The innovation and clinical application of ischemia-free organ transplantation

The incidence rate of liver cancer is increasing year by year globally. Liver transplantation has become one of the therapeutic methods for patients with liver cancer. In the past, ischemia-reperfusion injury (IRI) was unavoidable in liver transplantation, compromising recipient and graft survival. At the same time, the imbalance between the supply and demand of organs limits the use of transplantation in patients with liver cancer. Recently, advances have been made in machine perfusion techniques to reduce graft IRI. However, none of the techniques can completely abrogate graft IRI. In 2017, the concept of ischemia-free organ transplantation (IFOT) was proposed, and our group conducted the first case of ischemia-free liver transplantation (IFLT). We then extended the concept of IFOT to kidney transplantation in 2018 and to heart transplantation in 2021. Here, we review the history, strengths, and weaknesses, and the future direction of IFOT, particularly in patients with liver cancers

The Role of CD1d and MR1 Restricted T Cells in the Liver

The liver is one of the most important immunological organs that remains tolerogenic in homeostasis yet promotes rapid responses to pathogens in the presence of a systemic infection. The composition of leucocytes in the liver is highly distinct from that of the blood and other lymphoid organs, particularly with respect to enrichment of innate T cells, i.e., invariant NKT cells (iNKT cells) and Mucosal-Associated Invariant T cells (MAIT cells). In recent years, studies have revealed insights into their biology and potential roles in maintaining the immune-environment in the liver. As the primary liver-resident immune cells, they are emerging as significant players in the human immune system and are associated with an increasing number of clinical diseases. As such, innate T cells are promising targets for modifying host defense and inflammation of various liver diseases, including viral, autoimmune, and those of tumor origin. In this review, we emphasize and discuss some of the recent discoveries and advances in the biology of innate T cells, their recruitment and diversity in the liver, and their role in various liver diseases, postulating on their potential application in immunotherapy

Multidisciplinary Cooperation in a Simultaneous Combined Liver and Kidney Transplantation Patient of Primary Hyperoxaluria

Primary hyperoxaluria type 1 is an autosomal recessive hereditary glyoxylate metabolism disorder characterized by excessive production of oxalate, caused by the deficiency of liver specific peroxisomal enzyme: alanineglyoxylate aminotransferase. For patients with end-stage renal disease, combined liver and kidney transplantation was needed. This report describes one patient, with a diagnosis of end-stage renal disease and primary hyperoxaluria 1 confirmed by PCR and direct sequencing with genomic DNA, received the simultaneous combined liver and kidney transplantation after seven months’ waiting. However, there were several complications observed post surgery, such as protracted bleeding, common bile duct anastomotic stenosis, biliary calculi and recurrence of urolithiasis. All these were well solved by relevant department, and finally a satisfactory outcome was achieved. Multidisciplinary cooperation plays an important role on the PH1 patient management, especially when multiple complications are encountered. Keywords: primary hyperoxaluria type 1; end-stage renal disease; liver transplantation; kidney transplantation

Adoptive Transfer of Human Gingiva-derived Mesenchymal Stem Cells Ameliorates Collagen-induced Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of Regulatory T Cell Differentiation

Objective Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrow-derived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSC-based therapy faces many challenges, such as limited cell availability and reduced clinical feasibility. This study in mice with established collagen-induced arthritis (CIA) was undertaken to determine whether substitution of human gingiva-derived mesenchymal stem cells (G-MSCs) would significantly improve the therapeutic effects. Methods CIA was induced in DBA/1J mice by immunization with type II collagen and Freund\u27s complete adjuvant. G-MSCs were injected intravenously into the mice on day 14 after immunization. In some experiments, intraperitoneal injection of PC61 (anti-CD25 antibody) was used to deplete Treg cells in arthritic mice. Results Infusion of G-MSCs in DBA/1J mice with CIA significantly reduced the severity of arthritis, decreased the histopathology scores, and down-regulated the production of inflammatory cytokines (interferon-γ and interleukin-17A). Infusion of G-MSCs also resulted in increased levels of CD4+CD39+FoxP3+ cells in arthritic mice. These increases were noted early after infusion in the spleens and lymph nodes, and later after infusion in the synovial fluid. The FoxP3+ Treg cells that were increased in frequency mainly consisted of Helios-negative cells. When Treg cells were depleted, infusion of G-MSCs partially interfered with the progression of CIA. Pretreatment of G-MSCs with a CD39 or CD73 inhibitor significantly reversed the protective effect of G-MSCs on CIA. Conclusion The role of G-MSCs in controlling the development and severity of CIA mostly depends on CD39/CD73 signals and partially depends on the induction of CD4+CD39+FoxP3+ Treg cells. G-MSCs provide a promising approach for the treatment of autoimmune diseases. Copyright © 2013 by the American College of Rheumatology

Novel ceRNA network construction associated with programmed cell death in acute rejection of heart allograft in mice

