. At the core of this amazing capacity lie tissues called meristems, which are found at the growing tips of all plants. Meristems contain dividing stem cells. The daughters of these stem cells pass through nearby regions called transition domains. Over time,...
Article
Full-text available
In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Ser...
Article
Full-text available
Background Leukemias are malignant proliferative disorders of the blood forming system. Sequencing studies demonstrate that the leukemic cell population consists of multiple clones. The genetic relationship between the different clones, referred to as the clonal hierarchy, shows high interindividual variability. So far, the source of this heterogen...
Article
Full-text available
Acute myeloid leukemia is a heterogeneous disease in which a variety of distinct genetic alterations occur. Recent studies to identify the leukemia stem-like cells (LSCs) have also indicated heterogeneity of these cells. Based on mathematical modeling and computer simulations we have provided evidence that proliferation and self-renewal rates of th...
Article
Hematopoiesis is a complex and strongly regulated process. In case of regenerative pressure, efficient recovery of blood cell counts is crucial for survival of an individual. We propose a quantitative mathematical model of white blood cell formation based on the following cell parameters: (1) proliferation rate, (2) self-renewal, and (3) cell death...
Article
Full-text available
Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Ba...
Article
Full-text available
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 r...
Article
This thesis is devoted to mathematical modeling of acute leukemias, which form a heterogeneous group of severe blood cancers. New models of dynamic behavior of blood forming (hematopoietic) and leukemic cells are developed and studied analytically. Bone marrow aspiration data contributed from the University Hospital of Heidelberg (Prof. Dr. A. D. H...
Article
Full-text available
It is known that the number of transplanted cells has a significant impact on the outcome after SCT. We identify issues that cannot be addressed by conventional analysis of clinical trials and ask whether it is possible to develop a refined analysis to conclude about the outcome of individual patients given clinical trial results. To accomplish thi...
Article
Transplantation of bone marrow stem cells is a widely used option to treat leukemias and other diseases. Nevertheless this intervention is linked to life-threatening complications. Numerous clinical trials have been performed to evaluate various treatment options. Since there exist strong interindividual variations in patients’ responses, results o...
Article
The development of ovarian follicles is a unique instance of a morphogenesis process still occurring during adult life and resulting from the interactions between somatic and germ cells. In mammals, the initiation of follicular development from the pool of resting follicles is characterized by an increase in the oocyte size concomitant with the sur...
Article
The cancer stem cell hypothesis has evolved to one of the most important paradigms in biomedical research. During recent years evidence has been accumulating for the existence of stem cell-like populations in different cancers, especially in leukemias. In the current work we propose a mathematical model of cancer stem cell dynamics in leukemias. We...
Article
Mesenchymal stromal cells (MSC) are heterogeneous and only a subset possesses multipotent differentiation potential. It has been proven that long-term culture has functional implications for MSC. However, little is known how the composition of subpopulation changes during culture expansion. We addressed the heterogeneity of MSC using limiting-dilut...
Article
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...
Article
Full-text available
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...
Article
Full-text available
Hematopoietic stem cells (HSC) give rise to an enormous number of blood cells throughout our life. In contrast their number of cell divisions preceding senescence is limited underin vitro culture conditions. Here we consider the question whether HSC can rejuvenate indefinitely or if the number of cell divisions is restricted. We have developed a mu...
Article
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...

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