About
74
Publications
7,716
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
2,074
Citations
Introduction
Education
April 2010 - December 2014
October 2007 - July 2016
October 2003 - April 2010
Publications
Publications (74)
Voltage-gated sodium channels (VGSCs) in the peripheral nervous system shape action potentials (APs) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold chann...
Human dermal sleeping nociceptors display ongoing activity in neuropathic pain, affecting 10% of the population. Despite advances in rodents, a molecular marker for these mechano-insensitive C-fibers (CMis) in human skin remains elusive, preventing targeted therapy. In this translational Patch-seq study, we combine single-cell transcriptomics follo...
Introduction
Hematopoietic stem cell transplantation is a potentially curative intervention for a broad range of diseases. However, there is evidence that malignant or pre-malignant clones contained in the transplant can expand in the recipient and trigger donor-derived malignancies. This observation has gained much attention in the context of clon...
Background: The goal of the emerging ‘early diagnosis and treatment intervention‘ paradigm is to prevent complications and ultimately mortality associated with the current late-stage treatment of myeloproliferative neoplasms (MPNs). Screening of the background population indicates that MPNs are massively under-diagnosed and likely never discovered...
Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The “7+3 regimen”, which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol....
Non-cell autonomous induction of stem cell fate is a shared feature across multicellular organisms, however the underlying mechanisms diverge substantially between the kingdoms of live. In plants, cell to cell mobility of transcription factors has emerged as a key paradigm. For the shoot apical meristem of the reference plant Arabidopsis thaliana i...
Background
Epigenetic aging signatures can provide insights into the human aging process. Within the last decade many alternative epigenetic clocks have been described, which are typically based on linear regression analysis of DNA methylation at multiple CG dinucleotides (CpGs). However, this approach assumes that the epigenetic modifications foll...
Introduction
The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypoth...
The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study,...
Blood cell formation (hematopoiesis) is a complex and tightly regulated process. It is maintained by hematopoietic (blood-forming) stem cells and serves as a paradigmatic example for tissue maintenance, regeneration, and cancer. Quantitative modeling can provide relevant insights into the dynamics of hematopoiesis in health and disease. This chapte...
Voltage-gated sodium channels (VGSC) are responsible for the fast upstroke of an action potential (AP). In the peripheral nervous system, e.g., in sensory neurons responsible for detection of potentially painful stimuli, subthreshold depolarizations support the initiation of an AP. Nav1.7 was suggested to be a subthreshold channel, and recent studi...
Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play...
Hematopoiesis has been studied via stem cell labeling using barcodes, viral integration sites (VISs), or in situ methods. Subsequent proliferation and differentiation preserve the tag identity, thus defining a clone of mature cells across multiple cell type or lineages. By tracking the population of clones, measured within samples taken at discrete...
The hematopoietic stem cell (HSC) niche is a crucial driver of regeneration and malignancy. Its interaction with hematopoietic and malignant stem cells is highly complex and direct experimental observations are challenging. We here develop a mathematical model which helps relate processes in the niche to measurable changes of stem and non-stem cell...
This chapter is devoted to the question of whether mathematical intelligence exists and what it might be. Using simple textbook examples and applications from current research, we point out similarities and differences between mathematical intelligence and its human counterpart. We focus on so-called mechanistic mathematical modeling. Mechanistic m...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
SAM size quantification (panel C);
SAM cell number quantification (panel D); Quantification silique number (panel G); Mean plastochron quantification (panel H).
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).
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).
Intensity plot profiles pTCSn:erGFP (panel C);
TCS quantification plot profile (panel F); Source data also included for panels G and H.
Quantification auxin maxima SAM (panel C).
Quantification primordia number (panel C).
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...
Source data provided for panel E and intensity plot profiles pTCSn:erGFP under different light regimes (panel J).
Cell surface area MorphographX (Figure 10—figure supplement 1E);
Cell surface area: MorphoGraphX individual plants (Figure 10—figure supplement 1F).
Description of computational model
Quantification auxin maxima pDR5v2:3xYFP-NLS (panel E).
Calculation ARE_G-box enrichments (Figure 7—figure supplement 1G–I).
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).
ChIPseq, RNAseq and QRT-PCR analyses
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...
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,...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...