MetDFBA: incorporating time-resolved metabolomics measurements into dynamic flux balance analysis.

Understanding cellular adaptation to environmental changes is one of the major challenges in systems biology. To understand how cellular systems react towards perturbations of their steady state, the metabolic dynamics have to be described. Dynamic properties can be studied with kinetic models but development of such models is hampered by limited in vivo information, especially kinetic parameters. Therefore, there is a need for mathematical frameworks that use a minimal amount of kinetic information. One of these frameworks is dynamic flux balance analysis (DFBA), a method based on the assumption that cellular metabolism has evolved towards optimal changes to perturbations. However, DFBA has some limitations. It is less suitable for larger systems because of the high number of parameters to estimate and the computational complexity. In this paper, we propose MetDFBA, a modification of DFBA, that incorporates measured time series of both intracellular and extracellular metabolite concentrations, in order to reduce both the number of parameters to estimate and the computational complexity. MetDFBA can be used to estimate dynamic flux profiles and, in addition, test hypotheses about metabolic regulation. In a first case study, we demonstrate the validity of our method by comparing our results to flux estimations based on dynami

ETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis

BACKGROUND: The plasticity of pancreatic acinar cells to undergo acinar to ductal metaplasia (ADM) has been demonstrated to contribute to the regeneration of the pancreas in response to injury. Sox9 is critical for ductal cell fate and important in the formation of ADM, most likely in concert with a complex hierarchy of, as yet, not fully elucidated transcription factors. RESULTS: By using a mouse model of acute pancreatitis and three dimensional organoid culture of primary pancreatic ductal cells, we herein characterize the Ets-transcription factor Etv5 as a pivotal regulator of ductal cell identity and ADM that acts upstream of Sox9 and is essential for Sox9 expression in ADM. Loss of Etv5 is associated with increased severity of acute pancreatitis and impaired ADM formation leading to delayed tissue regeneration and recovery in response to injury. CONCLUSIONS: Our data provide new insights in the regulation of ADM with implications in our understanding of pancreatic homeostasis, pancreatitis and epithelial plasticity