Reading the Signals
New study, published in Hepatology, shows the regenerative capacity of liver cells
Patients suffering from chronic liver disease often develop liver fibrosis (the accumulation of scar tissue), which frequently results in cirrhosis, which means a loss of liver function, which often comes with a choice between a liver transplant and certain death.
It’s a perfect storm of terrible things as sustained fibrosis dampens the regenerative capacity of hepatocytes, thwarting their ability to make a therapeutic response, resulting in a grim prognosis and high mortality. At its essence, this is a communication problem, based on a study by a team of researchers in the lab of Chong Hyun Shin at the Georgia Institute of Technology.
Their findings explain how signaling pathways and cell-cell communications direct the cellular response to fibrogenic stimuli. But they also identify some novel potential therapeutic strategies for chronic liver disease. Results of the study (funded by the National Institutes of Health, the Emory/Georgia Tech Regenerative Engineering and Medicine Center, and Georgia Tech’s School of Biology) were published recently in the journal Hepatology.
“We aim to understand the molecular and cellular mechanisms that mediate the effects of sustained fibrosis on hepatocyte regeneration, using the zebrafish as a model,” explains Shin, assistant professor in the School of Biology, with a lab in the Parker H. Petit Institute for Bioengineering and Bioscience. Her fellow authors are Frank Anania (Emory), Mianbo Huang, Angela Chang, Minna Choi and David Zhou.
In their fibrotic zebrafish model, they studied the effects that different levels of signaling have on the regeneration of liver cells (hepatocytes). Specifically, they took note of the relationship between ‘Wnt’ and ‘Notch’ (signaling pathways). They discovered that lower level Notch signaling promotes cell regeneration (the proliferation and differentiation of hepatic progenitor cells, or HPCs, into hepatocytes), while high levels suppressed it. And they discovered that antagonistic interaction between Wnt and Notch modulates regenerative capacity: Wnt signals can suppress Notch signals, or, in other words, when Wnt is up, Notch is down, and hepatocyte regeneration can happen.
The data, says Shin, “suggest an essential interplay between Wnt and Notch signaling during hepatocyte regeneration in the fibrotic liver, providing legitimate therapeutic strategies for chronic liver failure in vivo.”
Inducing tissue regeneration via stem or progenitor cells, while delaying fibrosis, has been on the rise as antifibrogenic strategies of great potential, according to Shin, whose studies offer a clue of how to guide the differentiation of HPCs into hepatocytes in patients suffering from chronic liver failure. “Overall,” she explains, “employing the in vivo-based hepatic regeneration strategy may allow us to complement fundamental drawbacks in stem cell therapy, opening up new avenues of endogenous cellular regeneration therapy.”
This research is supported by grant number K01DK081351 from the National Institutes of Health (NIH), the Regenerative Engineering and Medicine Research Center Pilot Award (GTEC 2731336), and the School of Biology, Georgia Institute of Technology.
Read Hepatology journal abstract here