miR-182-5p Promotes Hepatocyte-Stellate Cell Crosstalk to Facilitate Liver Regeneration

A unique feature of the liver is its high regenerative capacity, which is essential to maintain liver homeostasis. However, key regulators of liver regeneration (LR) remain ill-defined. Here, we identify hepatic miR-182-5p as a key regulator of LR. Suppressing miR-182-5p, whose expression is significantly induced in the liver of mice post two-thirds partial hepatectomy (PH), abrogates PH-induced LR in mice. In contrast, liver-specific overexpression of miR-182-5p promotes LR in mice with PH. Overexpression of miR-182-5p failed to promote proliferation in hepatocytes, but stimulates proliferation when hepatocytes are cocultured with stellate cells. Mechanistically, miR-182-5p stimulates Cyp7a1-mediated cholic acid production in hepatocytes, which promotes hedgehog (Hh) ligand production in stellate cells, leading to the activation of Hh signaling in hepatocytes and consequent cell proliferation. Collectively, our study identified miR-182-5p as a critical regulator of LR and uncovers a Cyp7a1/cholic acid-dependent mechanism by which hepatocytes crosstalk to stellate cells to facilitate LR. Briefly, 8- to 10-week-old male mice were anesthetized with isoflurane, followed by a ventral midline incision. The left lateral, left middle, and right middle lobe of the liver (70% of the liver) were removed from the anesthetized mice after pedicle ligation with prolene 6/0. After surgery, the mice were placed on a warming pad for recovery until completely conscious. All partial hepatectomies were performed at early hours in the morning.