A hallmark of fetal growth restriction (FGR) is restricted placental development and insufficient nutrient supply to the fetus. It has previously been shown that activity levels of telomerase, the enzyme responsible for completing replication of telomeric DNA during cell division, is suppressed in FGR placenta samples as compared to control placenta samples from donors of the same gestational age. Here we examine whether telomere length maintenance is also compromised in FGR placenta samples. Southern analysis of telomere length for placenta and cord blood samples from 32 FGR and 36 control donors, ranging in gestational age from 37 to 40 weeks, revealed significantly shorter telomeres (P≤ 0.001) in FGR placenta samples, but not cord blood samples. Furthermore, analysis of telomerase extracts, RNA and DNA placental samples from donors with and without idiopathic FGR confirmed a direct association between suppression of telomerase activity and reduced telomere length in FGR placenta. In addition, expression levels of markers of telomere-induced senescence, p21, p16 and EF-1α, were significantly elevated in FGR placenta samples (P ≤ 0.01). These observations support a direct affect of reduced telomerase activity levels on the placental pathology associated with FGR.

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2–4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

In various types of stem cells, including embryonic stem (ES) cells and hematopoietic stem cells, telomerase functions to ensure long-term self-renewal capacity via maintenance of telomere reserve. Expression of the catalytic component of telomerase, telomerase reverse transcriptase (Tert), which is essential for telomerase activity, is limiting in many types of cells and therefore plays an important role in establishing telomerase activity levels. However, the mechanisms regulating expression of Tert in cells, including stem cells, are presently poorly understood. In the present study, we sought to identify genes involved in the regulation of Tert expression in stem cells by performing a screen in murine ES (mES) cells using a shRNA expression library targeting murine transcriptional regulators. Of 18 candidate transcriptional regulators of Tert expression identified in this screen, only one candidate, hypoxia inducible factor 1 alpha (Hif1α), did not have a significant effect on mES cell morphology, survival, or growth rate. Direct shRNA-mediated knockdown of Hif1α expression confirmed that suppression of Hif1α levels was accompanied by a reduction in both Tert mRNA and telomerase activity levels. Furthermore, gradual telomere attrition was observed during extensive proliferation of Hif1α-targeted mES cells. Switching Hif1α-targeted mES cells to a hypoxic environment largely restored Hif1α levels, as well as Tert expression, telomerase activity levels, and telomere length. Together, these findings suggest a direct effect of Hif1α on telomerase regulation in mES cells, and imply that Hif1α may have a physiologically relevant role in maintenance of functional levels of telomerase in stem cells.