Spurring Complete Liver Regrowth in Mice
Researchers have found a way to induce complete regrowth of the liver in mice, which intriguing involves inducing far greater cellular senescence than is normally the case. The liver is normally the most regenerative of organs in mammals, capable of regrowing sections of tissue following injury, but this result is somewhat more impressive than that.
Cellular senescence is known to be involved in and promote wound healing, and researchers have shown in past years that senescence in liver cells is both flexible and amenable to manipulation. However clearance of senescent cells is of general interest in the prospective treatment of aging: senescent cells accumulate in all tissues with age and contribute to damage and loss of function through a variety of mechanisms. A more sophisticated control of cellular senescence in tissues may well lead to a range of therapies that alternately encourage it and suppress it at various times and under various circumstances.
Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution.HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.