Mathematical Model of Liver Regeneration in Human Live Donors

Abstract

Liver regeneration after injury occurs in many mammals. Rat liver regenerates after partial hepatectomy over a period of 2 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.

Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

“…We therefore tested several alternate hypotheses that may be able to explain the differences in regeneration profiles between rats and humans. We tested the hypotheses that humans have an altered stress response compared to rats (Hyp 1); that humans have altered matrix remodeling dynamics and ECM-GF binding compared to rats (Hyp 2); that human hepatocytes have an altered transition time between physiological states (Hyp 3); and that human hepatocytes have a longer cell cycle, a higher apoptosis rate, a higher requiescence rate, and an altered transition rate between physiological states, as was assumed by Periwal et al [ 29 ] (Hyp 4). The study by Periwal et al [ 29 ] reduced the values of parameters controlling the hepatocyte cell cycle rate, apoptosis rate, and requiescence rate by a factor of 24, roughly the difference in lifespan between rats and humans.…”

Microarray-based characterization of differential gene expression during vocal fold wound healing in rats

“…Furthermore, evidence suggests that both the local injury response and eventual repair outcome differ as a function of tissue type. For example, injured adult skin heals more slowly, and with more scar formation, than adult oral mucosa ( Schrementi et al, 2008 ; Szpaderska et al, 2003 ) and, under permissive conditions, the regeneration-privileged adult liver ( Periwal et al, 2014 ).…”

Modeling Dynamics and Function of Bone Marrow Cells in Mouse Liver Regeneration

“…Thus, we adapted the phenomenological parameters in the cellular equations, whereas the molecular equations and the related parameters were kept as intact as possible (Table S1). Notably, the same approach has been successfully used in adapting the rat model (Furchtgott et al., 2009) to reproduce data from humans (Periwal et al., 2014) because the biochemistry of liver regeneration is probably similar in different mammals.…”

“…Modeling has been used to describe liver functions and dynamics in mammals under normal and pathological conditions (Cook et al., 2015, Furchtgott et al., 2009, Holzhütter et al., 2012, Periwal et al., 2014). …”