Abstract
The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM+ population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.
Highlights
The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs)
We first sorted by negative selection of red blood cells (CD235a) and immune cells (CD45), and positively selected for EpCAM and NCAM to enrich for potential human liver progenitors[10,21] (Supplementary Fig. 1)
We identified the transcriptional signature of a foetal human liver hepatobiliary hybrid progenitor (HHyP) population, validated its presence in primary human liver samples, and showed its bi-lineage differentiation potential in vivo
Summary
The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Our study suggests that hepatobiliary progenitor cells previously identified in mice exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles. In rodents both hepatocytes and biliary epithelial cells (BECs) are derived from a common bi-potent hepatoblast population during liver development[1]. It has been proposed that EpCAM+ human liver stem/progenitor cells reside in the ductal plate (DP) during foetal liver development After birth these cells localise to the Canals of Hering, where upon severe chronic liver injury they become reactivated forming what is pathologically described as ductular reactions[10,11]. Our in depth profiling of previously undefined HHyPs provides an accurate template for the human liver progenitor phenotype that will be a valuable roadmap for translating ex vivo hepatic progenitor studies into successful cell-based liver disease therapies
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