PTN and PTPRZ1 are known to control the egress of stem cells from bone marrow. Methods: Livers were harvested from PTN-GFP (PTN reporter) mice, PTN-PTN-knockout (KO) mice, PTPRZ1-KO mice, and wild type (WT) controls (n=6-9 mice/group) 2 weeks after bile duct ligation (BDL). Effects Sirolimus on expression of PTN and PTPRZ1, and the DR were evaluated by qRT PCR, quantitative immunohistochemistry (IHC), and hepatic hydroxyproline assay. LPCs and HSC

from WT, PTN-KO, and PTPRZ1-KO mice were also treated directly with PTN to characterize tyrosine-phosphorylated proteins and assess effects on gene expression, migration, and growth. Results: Although freshly-isolated HSC and LPC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was find more demonstrated in healthy liver. BDL induced strong expression of PTN mRNA and protein in MF-HSC and dramatically increased PTPRZ1 expression in MF-HSC and ductular-appearing LPCs. In WT mice, BDL triggered a DR characterized by periportal accumulation of collagen, Krt19(+) ductular cells, and aSMA(+) MF derived from desmin (+) HSC. All aspects

of this DR were significantly increased in PTN-KO mice and significantly suppressed in PTPRZ1-KO mice. PTN had no effect on the viability or growth of cultured LPCs or MF-HSC but directly inhibited migration of both cell types. The anti-migratory actions of PTN required PTPRZ1 because PTN inhibited migration in HSC that expressed PTPRZ1, but not PTPRZ1-KO HSC. PTN treatment of PTPRZ1(+) liver cells caused accumulation of several phosphoproteins, including an obligatory component of adherens junctions and a protein that regulates podosome function and integrins. Conclusions: The “stemness” factor, pleiotrophin, and its receptor, PTPRZ1, regulate the ductular reaction to liver injury by controlling the migration of resident cells in putative adult liver progenitor niches. Disclosures: John P. Chute – Board Membership: C2Regenerate Anna Mae Diehl – Consulting: 上海皓元医药股份有限公司 Roche; Grant/Research Support: Gilead, Genfit The following people have nothing to disclose: Gregory A. Michelotti,

Anikia Tucker, Mariana V. Machado, Marzena Swiderska-Syn, Steve S. Choi, Leandi Kruger, Katherine S. Garman, Cynthia A. Moylan, Cynthia D. Guy, Heather Himburg MicroRNAs (miRNAs) are small non-coding RNAs that regulate the course of cholestatic liver diseases. miR-125 is a highly conserved family of miRNAs that regulate cellular proliferation during cholestatic liver injury. These miRNAs also regulate the expression of VEGF that potentiates fibrosis during liver injury. miR-125 targets several growth factors (e.g., VEGF) and matrix metalloproteases (MMPs), a dysregulation of which leads to aberrant proliferation, metastasis and cell invasion. Biliary hyperplasia in bile duct ligated (BDL) rats is accompanied by enhanced angiogenesis and fibrosis.