RESUMO
Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.
Assuntos
Ciclo Celular , Proliferação de Células , Animais , Humanos , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células Tumorais CultivadasRESUMO
While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.
Assuntos
Pontos de Checagem do Ciclo Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença/genética , Humanos , Modelos Teóricos , Neuroblastoma/genética , Cultura Primária de Células , Transcriptoma/genéticaRESUMO
Maintenance of stem cell properties is associated with reduced proliferation. However, in mouse hematopoietic stem cells (HSCs), loss of quiescence results in a wide range of phenotypes, ranging from functional failure to extensive self-renewal. It remains unknown whether the function of human HSCs is controlled by the kinetics of cell cycle progression. Using human HSCs and human progenitor cells (HSPCs), we report here that elevated levels of CCND1-CDK4 complexes promoted the transit from G0 to G1 and shortened the G1 cell cycle phase, resulting in protection from differentiation-inducing signals in vitro and increasing human leukocyte engraftment in vivo. Further, CCND1-CDK4 overexpression conferred a competitive advantage without impacting HSPC numbers. In contrast, accelerated cell cycle progression mediated by elevated levels of CCNE1-CDK2 led to the loss of functional HSPCs in vivo. Collectively, these data suggest that the transition kinetics through the early cell cycle phases are key regulators of human HSPC function and important for lifelong hematopoiesis.
Assuntos
Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Modelos Biológicos , Animais , Western Blotting , Proliferação de Células , Primers do DNA/genética , Citometria de Fluxo , Técnicas de Transferência de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da PolimeraseRESUMO
A major challenge in biology is to understand how buds comprising a few cells can give rise to complex plant and animal appendages like leaves or limbs. We address this problem through a combination of time-lapse imaging, clonal analysis, and computational modeling. We arrive at a model that shows how leaf shape can arise through feedback between early patterns of oriented growth and tissue deformation. Experimental tests through partial leaf ablation support this model and allow reevaluation of previous experimental studies. Our model allows a range of observed leaf shapes to be generated and predicts observed clone patterns in different species. Thus, our experimentally validated model may underlie the development and evolution of diverse organ shapes.