Network Analysis for the Identification of Hub Genes and Related Molecules as Potential Biomarkers Associated With the Differentiation of Bone Marrow-derived Stem Cells Into Hepatocytes

Abstract The incidence of liver diseases has been increasing steadily. However, it has some shortcomings, such as high cost and organ donor scarcity. The application of stem cell research has brought new ideas for the treatment of liver diseases. Therefore, it is particularly important to clarify the molecular and regulatory mechanisms of differentiation of bone marrow-derived stem cells (BMSCs) into liver cells. Herein, we screened differentially expressed genes between hepatocytes and untreated BMSCs to identify the genes responsible for the differentiation of BMSCs into hepatocytes. GSE30419 gene microarray data of BMSCs and GSE72088 gene microarray data of primary hepatocytes were obtained from the Gene Expression Omnibus database. Transcriptome Analysis Console software showed that 1896 genes were upregulated and 2506 were downregulated in hepatocytes as compared with BMSCs. Hub genes were analyzed using the STRING, revealing that two hub genes, Cat and Cyp2e1, play a pivotal role in oxidation-reduction process. The results indicate that the lncRNA-miRNA-mRNA interaction chain may play an important role in the differentiation of BMSCs into hepatocytes, which provides a new therapeutic target for liver disease treatment.

Download Full-text

Therapeutic Potential of Bone Marrow Stem Cells for Liver Diseases

Current Stem Cell Research & Therapy ◽

10.2174/157488806778226759 ◽

2006 ◽

Vol 1 (3) ◽

pp. 411-418 ◽

Cited By ~ 31

Author(s):

Felix Popp ◽

Pompiliu Piso ◽

Hans Schlitt ◽

Marc Dahlke

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Diseases ◽

Therapeutic Potential ◽

Bone Marrow Stem Cells

Download Full-text

Therapeutic applications of bone marrow-derived stem cells in liver transplantation for end-stage liver diseases

Chinese Science Bulletin ◽

10.1007/s11434-007-0392-9 ◽

2007 ◽

Vol 52 (18) ◽

pp. 2449-2456

Author(s):

HaiYing Luo ◽

YunFang Wang ◽

Wei Kong ◽

XueTao Pei

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Liver Diseases ◽

Therapeutic Applications ◽

End Stage

Download Full-text

A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.622604 ◽

2021 ◽

Vol 12 ◽

Author(s):

Brian H. Johnstone ◽

Franka Messner ◽

Gerald Brandacher ◽

Erik J. Woods

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Living Donor ◽

Progenitor Cell ◽

Large Scale ◽

Organ Donor ◽

Mixed Chimerism ◽

Solid Organ ◽

Transplant Tolerance ◽

Hematopoietic Stem

Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed “hematopoietic progenitor cell (HPC), Marrow,” recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to “delayed tolerance.” Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.

Download Full-text

A Bioinformatics-Based Screening and Analysis of Key Genes in Hepatocellular Carcinoma

10.21203/rs.3.rs-131655/v1 ◽

2020 ◽

Author(s):

Yanfei Wei ◽

Shengshan Wang ◽

Wanjun Chen ◽

Yuning Lin ◽

Qi Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Reduction Process ◽

Heme Binding ◽

Sequencing Technology ◽

Hub Genes ◽

Hub Gene ◽

Oxidation Reduction ◽

Extracellular Region ◽

The World ◽

Key Genes

Abstract Hepatocellular carcinoma (HCC) is considered as the leading killer disease in the world. So far most of the diagnosis of HCC is mainly established on imaging and biopsy. As sequencing technology is developing quite fast, and it has already been widely applied in the medical area, such as cancer diagnosis. In this article, GSE121248, GSE76427 and GSE60502 datasets were chosen to analyze and screen key genes which could affect the development of liver cancer through the bioinformatics method. The results showed up regulated genes mainly reside in cell division, nucleus, protein binding pathway, and down regulated genes are mostly located in the Oxidation-reduction process, Extracellular region, Heme binding, Metabolic pathway. Secondly, hub gene analysis indicated there were twelve critical hub genes found: RFC4, RACGAP1, CCNB2, CDC20, UBE2C, PTTG1, AURKA, PRC1, NCAPG, CDKN3, TOP2A, KIF20A, AURKA and CDKN3. By applying bioinformatic measures , the genes associated with hepatocellular carcinoma can be efficiently analyzed, that would provide invaluable information for translational studies.

Download Full-text

Analysis of Hub Genes Involved in Distinction Between Aged and Fetal Bone Marrow Mesenchymal Stem Cells by Robust Rank Aggregation and Multiple Functional Annotation Methods

Frontiers in Genetics ◽

10.3389/fgene.2020.573877 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xiaoyao Liu ◽

