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Venugopal S.K.,Transplant Research Program | Jiang J.,University of California at Davis | Kim T.-H.,Transplant Research Program | Kim T.-H.,Ewha Womans University | And 6 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2010

Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis. microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation, and apoptosis. Hence, we have analyzed the miRNAs that were differentially expressed in HSC isolated from sham-operated and bile duct-ligated rats. Expression of two miRNAs, miRNA-150 and miRNA-194, was reduced in HSC isolated from fibrotic rats compared with sham-operated animals. These two miRNAs were overexpressed in LX-2 cells, and their ability to inhibit cell proliferation, the expression of smooth muscle α-actin (SMA), a marker for activation, and collagen type I, a marker for ECM secretion, was determined. Overexpression of these two miRNAs resulted in a significant inhibition of proliferation (P < 0.05) and reduced SMA and collagen I levels compared with either untreated cells or nonspecific miRNA-expressing cells. Next, the protein targets of these two miRNAs were found using bioinformatics approaches. C-myb was found to be a target for miRNA-150, and rac 1 was found to be one of the targets for miRNA-194. Therefore, we studied the expression of these two proteins by overexpressing these two miRNAs in LX-2 cells and found that overexpression of miRNA-150 and miRNA-194 resulted in a significant inhibition of c-myb and rac 1 expression, respectively. We conclude that both miRNA-150 and miRNA-194 inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac 1 expression. Copyright © 2010 the American Physiological Society.


PubMed | Transplant Research Program and Harvard University
Type: | Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | Year: 2016

Cardiac allograft vasculopathy (CAV) is the leading cause of chronic allograft loss after pediatric heart transplantation. We hypothesized that biomarkers of endothelial injury and repair would predict CAV development in pediatric heart transplant recipients.Blood was collected from pediatric heart transplant recipients at the time of routine annual coronary angiography, and the concentrations of 13 angiogenesis-related molecules were determined. The primary end point was the presence of moderate or severe CAV by angiography during a 5-year follow-up period.The study enrolled 48 recipients (57% male) with a median age of 15.5 years (range, 2-22 years) and median time post-transplant of 5.8 years (range, 2-15 years). Eight recipients developed moderate/severe CAV at a median follow-up of 4.7 years, of whom 3 died, 3 underwent retransplantation, 1 had a myocardial infarction, and 1 was listed for retransplantation. Clinical characteristics associated with the development of moderate/severe CAV included prednisone use at enrollment (p = 0.03) and positive recipient cytomegalovirus immunoglobulin G at the time of transplant (p = < 0.01). Multivariable Cox proportional hazards regression identified plasma vascular endothelial growth factor (VEGF)-A concentration greater than 90 pg/ml at the time of blood draw as a significant predictor of time to moderate or severe CAV (hazard ratio, 14.3; 95% confidence interval, 1.3-163). Receiver operating characteristic curve analysis demonstrated that VEGF-A shows moderate performance for association with the subsequent development of CAV (area under the curve, 0.77; 95% confidence interval, 0.61-0.92).VEGF-A levels in pediatric heart transplant recipients are associated with clinically important CAV progression within the subsequent 5 years.


Roedder S.,Transplant Research Program | Roedder S.,Biomarc Inc. | Gao X.,Transplant Research Program | Gao X.,Biomarc Inc. | And 2 more authors.
Current Opinion in Organ Transplantation | Year: 2012

PURPOSE OF REVIEW: This review highlights the importance and the role of key biomarker studies in liver and kidney transplant tolerance, discusses the most recent findings with respect to organ-type and cell-type specificity in blood and tissue, and points out the novel research directions in the field of immunological tolerance that involve both adult and pediatric recipients. RECENT FINDINGS: Recent studies indicate that biomarkers for solid organ transplant tolerance are distinct with respect to organ type and cell type, suggesting distinct tolerogenic mechanisms for different organs. In both liver and kidney transplant tolerant recipients, novel cellular mechanisms have been proposed for natural killer cells, B cells, and dendritic cells in the maintenance of stable operational tolerance. SUMMARY: Major advances have been made with respect to the understanding of mechanisms and the process of discovery and early validation of peripheral blood biomarkers for operational transplant tolerance both in kidney and liver transplantation. These studies have shed light on the findings that these tolerance mechanisms may be organ specific, as the peripheral blood transcriptional profiling attempts by microarrays and PCR reveal distinct differences and suggest roles for specific cell types. Although these studies are mostly in adults and limited in children, the first tolerance gene signature for pediatric liver transplant tolerance suggests that there are common mechanisms, yet distinct peripheral biomarkers across age. Prospective trials and organ integrative studies are now needed to further develop these biomarkers for future clinical application in addition to expanding novel approaches such as the investigation of miRNAs to better understand the tolerance mechanisms. Copyright © 2012 Lippincott Williams & Wilkins.


PubMed | Transplant Research Program
Type: Journal Article | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2010

Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis. microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation, and apoptosis. Hence, we have analyzed the miRNAs that were differentially expressed in HSC isolated from sham-operated and bile duct-ligated rats. Expression of two miRNAs, miRNA-150 and miRNA-194, was reduced in HSC isolated from fibrotic rats compared with sham-operated animals. These two miRNAs were overexpressed in LX-2 cells, and their ability to inhibit cell proliferation, the expression of smooth muscle alpha-actin (SMA), a marker for activation, and collagen type I, a marker for ECM secretion, was determined. Overexpression of these two miRNAs resulted in a significant inhibition of proliferation (P < 0.05) and reduced SMA and collagen I levels compared with either untreated cells or nonspecific miRNA-expressing cells. Next, the protein targets of these two miRNAs were found using bioinformatics approaches. C-myb was found to be a target for miRNA-150, and rac 1 was found to be one of the targets for miRNA-194. Therefore, we studied the expression of these two proteins by overexpressing these two miRNAs in LX-2 cells and found that overexpression of miRNA-150 and miRNA-194 resulted in a significant inhibition of c-myb and rac 1 expression, respectively. We conclude that both miRNA-150 and miRNA-194 inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac 1 expression.

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