Reconstruction of human tissue-specific genome-scale metabolic models for therapeutic applications

The objective of this study is the investigation of different human tissues including brain, liver and pancreas by using genome-scale metabolic models (GEMs) and their therapeutic applications. Brain cell-specific GEMs were reconstructed based on single-cell transcriptome data and the intercellular reactions between neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. These brain networks were used in the prediction of metabolic alterations in glucose, ketone bodies and oxygen change and reporter metabolites. Glucose supplementation increased the subsystems' activities in glycolysis and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in grey and white matter microglia in multiple sclerosis, respectively. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on liver metabolism was investigated using integrated GEMs of human hepatocytes and SARS-CoV-2. Computational approaches unraveled possible virus-induced hepatocellular reprogramming in fatty acid, glycerophospholipid, sphingolipid, cholesterol, and folate metabolisms, bile acid biosynthesis, and carnitine shuttle among others. Reaction knockout analysis provided critical reactions in glycolysis, oxidative phosphorylation, purine metabolism, and reactive oxygen species detoxification subsystems. The single-cell transcriptome data was used to generate context-specific GEMs for alpha, beta, delta and pancreatic polypeptide cells for non-diabetic and type 2 diabetes (T2D) states at single-cell resolution. The in silico analysis was performed for the investigation of metabolic activities in non-diabetic and T2D pancreatic cells. By altering glucose and oxygen uptakes to the metabolic networks, hypoglycemia, hyperglycemia and hypoxia led to changes in metabolic activities in various cellular subsystems. Taken together, single and integrated GEMs help us elucidate complex metabolism in various human tissues in health and disease.