Stem cells, a two-edged sword: Risks and potentials of regenerative medicine

The recent advancements in stem cell (SC) biology have led to the concept of regenerative medicine, which is based on the potential of SC for therapies aimed to facilitate the repair of degenerating or injured tissues. Nonetheless, prior to large scale clinical appli- cations, critical aspects need to be further addressed, including the long-term safety, tolerability, and efficacy of SC-based treatments. Most problematic among the risks of SC-based therapies, in addition to the pos- sible rejection or loss of function of the infused cells, is their potential neoplastic transformation. Indeed, SCs may be used to cure devastating diseases, but their specific properties of self-renewal and clonogenicity may render them prone to generate cancers. In this respect, ‘Stemness’ might be seen as a two-edged sword, its bright side being represented by normal SCs, its dark side by cancer SCs. A better understand- ing of SC biology will help fulfill the promise of regen- erative medicine aimed at curing human pathologies and fighting cancer from its roots.

Therapeutic application of stem cells in gastroenterology:An up-date

Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastro-enterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immunemediated conditions,further studies are needed to fully understand the biology of stem cellsand carefully assess their put ativeonco- genicproperties.Moreover,there searchonstemcellsarousesferventethical,socialandpoliticaldebate.TheItalianSocietyofGastroenterologysponsoredaworkshoponstemcellsheldinVeronaduringtheⅩⅥCongressoftheFederationofItalianSocietiesofDigestiveDiseases(March 6-9,2010).Here,we report on the issues discussed,including liver and intestinal diseases that may benefit from stemcell therapy,the biology of hepatic and intestinal tissue repair,and stem cell usage inclinical trials.

Dysregulation of Notch signaling related genes in oral lichen planus

Objective: To investigate a dysregulation of Notch signaling in oral lichen planus(OLP)using public available microarray dataset.Methods: A m RNA expression profiling dataset from Gene Expression Omnibus was downloaded. Differential gene expression between OLP and normal oral epithelium was examined using Network Analyst. The dysregulated genes related to Notch signaling were identified.Results: Thirteen genes in Notch signaling pathway were significantly differential expressed between OLP and normal epithelium. OLP samples significantly increased the m RNA levels of HEYL, APH1 B, CNTN1 and PSEN2. Whilst, ITCH, HES1, TLE2, DLK2,DTX2, NOTCH3, JAG2, RFNG, and SPEN were downregulated in OLP groups.Conclusions: Notch signaling was dysregulated and may participate in pathophysiologic process in OLP.

Adipose tissue-derived mesenchymal stem cells and chitosan/poly(vinyl alcohol)nanofibrous scaffolds for cartilage tissue engineering

Osteoarthritis(OA)has been defined as a chronic inflammatory joint disease characterized by progressive articular cartilage degeneration.Recently growing interest in regenerative medicine,using cell therapy and tissue engineering,where cellular components in combination with engineered scaffolds and bioactive materials were used to induce functional tissue regeneration.In the present study,nanofibrous scaffold based on chitosan(CS)/poly(vinyl alcohol)(PVA)were used to develop biologically functionalized biomaterial to mimic the extracellular matrix,allowing the human adipose tissue derived mesenchymal stem cells(ADSCs)to proliferate and differentiate to chondrogenic cells.The morphology of the nanofibrous mat was examined using field emission scanning electron microscope(FE/SEM).The characteristic functional groups and the nature of the chemical bonds between atoms were evaluated using Fourier transform infrared spectroscopy(FTIR)spectrum.Characterization of the seeded cells was morphologically evaluated by scanning electron microscopy and by flow cytometry for the expression of the stem cell surface markers.The differentiation potential was verified after chondrogenic induction by analyzing the expression of chondrogenic marker genes using real-time(RT PCR).Current study suggest significant potential for the use of ADSCs with the nanofibrous scaffolds in improving the osteoarthritis pathology.

