Objective: CELLular decision-making is a key process in which CELLs with similar genetic and environmental background make dissimilar decisions. This stochastic process, which happens in prokaryotic and eukaryotic CELLs including stem CELLs, causes CELLular diversity and phenotypic variation. In addition, fitness predicts and describes changes in the genetic composition of populations throughout the evolutionary history. Fitness may thus be defined as the ability to adapt and produce surviving offspring. Here, we present a mathematical model to predict the fitness of a CELL and to address the fundamental issue of phenotypic variation. We study a basic decision-making scenario where a bacteriophage lambda reproduces in E. coli, using both the lytic and the lysogenic pathways. In the lytic pathway, the bacteriophage replicates itself within the host bacterium. This fast replication overcrowds and in turn destroys the host bacterium. In the lysogenic pathway, however, the bacteriophage inserts its DNA into the host genome, and is replicated simultaneously with the host genome.Materials and Methods: In this prospective study, a mathematical predictive model was developed to estimate fitness as an index of survived offspring. We then leverage experimental data to validate the predictive power of our proposed model. A mathematical model based on game theory was also generated to elucidate a rationale behind CELL decision.Results: Our findings indicate that a rational decision that is aimed to maximize life expectancy of offspring is almost identical to bacteriophage behavior reported based on experimental data. The results also showed that stochastic decision on CELL FATE maximizes the expected number of survived offspring.Conclusion: We present a mathematical framework for analyzing a basic phenotypic variation problem and explain how bacteriophages maximize offspring longevity based on this model. We also introduce a mathematical benchmark for other investigations of phenotypic variation that exists in eukaryotes including stem CELL differentiation.

Proper tissue maintenance and regeneration relies on intricate spatial and temporal control of biochemical and biophysical microenvironmental cues, instructing stem CELLs to acquire particular FATEs, for example remaining quiescent or undergoing self-renewal divisions. Despite rapid progress in the identification of relevant niche proteins and signaling pathways using powerful in vivo models, to date, many adult stem CELL populations cannot be efficiently cultured in vitro without rapidly differentiating. To address this challenge, we and others have been developing biomaterial-based approaches to display and deliver stem CELL regulatory signals in a precise and near-physiological fashion, serving as powerful artificial microenvironments to study and manipulate stem CELL FATE both in culture and in vivo. In this talk I will highlight recent efforts in my laboratory to develop microarrayed artificial niches based on a combination of biomolecular hydrogel and microfabrication/robotic technologies. These platforms allow key biochemical characteristics of stem CELL niches to be mimicked and the physiological complexity deconstructed into a smaller, experimentally amenable number of distinct signaling interactions. The systematic deconstruction of a stem CELL niche may serve as a broadly applicable paradigm for defining and reconstructing artificial niches to accelerate the transition of stem CELL biology to the clinic.

Recent advances in stem CELL biology may make possible new approaches for the treatment of a number of diseases. A better understanding of molecular mechanisms that control stem CELL FATE as well as an improved ability to manipulate them are required. Toward these goals, we have developed and implemented high throughput CELL-based phenotypic screens of arrayed chemical and gene libraries to identify and further characterize small molecules and genes that can control stem CELL FATE in various systems. This talk will provide latest examples of discovery efforts in my lab that have advanced our ability and understanding toward controlling stem CELL FATE, including self-renewal, survival, differentiation and reprogramming of pluripotent stem CELLs.