p53 positively regulates the proliferation of hepatic progenitor cells promoted by laminin-521

Hepatic progenitor cells(HPCs)hold tremendous potential for liver regeneration,but their well-known limitation of proliferation hampers their broader use.There is evidence that laminin is required for the proliferation of HPCs,but the laminin isoform that plays the dominant role and the key intracellular downstream targets that mediate the regulation of HPC proliferation have yet to be determined.Here we showed that p53 expression increased gradually and reached maximal levels around 8 days when lamininα4,α5,β2,β1,andγ1 subunit levels also reached a maximum during HPC activation and expansion.Laminin-521(LN-521)promoted greater proliferation of HPCs than do laminin,matrigel or other laminin isoforms.Inactivation of p53 by PFT-αor Ad-p53^(V143A) inhibited the promotion of proliferation by LN-521.Further complementary MRI and bioluminescence imaging analysis showed that p53 inactivation decreased the proliferation of transplanted HPCs in vivo.p53 was activated by LN-521 through the Integrinα6β1/FAK-Src-Paxillin/Akt axis.Activated p53 was involved in the nuclear translocation of CDK4 and inactivation of Rb by inducing p27^(Kip1).Taken together,this study identifies LN-521 as an ideal candidate substrate for HPC culture and uncovers an unexpected positive role for p53 in regulating proliferation of HPCs,which makes it a potential target for HPC-based regenerative medicine.