Immunomodulatory and Antioxidativepotentials of adipose-derived Mesenchymalstem cells isolated from breast versusabdominal tissue: a comparative study

Background: Adipose-derived stem cells (ASCs) are considered ideal candidates for both research and cellular therapydue to ease of access, large yield, feasibility, and efficacy in preclinical and clinical studies. Unlike the subcutaneousabdominal fat depot, breast ASCs features are still not well recognized, limiting their possible therapeutic use. ASCswere found to exert immunomodulatory and antioxidative activities for maintaining homeostasis and functionality ofdiseased/damaged tissues. This study aims to investigate the immunomodulatory and antioxidative potentials of breastversus abdominal isolated ASCs to find out which anatomical site provides ASCs with better immunoregulatory andoxidative stress resistance capabilities.Methods: ASCs were isolated from abdominal and breast tissues. Gene expression analysis was conducted for a panelof immunomodulatory and antioxidative genes, as well as adipokines and proliferation genes. Flow cytometric analysisof a group of immunomodulatory surface proteins was also performed. Finally, the significantly expressed genes haveundergone protein-protein interaction and functional enrichment in silico analyses.Results: Our results revealed similar morphological and phenotypic characteristics for both breast and abdominalASCs. However, a significant elevation in the expression of two potent immunosuppressive genes, IL-10 and IDO aswell as the expression of the multifaceted immunomodulatory adipokine, visfatin, was detected in breast versusabdominal ASCs. Moreover, a significant overexpression of the antioxidative genes, GPX1, SIRT5, and STAT3 and theproliferation marker, Ki67, was also observed in breast ASCs relative to abdominal ones. In silico analysis showed thatboth of the differentially upregulated immunomodulatory and antioxidative mediators integratively involved inmultiple biological processes and pathways indicating their functional association.Conclusion: Breast ASCs possess superior immunomodulatory and antioxidative capabilities over abdominal ASCs. Ourfindings shed light on the possible therapeutic applications of breast ASCs in immune-related and oxidative stressassociateddiseases.

An Integrative Meta-analysis of MicroRNAs in Hepatocellular Carcinoma

We aimed to shed new light on the roles of microRNAs （miRNAs） in liver cancer using an integrative in silico bioinformatics analysis. A new protocol for target prediction and functional analysis is presented and applied to the 26 highly differentially deregulated miRNAs in hepatocellular carcinoma. This framework comprises： （1） the overlap of prediction results by four out of five target prediction tools, including TargetScan, PicTar, miRanda, DIANA-microT and miRDB （combining machine-learning, alignment, interaction energy and statistical tests in order to minimize false positives）, （2） evidence from previous microarray analysis on the expression of these targets, （3） gene ontology （GO） and pathway enrichment analysis of the miRNA targets and their pathways and （4） linking these results to oncogenesis and cancer hallmarks. This yielded new insights into the roles of miRNAs in cancer hallmarks. Here we presented several key targets and hundreds of new targets that are significantly enriched in many new cancer-related hallmarks. In addition, we also revealed some known and new oncogenic pathways for liver cancer. These included the famous MAPK, TGFβ and cell cycle pathways. New insights were also provided into Wnt signaling, prostate cancer, axon guidance and oocyte meiosis pathways. These signaling and developmental pathways crosstalk to regulate stem cell transformation and implicate a role of miRNAs in hepatic stem cell deregulation and cancer development. By analyzing their complete interactome, we proposed new categorization for some of these miRNAs as either tumor-suppressors or oncomiRs with dual roles. Therefore some of these miRNAs may be addressed as therapeutic targets or used as therapeutic agents. Such dual roles thus expand the view of miRNAs as active maintainers of cellular homeostasis.

Mutational Analysis of OCT4+ and OCT4− Circulating Tumour Cells by Single Cell Whole Exome Sequencing in Stage I Non-Small Cell Lung Cancer Patients

Circulating tumour cells(CTCs)were enriched in the peripheral blood of four patients with Stage I non-small cell lung cancer(NSCLC).Octamer-binding transcription factor-4 positive(OCT4+)and negative(OCT4−)CTCs were identified and captured by interphase fluorescence in situ hybridisation(iFISH).Single cell whole exome sequencing(WES)was performed and the corresponding bioinformatics data were analysed.OCT4+cells were successfully detected in peripheral blood collected from all four Stage I lung cancer patients.Moreover,the tumour mutational burden(TMB)values observed for OCT4+samples from the same patients were slightly smaller than those of the OCT4−samples;the difference was not statistically significant(P>0.05).Thirteen and six characteristic mutations were found in negative samples and positive samples,respectively.The findings indicate that this methodology provides a potential diagnostic index for the early detection of NSCLC.