RESUMO
Studying the progression of the proliferative and differentiative patterns of neural stem cells at the individual cell level is crucial to the understanding of cortex development and how the disruption of such patterns can lead to malformations and neurodevelopmental diseases. However, our understanding of the precise lineage progression programme at single-cell resolution is still incomplete due to the technical variations in lineage-tracing approaches. One of the key challenges involves developing a robust theoretical framework in which we can integrate experimental observations and introduce correction factors to obtain a reliable and representative description of the temporal modulation of proliferation and differentiation. In order to obtain more conclusive insights, we carry out virtual clonal analysis using mathematical modelling and compare our results against experimental data. Using a dataset obtained with Mosaic Analysis with Double Markers, we illustrate how the theoretical description can be exploited to interpret and reconcile the disparity between virtual and experimental results.
Assuntos
Linhagem da Célula , Córtex Cerebral/embriologia , Células Clonais , Modelos Biológicos , Neurogênese , Animais , CamundongosRESUMO
The successful development of the mammalian cerebral neocortex is linked to numerous cognitive functions such as language, voluntary movement, and episodic memory. Neocortex development occurs when neural progenitor cells divide and produce neurons. Critically, although the progenitor cells are able to self-renew they do not reproduce themselves endlessly. Hence, to fully understand the development of the neocortex we are faced with the challenge of understanding temporal changes in cell division strategy. Our approach to modelling neuronal production uses non-autonomous ordinary differential equations and allows us to use a ternary coordinate system in order to define a strategy space, through which we can visualise evolving cell division strategies. Using this strategy space, we fit the known data and use approximate Bayesian computation to predict the founding progenitor population sizes, currently unavailable in the experimental literature. Counter-intuitively, we show that humans can generate a larger number of neurons than a macaque's even when starting with a smaller number of progenitor cells. Accompanying the article is a self-contained piece of software, which provides the reader with immediate simulated results that will aid their intuition. The software can be found at www.dpag.ox.ac.uk/team/noemi-picco.
Assuntos
Divisão Celular/fisiologia , Simulação por Computador , Modelos Neurológicos , Neocórtex/embriologia , Software , Animais , Macaca , Mamíferos , Neocórtex/citologiaRESUMO
The mammalian cerebral neocortex has a unique structure, composed of layers of different neuron types, interconnected in a stereotyped fashion. While the overall developmental program seems to be conserved, there are divergent developmental factors generating cortical diversity amongst species. In terms of cortical neuronal numbers, some of the determining factors are the size of the founder population, the duration of cortical neurogenesis, the proportion of different progenitor types, and the fine-tuned balance between self-renewing and differentiative divisions. We develop a mathematical model of neurogenesis that, accounting for these factors, aims at explaining the high diversity in neuronal numbers found across species. By framing our hypotheses in rigorous mathematical terms, we are able to identify paths of neurogenesis that match experimentally observed patterns in mouse, macaque and human. Additionally, we use our model to identify key parameters that would particularly benefit from accurate experimental investigation. We find that the timing of a switch in favor of symmetric neurogenic divisions produces the highest variation in cortical neuronal numbers. Surprisingly, assuming similar cell cycle lengths in primate progenitors, the increase in cortical neuronal numbers does not reflect a larger size of founder population, a prediction that has identified a specific need for experimental quantifications.
Assuntos
Córtex Cerebral/citologia , Modelos Neurológicos , Modelos Teóricos , Neurogênese/fisiologia , Neurônios/fisiologia , Fatores Etários , Animais , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células , Córtex Cerebral/embriologia , Humanos , Macaca , Camundongos , Especificidade da EspécieRESUMO
Introduction: Sepsis is a disease that occurs due to an adverse immune response to infection by bacteria, viruses and fungi and is the leading pathway to death by infection. The hallmarks for maladapted immune reactions in severe sepsis, which contribute to multiple organ failure and death, are bookended by the exacerbated activation of the complement system to protracted T-cell dysfunction states orchestrated by immune checkpoint control. Despite major advances in our understanding of the condition, there remains to be either a definitive test or an effective therapeutic intervention.Areas covered: The authors consider a combinational drug therapy approach using new biologics, and mathematical modeling for predicting patient responses, in targeting innate and adaptive immune mediators underlying sepsis. Special consideration is given for emerging complement and immune checkpoint inhibitors that may be repurposed for sepsis treatment.Expert opinion: In order to overcome the challenges inherent to finding new therapies for the complex dysregulated host response to infection that drives sepsis, it is necessary to move away from monotherapy and promote precision for personalized combinatory therapies. Notably, combinatory therapy should be guided by predictive systems models of the immune-metabolic characteristics of an individual's disease progression.
Assuntos
Ativação do Complemento/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/administração & dosagem , Sepse/tratamento farmacológico , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacologia , Reposicionamento de Medicamentos , Quimioterapia Combinada , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Modelos Teóricos , Medicina de Precisão , Sepse/imunologiaRESUMO
OBJECTIVE: Cancer stem cells (CSCs) have been hypothesized to initiate and drive tumor growth and recurrence due to their self-renewal ability. If correct, this hypothesis implies that successful therapy must focus primarily on eradication of this CSC fraction. However, recent evidence suggests stemness is niche dependent and may represent one of many phenotypic states that can be accessed by many cancer genotypes when presented with specific environmental cues. A better understanding of the relationship of stemness to niche-related phenotypic plasticity could lead to alternative treatment strategies. METHODS: Here, we investigate the role of environmental context in the expression of stem-like cell properties through in-silico simulation of ductal carcinoma. We develop a two-dimensional hybrid discrete-continuum cellular automata model to describe the single-cell scale dynamics of multicellular tissue formation. Through a suite of simulations, we investigate interactions between a phenotypically heterogeneous cancer cell population and a dynamic environment. RESULTS: We generate homeostatic ductal structures that consist of a mixture of stem and differentiated cells governed by both intracellular and environmental dynamics. We demonstrate that a wide spectrum of tumor-like histologies can result from these structures by varying microenvironmental parameters. CONCLUSION: Niche driven phenotypic plasticity offers a simple first-principle explanation for the diverse ductal structures observed in histological sections from breast cancer. SIGNIFICANCE: Conventional models of carcinogenesis largely focus on mutational events. We demonstrate that variations in the environmental niche can produce intraductal cancers independent of genetic changes in the resident cells. Therapies targeting the microenvironmental niche may offer an alternative cancer prevention strategy.
Assuntos
Plasticidade Celular , Modelos Biológicos , Neoplasias/patologia , Neoplasias/fisiopatologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Animais , Diferenciação Celular , Proliferação de Células , Simulação por Computador , Humanos , Microambiente TumoralRESUMO
Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialog between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor-stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates. Cancer Res; 77(19); 5409-18. ©2017 AACR.