A potential role of somatostatin and its receptor SSTR4 in the migration of hepatic oval cells

Abstract

Somatostatin (SST) is a regulatory peptide that activates G protein-coupled receptors comprised of five members (somatostatin receptors (SSTRs) 1-5). Despite the broad use of SST and its analogs in clinical practice, the spectrum of SST activities has been incompletely defined. Recently, it has been demonstrated that SST can be a chemoattractant for hematopoietic precursor cells. Since hepatic oval cells (HOCs) share common characteristics with hematopoietic stem cells, we hypothesized that SST could act as a chemoattractant for HOCs by stimulating SSTRs. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot assay revealed an increased expression of SST in the 2-acetyl-aminofluorene (2AAF)/partial hepatectomy (PHx) HOC induction model. Immunohistochemical staining showed the expression of SST in 2AAF/PHx-treated rat liver, as compared to normal liver. Proliferation and migration assays demonstrated that the increase of SST was related to migration of HOCs, but not their proliferation. RT-PCR and quantitative real-time PCR showed that SSTR4 was preferentially expressed by HOCs. Western blot assay and immunohistochemical staining confirmed the expression of SSTR4 by HOCs. In addition, pretreatment with anti-SSTR4 antibody cultures resulted in a dramatic reduction of cell migration as compared to that of control. Lastly, SST stimulated the rearrangement of actin filaments in HOCs, while HOCs treated with anti-SSTR4 antibody failed to do so. These results suggest a positive role for SST in the migration of HOCs, and that this effect is mediated through SSTR4.

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Oval cells are derived from the canal of Hering, and in rodents this canal barely extends beyond the limiting plate ( Figures 4, 5); in contrast, in human liver the organization of the biliary tree is different, with the canal of Hering extending to the proximate third of the lobule [68] and so apparently requiring a name change from oval cells to 'hepatic progenitor cells' (HPCs) [69]. An enormous range of markers has been used to identify ovals cells (Table 2) [70][71][72][73][74][75][76][77][78][79][80][81][82][83] and some, such as Dlk, may signal imminent hepatocyte differentiation [71]. A popular experimental procedure to elicit an oval cell response in rats is to pre-treat the animals with 2-acetylaminofluorene (2-AAF) before performing a two-thirds PH (the 2-AAF/PH protocol).…”

Granulocyte–Colony Stimulating Factor Promotes Liver Repair and Induces Oval Cell Migration and Proliferation in Rats

“…10,23 Briefly, isolation was achieved by using a standard 2-step collagenase perfusion. Cells were centrifuged at 55 × g to separate the hepatocyte fraction from nonparenchymal cells, the latter were collected at 220 × g. Nonparenchymal cells were incubated with Thy-1-fluorescein isothiocyanate-conjugated antibody (BD Biosciences Pharmingen), followed by incubation with anti-fluorescein isothiocyanate microbeads.…”

“…23 Briefly, transwell culture dishes (Coring, Inc., Costar, NY) with 5-μm pore filters were precoated overnight with 0.006% rat-tail collagen. Cells (1 × 10 5 ) were suspended in migration buffer (IMDM, 10% fetal bovine serum, and 1% insulin), and allowed to attach overnight.…”

Liver regeneration

“…Oval cells proliferate intensely in the periportal areas of the hepatic lobule and they are heavily infiltrated by stellate cells; the latter intertwine with the oval cells and produce HGF, FGF1, FGF2, and VEGF (Evarts et al, 1993;Fujio et al, 1994). Other factors, such as somatostatin, stromal cell derived factor 1 (SDF1) and connective tissue growth factor also play a role (Pi et al, 2005;Jung et al, 2006;Zheng et al, 2006). Oval cells express both albumin and alpha fetoprotein.…”