Co-stimulation of LPAR ₁ and S1PR _1/3 increases the transplantation efficacy of human mesenchymal stem cells in drug-induced and alcoholic liver diseases

Background: One of the major obstacles facing stem cell therapy is the limited number of functional stem cells available after transplantation due to the harsh microenvironment surrounding the damaged tissue. The aim of this study was to delineate the mechanistic involvement of lysophosphatidic acid receptors (LPARs) and sphingosine-1-phosphate receptors (S1PRs) in the regulation of anti-stress and transplantation efficacy of stem cells. Methods: Human adipose-derived mesenchymal stem cells (hADMSCs) were treated with chemical toxin or ethanol to induce cell stress. Lysophosphatidic acid (LPA) and/or sphingosine-1-phosphate (S1P) were co-treated to examine their protective effects and mechanisms on stem cell damage. Acute liver failure and alcoholic liver disease murine models were also established to test the transplantation efficacy of hADMSCs with or without LPA/S1P pre-incubation. Results: Co-stimulation of LPAR ₁ by LPA and S1PR _1/3 by S1P synergistically enhanced the anti-stress ability of hADMSCs induced by chemical or ethanol incubation in vitro. Downstream pathways involved in this process included the Gi protein (but not the G _12/13 proteins), the RAS/ERK pathway, and the PI3K/Akt pathway. Upon cell injury, the nuclear translocation of nuclear factor-kappa B (NF-κB) was promoted to facilitate the activation of downstream pro-inflammatory gene transcription, which was ameliorated by co-treatment with LPA and/or S1P. Increased secretion of interleukin (IL)-10 from stem cells by LPA and/or S1P seemed to be one of the major protective mechanisms since blocking IL-10 expression significantly aggravated stress-induced cell damage. In a drug-induced acute liver failure model and a chronic alcoholic liver disease model, pre-conditioning with LPA and/or S1P significantly enhanced the survival ratio and the therapeutic efficacy of hADMSCs in mice, including ameliorating histological damage, oxidative stress, inflammation, fibrosis, lipid metabolism dysfunction, and enhancing alcohol metabolizing enzyme activity. Importantly, supplementing LPA and/or S1P did not alter the basic characteristics of the hADMSCs nor induce tumour formation after cell transplantation. Conclusions: Co-use of LPA and S1P represents a novel and safe strategy to enhance stem cell transplantation efficacy for future drug- and alcoholic-related liver disease therapies.