Biomechanics of hepatic cells and engineered construction of liver (INVITED)

Abstract eng:
Based on the unique sinusoidal structure of liver microcirculation and its essential biological function, we evaluated systematically the multi-scale biomechanics and mechanobiology of liver at molecular, cellular, or tissue level, which included the contribution of !2-integrinICAM-1 ligand interactions to the cell-cell adhesion, flow-induced crawling of mouse PMN on LSEC monolayer, the impact of substrate stiffness and microtopography on hepatic differentiation of embryonic stem cells (ESCs) , as well as the impact of a in-house built 3D in vitro sinusoidal model and engineered liver bioreactor in implementing hepatic functions. This work provides an insight for quantifying the intrinsic binding kinetics and the blood flow-induced crawling features of hepatic cells, and also proposes a novel 3D supporting system for liver function with well defined blood hemodynamics. Liver microcirculation is unique due to its complexity of sinusoidal structure, in which multiple types of hepatic and/or hemapoietic cells interact with each other under blood flow in a three-dimensional (3D) environment. Adhesion of flowing leukocytes to liver sinusoidal endothelial cells (LSECs) or Kupffer cells (KCs) is crucial in liver immune responses. While it is known that two !2-integrins LFA-1 and Mac1 play distinct roles in the most of organ-specific microcirculations, Mac-1 seems to be predominant in neutrophil (PMN) adhesion and crawling in localized inflammation while the role of LFA-1 is controversial in liver. We combined the probabilistic model of small system kinetics with the mechano-chemical coupling theory to quantify the cell-cell adhesion mediated by !2-integrin-ICAM-1 ligand interactions. Upon these models, we compared experimentally the binding kinetics of LFA-1 and Mac1 to ICAM-1s on mouse LSECs or KCs and found that the binding kinetics between these two integrin molecules is different when ICAM-1s were expressed on distinct cells, supporting that Mac-1 predominantly mediates the adhesion between leukocytes and LSECs and KCs. Next, we tested the flow-induced crawling of mouse PMNs on LSEC monolayer and indicated that PMNs tend to migrate along the direction of shear flow and yield high crawling velocity and moving displacement than those under static case, mainly mediated by LFA-1. We also quantified the impact of substrate stiffness and microtopography on hepatic differentiation of embryonic stem cells (ESCs) and demonstrated that substrate microtopography (grooved, pillar, or hexagonal configuration) works cooperatively with its stiffness to manipulate ESC stemness and hepatic differentiation. Finally, a 3D in vitro sinusoidal model and engineered liver bioreactor were in-house built, in which physiologically-mimicking microenvironment is critical for implementing hepatic functions. Multi-scale biomechanics and mechanobiology of liver at molecular, cellular, or tissue level were systematically evaluated, which provides an insight for quantifying the intrinsic binding kinetics and the blood flow-induced crawling features of hepatic cells. This work also proposes a novel 3D supporting system for liver function with well defined blood hemodynamics. This work was supported by National Natural Science Foundation of China grants 31230027 and 31110103918 and Strategic Priority Research Program of Chinese Academy of Sciences grant XDA01030102.

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