The network of interactions underlying liver regeneration is robust and precise with liver resections resulting in controlled hyperplasia (cell proliferation) that terminates when the liver regains its lost mass. The interplay of cytokines and growth factors responsible for the inception and termination of this hyperplasia is not well understood. We developed a model for this network of interactions based on the known data of liver resections. This model reproduces the relevant published data on liver regeneration and provides geometric insights into the experimental observations. We are collaborating with Dr. Doria, a transplant surgeon at Thomas Jefferson University, to see what changes are required in our model of rat liver regeneration to be able to predict the process in human.
The aim i s to ascertain which of the numerous parameters in our rat liver model needs to be changed to account for the human process, which appears to take roughly 20 times as long as that in rat. Evolution implies that phylogenetic relationships between species are predictive of function, albeit with modifications. Attempts to extrapolate animal model data without a mechanistic underpinning to human for translational medicine founder on the unknown modifications that relate the animal dynamic network of interactions to human. Mathematical modeling of such networks can winnow the range of possible modifications, and hence it holds the promise of allowing predictive extrapolation between species. There are, however, few extant examples. Liver regeneration after injury occurs in many mammals. Rat liver regenerates after partial hepatectomy over a period of two weeks while human liver regeneration takes several months. Notwithstanding this enormous difference in time-scales, with new data from five human live liver transplant donors, we show that a mathematical model of rat liver regeneration can be transferred to human, with all biochemical interactions and signaling unchanged. Only six phenomenological parameters need change, and three of these parameter changes are rescalings of rate constants by the ratio of human lifespan to rat lifespan. Data from three donor subjects with approximately equal resections were used to fit the three parameters and the data from the other two donor subjects was used to independently verify the fit.
| Periwal, V; Gaillard, J R; Needleman, L et al. (2014) Mathematical model of liver regeneration in human live donors. J Cell Physiol 229:599-606 |
