Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure

<p>Abstract</p> <p>Background</p> <p>Stem cell-based therapy to treat liver diseases is a focus of current research worldwide. So far, most such studies depend on rodent hepatic failure models. The purpose of this study was to isolate mesenchymal stem cells from human placenta (hPMSCs) and determine their therapeutic potential for treating Chinese experimental miniature pigs with acute liver failure (ALF).</p> <p>Methods</p> <p>hPMSCs were isolated and analyzed for their purity and differentiation potential before being employed as the donor cells for transplantation. ALF models of Chinese experimental miniature pigs were established and divided into four groups: no cell transplantation; hPMSCs transplantation via the jugular vein; X-ray-treated hPMSCs transplantation via the portal vein; and hPMSCs transplantation via the portal vein. The restoration of biological functions of the livers receiving transplantation was assessed via a variety of approaches such as mortality rate determination, serum biochemical analysis, and histological, immunohistochemical, and genetic analysis.</p> <p>Results</p> <p>hPMSCs expressed high levels of CD29, CD73, CD13, and CD90, had adipogenic, osteogenic, and hepatic differentiation potential. They improved liver functions <it>in vivo </it>after transplantation into the D-galactosamine-injured pig livers as evidenced by the fact that ALT, AST, ALP, CHE, TBIL, and TBA concentrations returned to normal levels in recipient ALF pigs. Meanwhile, histological data revealed that transplantation of hPMSCs via the portal vein reduced liver inflammation, decreased hepatic denaturation and necrosis, and promoted liver regeneration. These ameliorations were not found in the other three groups. The result of 7-day survival rates suggested that hPMSCs transplantation via the portal vein was able to significantly prolong the survival of ALF pigs compared with the other three groups. Histochemistry and RT-PCR results confirmed the presence of transplanted human cells in recipient pig livers (Groups III, IV).</p> <p>Conclusions</p> <p>Our data revealed that hPMSCs could not only differentiate into hepatocyte-like cells <it>in vitro </it>and <it>in vivo</it>, but could also prolong the survival time of ALF pigs. Regarding the transplantation pathways, the left branch of the portal vein inside the liver was superior to the jugular vein pathway. Thus, hPMSCs transplantation through the portal vein by B-ultrasonography may represent a superior approach for treating liver diseases.</p

On determination of cointegration ranks

We propose a new method to determine the cointegration rank in the error correction model of Engle and Granger (1987). To this end, we first estimate the cointegration vectors in terms of a residual-based principal component analysis. Then the cointegration rank, together with the lag order, is determined by a penalized goodness-of-fit measure. We have shown that the estimated cointegration vectors are asymptotically normal, and our estimation for the cointegration rank is consistent. Our approach is more robust than the conventional likelihood based methods, as we do not impose any assumption on the form of the error distribution in the model, and furthermore we allow the serial dependence in the error sequence. The proposed methodology is illustrated with both simulated and real data examples. The advantage of the new method is particularly pronounced in the simulation with non-Gaussian and/or serially dependent errors

Decreased expression of Na+-H+ exchanger isoforms 1 and 3 in denervated spontaneously hypertensive rat kidney

To determine whether the sympathetic nerve plays a role in the regulation of Na+-H+ exchange (NHE) in the kidney of spontaneously hypertensive rats (SHR), we investigated the expression of NHE and NHE regulatory protein family (NHERF) in the denervated kidneys compared with intact kidneys. Twelve-week-old male SHR and age-matched Wistar Kyoto (WKY) rats were used. SHR were randomly assigned to the renal denervated (RDNX, n = 8) or Sham (n = 8) groups. The protein and mRNA expression of NHE1, NHE3, NHERF1 and NHERF2 were assessed in the kidney of the groups. Following the renal denervation, immunohistochemistry and western blot analysis showed that NHE1 and NHE3 protein were significantly decreased in the kidney compared with Sham group. NHERF1 protein expression was significantly increased in RDNX compared with Sham group, whereas NHERF2 protein expression was significantly decreased after renal denervation. Similar results were observed at the mRNA level of NHE1, NHE3, NHERF1 and NHERF2 expression. The present findings suggest that the renal sympathetic nervous system plays a role in the regulation of NHE1 and NHE3 in the kidney of SHR, and NHERF1 may be involved in the expression of NHE3 in the kidney of SHR

MicroRNA-9 Enhanced Cisplatin Sensitivity in Nonsmall Cell Lung Cancer Cells by Regulating Eukaryotic Translation Initiation Factor 5A2

We determined the role of microRNA (miR)-9 in regulating cisplatin chemoresistance in nonsmall cell lung cancer (NSCLC) cells. miR-9 and eukaryotic translation initiation factor 5A2 (eIF5A2) levels were examined by reverse transcription–quantitative PCR. Cell Counting Kit-8 and the 5-ethynyl-2′-deoxyuridine (EdU) assay were used to determine the effects of miR-9 mimic or inhibitor on NSCLC cell proliferation and viability, respectively. Bioinformatics was used to analyze the relationship between miR-9 and eIF5A2. Flow cytometry was used to analyze the percentage of apoptotic cells. miR-9 mimic enhanced cisplatin sensitivity, while miR-9 inhibitor produced the opposite result. eIF5A2 was identified as a potential target of miR-9, where miR-9 regulated eIF5A2 expression at mRNA and protein level. miR-9 mimic decreased the expression of eIF5A2 mRNA and protein, while miR-9 inhibitor increased eIF5A2 expression. eIF5A2 knockdown resolved the effects of miR-9 mimic or inhibitor on cisplatin sensitivity. miR-9 may be a potential biomarker for enhancing cisplatin sensitivity by regulating eIF5A2 in NSCLC cells

Characteristics of Intestinal Microecology during Mesenchymal Stem Cell-Based Therapy for Mouse Acute Liver Injury

Background. The mechanisms of mesenchymal stem cell (MSC) transplantation to protect against acute liver injury have been well studied within the liver. However, the associated changes in the intestinal microbiota during this process are poorly understood. Methods. In this study, compact bone-derived MSCs were injected into mice after carbon tetrachloride (CCl4) administration. Potential curative effect of MSC was evaluated by survival rate and biochemical and pathological results. Overall structural changes of microbial communities and alterations in the intestinal microbiota were assessed by sequenced 16S rRNA amplicon libraries from the contents of the cecum and colon. Results. MSCs significantly reduced the serum levels of aspartate transaminase and alanine transaminase and improved the histopathology and survival rate. Lower expression and discontinuous staining of zonula occludens, as well as disrupted tight junctions, were observed in CCl4-treated mice at 48 h compared with MSC-transplanted mice. Moreover, MSC transplantation to the liver leads to intestinal microbiota changes that were reflected in the decreased abundance of Bacteroidetes S24-7 and Bacteroidaceae and increased abundance of Firmicutes Clostridiales, Ruminococcaceae, and Lactobacillus at the initial time point compared with that in CCl4-treated mice. In addition, phylogenetic investigation of communities by the reconstruction of unobserved states (PICRUSt) based on the Greengenes database revealed functional biomarkers of MSC-transplanted mice involved in cell motility, signal transduction, membrane transport, transcription, and metabolism of lipids, cofactors, vitamins, terpenoids, and polyketides, as well as xenobiotics. Conclusion. The initial alterations in the Firmicutes/Bacteroidetes ratio, which resulted from MSC infusion to the liver, maintain intestinal mucosal biology and homeostasis that may be beneficial to liver repair