Holger Willenbring, MD, PhD

Unlike other vertebrates, adult mammals have limited organ regeneration capabilities. A notable exception is the liver. Hepatocytes, the cells of the liver that provide its characteristic functions, are normally mitotically inactive, but, in contrast to other differentiated cells such as cardiomyocytes or neurons, have retained the ability to divide upon tissue loss or damage. A hepatocyte can divide more than 100 times and this ability is maintained in its progeny so that a single cell could theoretically be used to regenerate an entire liver. We are investigating the molecular mechanisms underlying hepatocyte regeneration with the goal of unlocking the regenerative capabilities of other differentiated cell types. 

In chronic liver diseases the stem cell-like proliferative capabilities of hepatocytes are exhausted or suppressed to prevent malignant transformation of damaged cells. Hepatocyte cell-cycle arrest stimulates the emergence and expansion of liver progenitor cells, which can give rise to hepatocytes and cholangiocytes, the cells that line the bile ducts. Liver progenitor cells are thought to derive from liver stem cells residing in bile ducts. However, whether liver stem cells are bona fide stem cells set aside during development, or dedifferentiated cholangiocytes, remains to be determined. We are using lineage tracing to identify and isolate the adult liver stem cell with the goal of understanding how proliferation and differentiation of this cell are regulated. These analyses inform our efforts to generate therapeutically effective surrogate hepatocytes either by directed differentiation of embryonic stem cells or induced pluripotent stem cells, or by direct reprogramming of somatic cells. 

The staggered regenerative processes in the adult liver have obscured the identity of the cell of origin of liver cancer. The previously prevailing paradigm was that liver cancers originate from damaged hepatocytes undergoing dedifferentiation. However, recent evidence suggests a liver progenitor cell origin of some liver cancers. Progenitor cell characteristics could explain why liver cancer is refractory to currently available therapies. We are using our ability to follow the fate of liver progenitor cells or differentiated hepatocytes to identify and isolate the cell that gives rise to liver cancer. Our goal is to determine the molecular mechanisms involved in liver cancer initiation and recurrence, which we hope will enable new strategies for early detection and effective eradication.