Mingjing Yin ◽

Xinpeng Liu ◽

Junlong Da ◽

Kai Zhang ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Bone Marrow ◽

Immune Response ◽

Mesenchymal Stem Cells ◽

Functional Annotation ◽

Rank Aggregation ◽

Ppi Network ◽

Hub Genes ◽

Marrow Mesenchymal Stem Cells

Stem cells from fetal tissue protect against aging and possess greater proliferative capacity than their adult counterparts. These cells can more readily expand in vitro and senesce later in culture. However, the underlying molecular mechanisms for these differences are still not fully understood. In this study, we used a robust rank aggregation (RRA) method to discover robust differentially expressed genes (DEGs) between fetal bone marrow mesenchymal stem cells (fMSCs) and aged adult bone marrow mesenchymal stem cells (aMSCs). Multiple methods, including gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed for functional annotation of the robust DEGs, and the results were visualized using the R software. The hub genes and other genes with which they interacted directly were detected by protein–protein interaction (PPI) network analysis. Correlation of gene expression was measured by Pearson correlation coefficient. A total of 388 up-regulated and 289 down-regulated DEGs were identified between aMSCs and fMSCs. We found that the down-regulated genes were mainly involved in the cell cycle, telomerase activity, and stem cell proliferation. The up-regulated DEGs were associated with cell adhesion molecules, extracellular matrix (ECM)–receptor interactions, and the immune response. We screened out four hub genes, MYC, KIF20A, HLA-DRA, and HLA-DPA1, through PPI-network analysis. The MYC gene was negatively correlated with TXNIP, an age-related gene, and KIF20A was extensively involved in the cell cycle. The results suggested that MSCs derived from the bone marrow of an elderly donor present a pro-inflammatory phenotype compared with that of fMSCs, and the HLA-DRA and HLA-DPA1 genes are related to the immune response. These findings provide new insights into the differences between aMSCs and fMSCs and may suggest novel strategies for ex vivo expansion and application of adult MSCs.

Download Full-text

An integrative bioinformatics analysis of microarray data for identifying hub genes as diagnostic biomarkers of preeclampsia

Bioscience Reports ◽

10.1042/bsr20190187 ◽

2019 ◽

Vol 39 (9) ◽

Cited By ~ 2

Author(s):

Keling Liu ◽

Qingmei Fu ◽

Yao Liu ◽

Chenhong Wang

Keyword(s):

Gene Expression ◽

Microarray Data ◽

Bioinformatics Analysis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gene Expression Omnibus ◽

Differentially Expressed ◽

Support Vector ◽

Hub Genes ◽

Diagnostic Biomarkers

Abstract Preeclampsia (PE) is a disorder of pregnancy that is characterised by hypertension and a significant amount of proteinuria beginning after 20 weeks of pregnancy. It is closely associated with high maternal morbidity, mortality, maternal organ dysfunction or foetal growth restriction. Therefore, it is necessary to identify early and novel diagnostic biomarkers of PE. In the present study, we performed a multi-step integrative bioinformatics analysis of microarray data for identifying hub genes as diagnostic biomarkers of PE. With the help of gene expression profiles of the Gene Expression Omnibus (GEO) dataset GSE60438, a total of 268 dysregulated genes were identified including 131 up- and 137 down-regulated differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs suggested that DEGs were significantly enriched in disease-related biological processes (BPs) such as hormone activity, immune response, steroid hormone biosynthesis, metabolic pathways, and other signalling pathways. Using the STRING database, we established a protein–protein interaction (PPI) network based on the above DEGs. Module analysis and identification of hub genes were performed to screen a total of 17 significant hub genes. The support vector machines (SVMs) model was used to predict the potential application of biomarkers in PE diagnosis with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.958 in the training set and 0.834 in the test set, suggesting that this risk classifier has good discrimination between PE patients and control samples. Our results demonstrated that these 17 differentially expressed hub genes can be used as potential biomarkers for diagnosis of PE.

Download Full-text

Therapeutic Potential of Autologous Adipose-Derived Stem Cells for the Treatment of Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms19124064 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4064 ◽

Cited By ~ 9

Author(s):

Chiara Gardin ◽

Letizia Ferroni ◽

Gloria Bellin ◽

Giuseppe Rubini ◽

Simone Barosio ◽

...

Keyword(s):

Stem Cells ◽

Liver Diseases ◽

Therapeutic Potential ◽

Organ Donor ◽

Canine Model ◽

Cell Populations ◽

Tissue Samples ◽

Promising Alternative ◽

Cell Based Therapy ◽

Starting Point

Currently, the most effective therapy for liver diseases is liver transplantation, but its use is limited by organ donor shortage, economic reasons, and the requirement for lifelong immunosuppression. Mesenchymal stem cell (MSC) transplantation represents a promising alternative for treating liver pathologies in both human and veterinary medicine. Interestingly, these pathologies appear with a common clinical and pathological profile in the human and canine species; as a consequence, dogs may be a spontaneous model for clinical investigations in humans. The aim of this work was to characterize canine adipose-derived MSCs (cADSCs) and compare them to their human counterpart (hADSCs) in order to support the application of the canine model in cell-based therapy of liver diseases. Both cADSCs and hADSCs were successfully isolated from adipose tissue samples. The two cell populations shared a common fibroblast-like morphology, expression of stemness surface markers, and proliferation rate. When examining multilineage differentiation abilities, cADSCs showed lower adipogenic potential and higher osteogenic differentiation than human cells. Both cell populations retained high viability when kept in PBS at controlled temperature and up to 72 h, indicating the possibility of short-term storage and transportation. In addition, we evaluated the efficacy of autologous ADSCs transplantation in dogs with liver diseases. All animals exhibited significantly improved liver function, as evidenced by lower liver biomarkers levels measured after cells transplantation and evaluation of cytological specimens. These beneficial effects seem to be related to the immunomodulatory properties of stem cells. We therefore believe that such an approach could be a starting point for translating the results to the human clinical practice in future.

Download Full-text

Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse

PeerJ ◽

10.7717/peerj.4336 ◽

2018 ◽

Vol 6 ◽

pp. e4336 ◽

Cited By ~ 7

Author(s):

Xufeng Fu ◽

Bin Jiang ◽

Bingrong Zheng ◽

Yaping Yan ◽

Junfeng Wang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Mesenchymal Stem Cells ◽

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Liver Diseases ◽

Pathological Examination ◽

Paracrine Effects ◽

End Stage

Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma). Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs) have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP). The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells) were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the paracrine effects of MSCs may play an important role in the improvement of liver fibrosis.

Download Full-text