Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2

Abstract

Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, stimulates proliferation and contractility in hepatic stellate cells, the principal matrix-producing cells in the liver, and inhibits proliferation via S1P receptor 2 (S1P 2 ) in hepatocytes in rats in vitro. A potential role of S1P and S1P 2 in liver regeneration and fibrosis was examined in S1P 2 -deficient mice. Nuclear 5-bromo-2′-deoxy-uridine labeling, proliferating cell nuclear antigen (PCNA) staining in hepatocytes, and the ratio of liver weight to body weight were enhanced at 48 h in S1P 2 -deficient mice after a single carbon tetrachloride (CCl 4 ) injection. After dimethylnitrosamine (DMN) administration with a lethal dose, PCNA staining in hepatocytes was enhanced at 48 h and survival rate was higher in S1P 2 -deficient mice. Serum aminotransferase level was unaltered in those mice compared with wild-type mice in both CCl 4 -and DMN-induced liver injury, suggesting that S1P 2 inactivation accelerated regeneration not as a response to enhanced liver damage. After chronic CCl 4 administration, fibrosis was less apparent, with reduced expression of smooth-muscle a-actin-positive cells in the livers of S1P 2 -deficient mice, suggesting that S1P 2 inactivation ameliorated CCl 4 -induced fibrosis due to the decreased accumulation of hepatic stellate cells. Thus, S1P plays a significant role in regeneration and fibrosis after liver injury via S1P 2 . Sphingosine 1-phosphate (S1P), which elicits a wide variety of cell responses (1), has emerged as a novel lipid intracellular mediator. S1P was shown to act as an intracellular second messenger of platelet-derived growth factor and serum in their mitogenic actions in cultured fibroblasts (2, 3), and furthermore, intracellular levels of S1P and ceramide were reported to determine cell survival or death (4, 5). However, evidence indicating that S1P also acts as an extracellular mediator has been reported; some of the diverse effects of S1P, such as stimulation of cell proliferation or contractility, are known to be sensitive to pertussis toxin (6) or ADP-ribosyltransferase C3 from Clostridium botulinum (7, 8), suggesting that S1P may activate a receptor coupled to G protein(s). Indeed, recent investigation has revealed that S1P acts through at least five high-affinity G proteincoupled receptors referred to as S1P 1-5 (9, 10). Regarding the source of S1P in vivo, it is shown to be stored in platelets (11), and recent data using conditional knockouts of sphingosine kinases support release of S1P from erythrocytes (12, 13). These findings suggest that S1P has normal in vivo roles as well as potentially pathophysiological roles as a circulating paracrine mediator, a view further supported by the phenotypes of S1P receptor mutants (10,14,15). S1P receptors are also expressed in the liver (14). To investigate the function of S1P in liver pathophysiology, we have determined the effect of S1P on liver cells in culture. We first demonstrated that S1P stimulates proliferation and contractility in rat hepati...

Exosomes from Human-Induced Pluripotent Stem Cell–Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway

“…Furthermore, we found that hiPSC-MSCs-Exo could promote hepatocytes proliferation. Consistently, another report also showed that exosomes isolated from mesenchymal stem cells increased hepatocytes proliferation after liver injury induced by carbon tetrachloride [37]. Thus, both results suggest that hiPSC-MSCs derived exosomes are able to trigger homeostatic liver protection after injury.…”

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

“…of receptor signaling by extravasated S1P on parenchymal and immune cells in tissues under acute and chronic inflammatory conditions is not well understood but could potentially lead to reparative processes. Whether dysregulated S1P signaling in tissues leads to fibrotic responses is not yet known; however, S1P 2 and S1P 3 have been associated with tissue fibrotic processes in organs, such as the liver, lung, and kidney (81)(82)(83).…”

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature: TABLE 1

“…S1P 2 also promotes pathologic angiogenesis and retards normal vascularization in the retinas of mice during hypoxia-induced retinopathy [on the basis of loss-of-function in receptor-null animals ] and, in conjunction with S1P 3 , can provide protection in myocardial ischemia-reperfusion models (Means et al, 2007). It has similarly been linked to reduced fertility, in conjunction with S1P 3 loss , as well as to hepatic wound healing, fibrosis, and regenerative capacity (Serriere-Lanneau et al, 2007;Ikeda et al, 2009).…”