440 publications from this institution
LAMA2-related muscular dystrophy (LAMA2-MD) results from mutations in LAMA2 gene, encoding laminin α-2. It is a congenital disease characterized by muscle wasting, with the most severe version being diagnosed within first few months after birth. To generate LAMA2-DM in vitro model, we excised exon 3 from the LAMA2 gene in our previously derived healthy human induced pluripotent stem cells (hiPSCs). Obtained hiPSCs show expression of pluripotency markers, differentiation capacity into all three germ layers, normal karyotype and lack of LAMA2 expression on mRNA and protein level after differentiation into skeletal myocytes. Accordingly, it may provide novel insight into the molecular basis of LAMA2-MD.
Summary: Background: New blood vessel development can be induced by supplementation with angiogenic growth factors. In some older diabetic or hypercholesterolaemic patients, however, endothelial cells are defective and cannot support angiogenesis. Methods: Endothelial progenitor cells (EPC) can help to overcome this limitation, providing a source of viable endothelial cells. Results: It has been demonstrated that EPC can improve neovascularization in ischaemic hind limb, accelerate blood flow in diabetic mice, and improve cardiac function. Conclusions: In this review, we will summarize the effects of EPC in the treatment for experimental peripheral ischaemia. Zusammenfassung: Grundlagen: Die Entwicklung neuer Blutgefäße kann durch die Gabe von angiogenetischen Wachstumsfaktoren induziert werden. Bei älteren Zuckerkranken oder Hypercholesterinämie-Patienten sind die Endothelzellen geschädigt und können die Angiogenese nicht unterstützen. Methodik: Mit Hilfe der endothelialen Progenitorzellen (EPC) können funktionsfähige Endothelzellen gebildet werden. Ergebnisse: Es konnte gezeigt werden, daß die EPC zu einer Neovaskularisation in ischämischen Extremitäten führt, den Blutfluß bei diabetischen Mäusen und die Herzfunktion verbessert. Schlußfolgerungen: In diesem Review diskutieren wir die Effekte der EPC bei der Behandlung experimenteller peripherer Ischämien.
Angiogenesis is indispensable for the growth of solid tumors and angiogenic factors are also involved in the progression of hematological malignancies. Targeting the formation of blood vessels is therefore regarded as a promising strategy in cancer therapy. Interestingly, besides demonstration of some beneficial effects of novel anti-angiogenic compounds, recent data on the activity of already available drugs point to their potential application in anti-angiogenic therapy. Among these are the statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Statins are very efficient in the treatment of hypercholesterolemia in cardiovascular disorders; however, their effects are pleiotropic and some are not directly related to the inhibition of cholesterol synthesis. Some reports particularly highlight the pro-angiogenic effects of statins, which are caused by low, nanomolar concentrations and are regarded as beneficial for the treatment of cardiovascular diseases. On the other hand, the anti-angiogenic activities, observed at micromolar concentrations of statins, may be of special significance for cancer therapy. Those effects are caused by the inhibition of both proliferation and migration and induction of apoptosis in endothelial cells. Moreover, the statin-mediated inhibition of vascular endothelial growth factor synthesis, the major angiogenic mediator, may contribute to the attenuation of angiogenesis. It has been suggested that the anti-cancer effect of statins can be potentially exploited for the cancer therapy. However, several clinical trials aimed at the inhibition of tumor growth by treatment with very high doses of statins did not provide conclusive data. Herein, the reasons for those outcomes are discussed and the rationale for further studies is presented.
Gene therapy is based on the delivery of exogenous genetic material in order to influence the endogenous genetic components involved in disease development. This new therapeutic approach has been suggested to have great potential in the treatment of insufficient angiogenesis or in prevention of restenosis after balloon angioplasty of atherosclerotic arteries. As both vascular endothelial growth factor (VEGF) and nitric oxide (NO) exert beneficial effects on vascular physiology, we studied the generation of both compounds after in vitro transfection of relevant genes. The plasmid vectors, containing VEGF cDNA were constructed and lipotransfected into vascular smooth muscle cells (VSMC). Transfected cells generated up to a few nanograms of VEGF, which induced proliferation of endothelial cells. VSMC transfected with another plasmid, containing endothelial constitutive NO synthase (ecNOS) cDNA generated micromolar quantities of nitrite. Moreover, such NO-producing cells synthesized significantly more VEGF than VSMC transfected with control plasmids. Thus, the study demonstrated that transfer of VEGF and/or NOS genes to VSMC led to the production of measurable amounts of both VEGF protein and NO. Additionally, we evidenced that NO can enhance the endogenous generation of VEGF. A new protective mechanism of NO has been thus revealed.
Angiogenesis occurring during reparative or pathological processes is driven by various inflammatory mediators that influence the synthesis of growth factors. It has been recognized recently that reactive oxygen species (ROS) and nitric oxide (NO) are important modulators of the synthesis and activity of vascular endothelial growth factor (VEGF), a major angiogenic molecule. Moreover, heme oxygenase-1 (HO-1), a ubiquitous stress-inducible enzyme that is induced by ROS and NO, was recently discovered to be involved in angiogenesis. Genetic overexpression of HO-1 enhanced VEGF synthesis and augmented formation of vascular capillaries, improving the blood flow in ischemic tissues. In addition, by-products of HO-1 exert numerous effects that can also influence angiogenesis in both positive and negative ways. Therefore, the antiinflammatory effects of HO-1 can attenuate the excess formation of blood vessels in inflammatory angiogenesis. In this review, the recent data on the role of HO-1 in angiogenesis are critically discussed. It is suggested that further studies using potent and specific augmentation of HO-1 gene expression by viral vectors, as well as targeted, specific inhibition of HO-1 expression, are required to elucidate fully the complex role of this enzymatic pathway in angiogenesis.
Reprogramming of somatic cells with defined transcription factors which leads to the acquisition of pluripotent phenotype requires many modifications in gene expression profile, metabolism and chromatin structure. MicroRNAs, a short non-coding RNA that inhibit translation of recognized mRNA sequences play an important role in this process. Because of the pleiotropism of their action microRNAs regulate subsequent steps in cellular reprogramming, among others activation of p53, mesenchymal-to-epithelial transition and development of embryonic gene expression profile. Further studies on the function of microRNA in reprogramming can increase our understandbing of generation, maintenance and differentiation of induced pluripotent stem cells.
