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*Contributed equally; #Co-corresponding author
The cellular basis of liver regeneration has been highly contentious. We generated 12 CreER strains to perform systematic, side-by-side comparisons of hepatocytes in various zones, including populations previously implicated as stem cells (
Somatic mosaicism is a new frontier for human genetics and represents an untapped source of disease genes. While somatic mutations can now be identified using deep sequencing, the functional analysis of such mutations remains challenging and will require new approaches. We are currently using in vivo screening and lineage tracing as well as CRISPR technologies to rapidly model the phenotypic impact of somatic mutations. Just as germline sequencing has identified genes that have transformed fields, the discovery of genes that are recurrently mutated in chronically injured tissues but not in cancer has the potential to transform our understanding of regeneration and wound healing.
It is widely assumed that cancer risk increases with regenerative capacity, but we suspect the relationship is more complicated. In mammals, chronic organ damage in the skin, lung, intestine, and liver is strongly associated with cancer, but it is possible that the potent regenerative abilities of these organs serve to preserve tissue integrity, reduce inflammation, and resist transformation in the context of recurrent injury.
