The liver is the most regenerative organ in adult mammals. Unlike any other organ, it is possible to cut out sections and the liver will regrow the lost tissue. The regrowth isn't perfect, unlike the case in highly regenerative species such as salamanders and zebrafish, but it does produce functional liver tissue. What makes the liver different? Despite a great deal of interest and activity in the research community, that question is nowhere near being comprehensively answered. Will practical regenerative therapies for the liver emerge before regenerative therapies for other organs? Maybe, maybe not. So far there is little sign that work on the liver is racing ahead of work on the rest of the portfolio of internal organs.
Today's open access paper is a recent output from just one line of investigation into liver regeneration, among the many lines that are presently ongoing. While the search for stem cell like populations in adult liver tissue is the focus here, with hybrid hepatocytes as the starting point, other research groups are looking into alternative splicing and the Hippo pathway that influences regeneration in a number of organs, or the subset of liver cells that express telomerase, behavior usually reserved for stem cells in the human body. It remains to be seen which lines of work will give rise to the next generation of regenerative medicine for the liver.
Scientists have identified a new type of cell called a hepatobiliary hybrid progenitor (HHyP), that forms during our early development in the womb. Surprisingly, HHyP also persists in small quantities in adults and these cells can grow into the two main cell types of the adult liver (Hepatocytes and Cholangiocytes) giving HHyPs stem cell-like properties. The team examined HHyPs and found that they resemble mouse stem cells which have been found to rapidly repair mice liver following major injury, such as occurs in cirrhosis.
"For the first time, we have found that cells with true stem cell-like properties may well exist in the human liver. This, in turn, could provide a wide range of regenerative medicine applications for treating liver disease, including the possibility of bypassing the need for liver transplants. We now need to work quickly to unlock the recipe for converting pluripotent stem cells into HHyPs so that we could transplant those cells into patients at will. In the longer term, we will also be working to see if we can reprogramme HHyPs within the body using traditional pharmacological drugs to repair diseased livers without either cell or organ transplantation."
In rodents both hepatocytes and biliary epithelial cells (BECs) are derived from a common bi-potent hepatoblast population during liver development. In adult mice, conflicting evidence exists regarding the presence of a distinct bi-potent progenitor capable of regenerating both hepatocytes and BECs. The regenerative potential of the rodent liver has been attributed to hepatocytes, BECs, biliary-like progenitor cells or 'oval cells' arising in the ductal region, stem cells located around the central vein and hepatocyte or cholangiocyte de-differentiation into a hybrid bi-potent progenitor.
In comparison, the mechanisms of human liver regeneration are poorly characterised, and the existence of a bi-potent human liver 'progenitor' cell remains unclear. This issue is in part due to a substantial overlap in markers between potential progenitor populations, hepatic precursors and mature BECs, challenging the field to define the true transcriptional nature of a bi-potent progenitor phenotype that can be replicated for clinical use. Several recent studies have captured a bi-potent progenitor-like state via small molecule-reprogramming of primary hepatocytes, capable of in vitro hepatic and biliary maturation, imitating a process that has been observed during chronic mouse liver injury. Despite several well-established phenotypic criteria for liver progenitor cells, no benchmark exits that truly distinguishes them from other human hepatic and biliary cells. To facilitate the in vitro development of cell-based therapies for treating liver disease, it is critical to precisely define a liver progenitor cell that accurately captures the developmental origin of human liver parenchyma.
In this study we utilise single-cell RNA sequencing (scRNA-seq) to interrogate the transcriptome of human foetal and adult liver at single-cell resolution. In recent years scRNA-seq has helped identify unreported cell types within populations previously defined as homogenous. Here, we report the transcriptional signature of distinct hepatic cell types in foetal and adult human liver, including a foetal hepatobiliary hybrid progenitor (HHyP) population. We identify a gene expression profile that can distinguish between foetal HHyPs, foetal hepatocytes, and mature BECs. We further identify HHyP-like cells maintained in uninjured adult primary liver tissue. Finally, we sorted HHyPs from freshly isolated human foetal liver and show evidence of hepatic and biliary phenotypes in vivo. Our in depth profiling of previously undefined HHyPs finally 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.