Abstract
BackgroundOne 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.MethodsHuman 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.ResultsCo-stimulation of LPAR1 by LPA and S1PR1/3 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 G12/13 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.ConclusionsCo-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.
Highlights
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
We demonstrated that the concurrent stimulation of LPAR1 and S1PR1/3 synergistically enhanced the anti-stress ability of human adipose-derived mesenchymal stem cells in vitro and enhanced the transplantation therapeutic efficacy in a drug-induced acute liver failure and a chronic alcoholic liver disease (ALD) model in vivo
Lysophosphatidic acid (LPA) and S1P prevents stem cell damage through the RAS/Extracellular signal regulated kinase (ERK), Phosphoinositide 3kinase (PI3K)/Protein kinase B (Akt), and Nuclear factor-kappa B (NF-κB)/IL-10 pathways Since the RAS/ERK and PI3K/Akt pathways are reported to be important in stem cell survival in harsh environments [16, 30, 31], we investigated whether those pathways were involved in LPA- and S1P-mediated cell protection
Summary
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. Drug-induced and alcoholic liver diseases are common but severe clinical problems worldwide. Drug-induced liver injury (DILI) occurs between 10 and 15 per 10,000 to 100,000 persons exposed to prescription medications annually and accounts for approximately 10% of all cases of acute hepatitis [1, 2]. When excessive drugs/alcohol are consumed, the hepatic metabolizing system fails to detoxify them, and subsequent inflammation and oxidative stress may induce liver failure which warrants timely liver transplantation. Due to the rapid progress of regenerative medicine, stem cell-based transplantation has become a promising strategy to cover shortages in liver transplantation availability due to insufficient donor organs, rejection, and infection [4, 5]
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