Tissue-Specific Ultra-Short Telomeres in Chronic Obstructive Pulmonary Disease.

Purpose: Telomere biology, especially tissue-specific ultra-short telomeres, might provide a strong contribution to our current knowledge in COPD development as well as a predictive marker for prognosis. To test this hypothesis, we investigated telomere lengths in lung tissue and leukocytes in patients diagnosed with COPD. Patients and Methods: Thirty-two patients were included in the current study. All patients showed a post-bronchodilator ratio of less than 70% post-bronchodilator predicted value of forced expiratory volume in second (FEV1%), mean 56%; range [19% to 86%]. To be able to investigate ultra-short telomeres, universal single telomere length analysis (U-STELA) was used. Results: Our results showed a higher level of the ultra-short telomere presence in bronchoalveolar lavage (BAL) cells when compared to leukocytes with statistical significance t(62)=5.771, p<0.00001. The FEV1% was lower in subjects with ultra-short telomeres in BAL (50.6% vs 81.6%: p<0.001) and in ultra-short telomeres in blood leukocytes (37.3% vs 58.5%: p=0.051) when compared to subjects without ultra-short telomeres in leukocytes. Furthermore, the patients who had ultra-short telomeres in BAL samples were significantly older (p=0.014) than patients who did not have ultra-short telomeres. Ultra-short telomeres in BAL (p=0.05) but not in leukocytes (p=0.33) were associated with FEV1% in a regressions model adjusting for age (p<0.0001), ever smoking (p<0.0001) and sex (p=0.71). The patients with ultra-short telomeres were graded higher in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (p=0.006). Conclusion: This study emphasizes the need to investigate the correct tissue to get a representative evaluation of the stage or advancedness of COPD. To our knowledge, this is the first study to show that there is a correlation between the presence of ultra-short telomeres in lung tissue and COPD severity. Our results suggest that ultra-short telomeres are involved in the molecular pathogenesis of COPD and might be used as a tissue-specific predictive biomarker.

Programming hMSCs into Potential Genetic Therapy in Cancer.

Based on their distinct characteristics, such as self-renewal and differentiation potential, human mesenchymal stem cells (hMSCs) have been proposed as a feasible tool for cancer therapy. The characteristic of hMSCs that can be used in cancer therapy is their ability to home to primary and metastatic tumor sites. Recent studies have shown that use of stem cells obtained from adult tissue may be a novel vehicle for stem cell-mediated cancer therapy with improved antitumor effects. Stem cells have been used as vehicles to deliver various agents to tumor sites in order to decrease the size of the tumor or increase the lifespan of the organism. Genetically modified MSCs have been shown to increase apoptosis and decrease growth and angiogenesis in solid tumors. In this review, we will focus on the potential of the genetically modified hMSC-based genetic therapy that is a combination of stem cell and gene therapy approaches and its potential advantages over current therapies.

Role of TRF2 and TPP1 regulation in idiopathic recurrent pregnancy loss.

Telomeres are the tandem repeats (TTAGGG) present at the ends of the chromosomes that ensure chromosome stability and protect chromosomes from degradation. Telomeres in somatic human cells shorten after every cellular division and are linked to the cellular senescence. In this study we have investigated telomere length and expression of shelterin genes in aborted fetus material from idiopathic recurrent pregnancy losses. Telomere length was measured using Telomere Restriction Fragment Length (TRF) analysis. The gene expression levels for important shelterin complex proteins (TRF1, TRF2, POT1, and TPP1) were determined by Real-time Quantitative Reverse Transcriptase PCR (qRT-PCR). Our results demonstrated down regulation of TRF2 and TPP1 and a strong decline in average telomere length in abort material from women suffering from idiopathic recurrent pregnancy loss. We suggest that shorter telomere length and downregulation of the major shelterin components TRF2 and TPP1 leading to "telomere uncapping", might play a critical role in recurrent pregnancy loss.

Use of U-STELA for Accurate Measurement of Extremely Short Telomeres.

Telomeres are repetitive genetic materials that protect the chromosomes by capping the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in the embryonic stem cells in high concentrations and declines with age. It is still unclear to what extend there is telomerase in adult stem cells, but considering these are the founder cells to the cells of the all tissues in a body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important.Telomere length has been implicated as one of the markers for neoplastic transformation in both in vivo and in vitro studies. During cancerogenesis, telomeres shorten due to high cell turnover and repeats are added by active telomerase or alternative lengthening of telomeres (ALT). This gradual shortening is replication driven and does not necessarily explain the presence of ultrashort telomeres. Ultrashort telomeres are observed when there is a sudden shortening in telomeres not related with cell division and may arise from breaks in telomeres due to oxidative damage and replication slippage.Universal STELA is an accurate method for evaluation of ultrashort telomeres in hMSC-telo1 cells. Compared to TRF assay, U-STELA is developed to overcome several problems in detecting abrupt telomere shortening in a single chromosome.