BackgroundT cell-mediated acute rejection(AR) after heart transplantation(HT) ultimately results in graft failure and is a common indication for secondary transplantation. It’s a serious threat to heart transplant recipients. This study aimed to explore the novel lncRNA-miRNA-mRNA networks that contributed to AR in a mouse heart transplantation model.MethodsThe donor heart from Babl/C mice was transplanted to C57BL/6 mice with heterotopic implantation to the abdominal cavity. The control group was syngeneic heart transplantation with the same kind of mice donor. The whole-transcriptome sequencing was performed to obtain differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in mouse heart allograft. The biological functions of ceRNA networks was analyzed by GO and KEGG enrichment. Differentially expressed ceRNA involved in programmed cell death were further verified with qRT-PCR testing.ResultsLots of DEmRNAs, DEmiRNAs and DElncRNAs were identified in acute rejection and control after heart transplantation, including up-regulated 4754 DEmRNAs, 1634 DElncRNAs, 182 DEmiRNAs, and down-regulated 4365 DEmRNAs, 1761 DElncRNAs, 132 DEmiRNAs. Based on the ceRNA theory, lncRNA-miRNA-mRNA regulatory networks were constructed in allograft acute rejection response. The functional enrichment analysis indicate that the down-regulated mRNAs are mainly involved in cardiac muscle cell contraction, potassium channel activity, etc. and the up-regulated mRNAs are mainly involved in T cell differentiation and mononuclear cell migration, etc. The KEGG pathway enrichment analysis showed that the down-regulated DEmRNAs were mainly enriched in adrenergic signaling, axon guidance, calcium signaling pathway, etc. The up-regulated DEmRNAs were enriched in the adhesion function, chemokine signaling pathway, apoptosis, etc. Four lncRNA-mediated ceRNA regulatory pathways, Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox, 1700071M16Rik/miR-145a-3p/Themis2, were finally validated. In addition, increased expression of PVT1, 1700071M16Rik, Tox and Themis2 may be considered as potential diagnostic gene biomarkers in AR.ConclusionWe speculated that Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox and 1700071M16Rik/miR-145a-3p/Themis2 interaction pairs may serve as potential biomarkers in AR after HT

Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer

Repulsive guidance molecules (RGMs) are co-receptors of bone morphogenetic proteins (BMPs) and programmed death ligand 2 (PD-L2), and might be involved in lung and other cancers. We evaluated repulsive guidance molecule B (RGMB) expression in 165 non-small cell lung cancer (NSCLC) tumors and 22 normal lung tissue samples, and validated the results in an independent series of 131 samples. RGMB was downregulated in NSCLC (P ≤ 0.001), possibly through promoter hypermethylation. Reduced RGMB expression was observed in advanced-stage tumors (P = 0.017) and in tumors with vascular invasion (P < 0.01), and was significantly associated with poor overall survival (39 vs. 62 months, P < 0.001) and with disease-associated patient mortality (P = 0.015). RGMB knockdown promoted cell adhesion, invasion and migration, in both NSCLC cell lines and an in vivo mouse model, which enhanced metastatic potential. Conversely, RGMB overexpression and secretion suppressed cancer progression. The tumor-suppressing effect of RGMB was exerted through inhibition of the Smad1/5/8 pathway. Our results demonstrate that RGMB is an important inhibitor of NSCLC metastasis and that low RGMB expression is a novel predictor or a poor prognosis

The First Case of Ischemia-Free Kidney Transplantation in Humans

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation

Down-Regulation of microRNA-26a Promotes Mouse Hepatocyte Proliferation during Liver Regeneration

BACKGROUND: Inadequate liver regeneration (LR) is still an unsolved problem in major liver resection and small-for-size syndrome post-living donor liver transplantation. A number of microRNAs have been shown to play important roles in cell proliferation. Herein, we investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR. METHODOLOGY/PRINCIPAL FINDINGS: Adult male C57BL/6J mice, undergoing 70% partial hepatectomy (PH), were treated with Ad5-anti-miR-26a-LUC or Ad5-miR-26a-LUC or Ad5-LUC vector via portal vein. The animals were subjected to in vivo bioluminescence imaging. Serum and liver samples were collected to test liver function, calculate liver-to-body weight ratio (LBWR), document hepatocyte proliferation (Ki-67 staining), and investigate potential targeted gene expression of miR-26a by quantitative real-time PCR and Western blot. The miR-26a level declined during LR after 70% PH. Down-regulation of miR-26a by anti-miR-26a expression led to enhanced proliferation of hepatocytes, and both LBWR and hepatocyte proliferation (Ki-67(+) cells %) showed an increased tendency, while liver damage, indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T-Bil), was reduced. Furthermore, CCND2 and CCNE2, as possible targeted genes of miR-26a, were up-regulated. In addition, miR-26a over-expression showed converse results. CONCLUSIONS/SIGNIFICANCE: MiR-26a plays crucial role in regulating the proliferative phase of LR, probably by repressing expressions of cell cycle proteins CCND2 and CCNE2. The current study reveals a novel miRNA-mediated regulation pattern during the proliferative phase of LR