期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：28
DOI：10.1073/pnas.2115867119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Liver disease causes ∼2 million annual deaths, yet medical treatments and transplantable organs are both lacking. The liver can regenerate when mature hepatocytes divide, and while this process is well studied in rodents, parallel study of human biology has been impossible. We developed a microfluidic device that allows us to manipulate fluid flow, circulating cytokines, and/or paracrine interactions between liver and vascular cells, in order to model multicellular aspects of human liver regeneration. We found that physiologically relevant shear stresses increased the secretion of angiogenesis- and regeneration-associated factors, including prostaglandin E
2 from endothelial cells, and induced primary human hepatocytes to enter the cell cycle. Next, we can dissect the resulting secretome data to identify factors that stimulate liver regeneration.
Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver regeneration, human biology is less well understood. To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. Collectively, the data presented here underscore the importance of multicellular models that can recapitulate high-level tissue functions and demonstrate that the SHEAR device can be used to discover and validate conditions that promote human liver regeneration.
