Abstract
Liver injury modulates local microenvironment, triggering production of signals that instruct stem cell fate choices. In this study, we employed a microfluidic co-culture system to recreate important interactions in the liver stem cell niche, those between adult hepatocytes and liver progenitor cells (LPCs). We demonstrate that pluripotent stem cell-derived LPCs choose hepatic fate when cultured next to healthy hepatocytes but begin biliary differentiation program when co-cultured with injured hepatocytes. We connect this fate selection to skewing in production of hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β1 caused by injury. Significantly, biliary fate selection of LPCs was not observed in the absence of hepatocytes nor did it happen in the presence of TGF-β inhibitors. Our study demonstrates that microfluidic culture systems may offer an interesting new tool for dissecting cellular interactions leading to aberrant stem cell differentiation during injury.
Highlights
Several groups, including ours, have demonstrated that microfluidic devices hold significant promise for cell cultivation and analysis[17,18,19,20,21]
A putative liver stem cell niche is located in the Canals of Hering, the junctional structure connecting bile canaliculi formed by hepatocytes with bile ducts lined by cholangiocytes[7,8]
We demonstrated that differentiation of progenitor cells inside microfluidic chambers is driven, at least in part, by the paracrine signals originating from neighboring hepatocytes and that composition of the milieu of signals is modulated by ethanol exposure
Summary
Several groups, including ours, have demonstrated that microfluidic devices hold significant promise for cell cultivation and analysis[17,18,19,20,21]. Our group has demonstrated that hepatocytes engage in both autocrine and paracrine signaling inside multi-chamber microfluidic devices[19] This past study revealed that hepatocytes produced sufficient amounts of HGF to affect phenotype of recipient cells located in a neighboring chamber several hundreds of micrometers away. In another recent study we employed multi-chamber microfluidic co-cultures of hepatocytes and stellate cells to study heterotypic interactions vis-a-vis TGF-β1 during alcohol injury[21]. This study revealed that alcohol injury triggered hepatic production of TGF-β1 which in turn caused stellate cells to become activated and begin producing TGF-β1 of their own These past studies led us to hypothesize that injured hepatocytes may be a significant source of paracrine signals contributing to stem cell fate choices in the liver stem cell niche. LPC differentiation in these microfluidic chambers was investigated as a function of alcohol injury
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