Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects.

BACKGROUND: Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants. SUMMARY: This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT. KEY MESSAGES: MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.

Immunologic barriers in liver transplantation: a single-cell analysis of the role of mesenchymal stem cells.

Background: This study aimed to analyze the biomarkers that may reliably indicate rejection or tolerance and the mechanism that underlie the induction and maintenance of liver transplantation (LT) tolerance related to immunosuppressant or mesenchymal stem cells (MSCs). Methods: LT models of Lewis-Lewis and F344-Lewis rats were established. Lewis-Lewis rats model served as a control (Syn). F344-Lewis rats were treated with immunosuppressant alone (Allo+IS) or in combination with MSCs (Allo+IS+MSCs). Intrahepatic cell composition particularly immune cells was compared between the groups by single-cell sequencing. Analysis of subclusters, KEGG pathway analysis, and pseudotime trajectory analysis were performed to explore the potential immunoregulatory mechanisms of immunosuppressant alone or combined with MSCs. Results: Immunosuppressants alone or combined with MSCs increases the liver tolerance, to a certain extent. Single-cell sequencing identified intrahepatic cell composition signature, including cell subpopulations of B cells, cholangiocytes, endothelial cells, erythrocytes, hepatic stellate cells, hepatocytes, mononuclear phagocytes, neutrophils, T cells, and plasmacytoid dendritic cells. Immunosuppressant particularly its combination with MSCs altered the landscape of intrahepatic cells in transplanted livers, as well as gene expression patterns in immune cells. MSCs may be included in the differentiation of T cells, classical monocytes, and non-classical monocytes. Conclusion: These findings provided novel insights for better understanding the heterogeneity and biological functions of intrahepatic immune cells after LT treated by IS alone or in combination with MSCs. The identified markers of immune cells may serve as the immunotherapeutic targets for MSC treatment of liver transplant rejection.

Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases.

Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.

Computer identification of snoRNA genes using a Mammalian Orthologous Intron Database.

Based on comparative genomics, we created a bioinformatic package for computer prediction of small nucleolar RNA (snoRNA) genes in mammalian introns. The core of our approach was the use of the Mammalian Orthologous Intron Database (MOID), which contains all known introns within the human, mouse and rat genomes. Introns from orthologous genes from these three species, that have the same position relative to the reading frame, are grouped in a special orthologous intron table. Our program SNO.pl searches for conserved snoRNA motifs within MOID and reports all cases when characteristic snoRNA-like structures are present in all three orthologous introns of human, mouse and rat sequences. Here we report an example of the SNO.pl usage for searching a particular pattern of conserved C/D-box snoRNA motifs (canonical C- and D-boxes and the 6 nt long terminal stem). In this computer analysis, we detected 57 triplets of snoRNA-like structures in three mammals. Among them were 15 triplets that represented known C/D-box snoRNA genes. Six triplets represented snoRNA genes that had only been partially characterized in the mouse genome. One case represented a novel snoRNA gene, and another three cases, putative snoRNAs. Our programs are publicly available and can be easily adapted and/or modified for searching any conserved motifs within mammalian introns.