Cell proliferation is known to play a fundamental role during development, homeostasis and regeneration. However, understanding how a particular cell lineage proliferates in the context of a whole organism has remained a challenge. Now, Bin Zhou and colleagues develop a genetic strategy for tissue-specific inhibition of cell proliferation in mice. They employ a Cre-loxP recombination system to achieve controlled expression of the cell cycle inhibitor gene p21, alongside GFP expression to mark targeted cells. By crossing the resultant R26-p21-GFP mouse line with a fibroblast-specific CreER line, they first demonstrate that p21 overexpression effectively inhibits proliferation in fibroblasts. Following on from this, they show that inhibiting fibroblast proliferation significantly reduces scar formation and promotes neovascularization following heart injury. They also demonstrate that inhibiting proliferation in liver hepatocytes induces other liver cell types to convert into hepatocytes following injury. Finally, the researchers develop an orthogonal R26-rox-p21-GFP allele, which responds to Dre recombinase rather than Cre, and show that this can be combined with the Cre-loxP system to simultaneously inhibit proliferation in one lineage while genetically tracing another; using this approach, they reveal that the inhibition of hepatocyte proliferation during chronic liver injury induces a biliary epithelial cell-to-hepatocyte conversion. Overall, these tools promise to be valuable for exploring the contribution of specific cell types to organ homeostasis and regeneration.
