Genome-Wide methylation and transcriptome analyses of bone marrow mesenchymal stem cells from osteoporotic patients

RESUMEN: La diferenciación de las células madre mesenquimales (MSCs) es esencial para el mantenimiento de la masa ósea. Nuestro objetivo fue caracterizar las marcas de metilación, la expresión génica (codificante y no codificante de proteína) y la capacidad de diferenciación de las MSC de médula ósea (BMSCs) de pacientes con fracturas de cadera osteoporóticas. Las BMSCs de pacientes con fracturas mostraron una mayor proliferación y una capacidad de diferenciación alterada. Los análisis de metilación de ADN revelaron que la mayoría los sitios diferencialmente metilados se dan en regiones genómicas con actividad potenciadora que a su vez se asociaron con genes expresados diferencialmente enriquecidos en vías relacionadas con la diferenciación osteogénica. Nuestros resultados sugieren que los mecanismos epigenéticos estudiados juegan un papel importante en la determinación del patrón de expresión génica de BMSCs derivadas de pacientes con osteoporosis. Y un mejor conocimiento de estas vías nos permitirá mejorar el metabolismo óseo en la osteoporosis.ABSTRACT: Mesenchymal stem cells (MSCs) osteogenic differentiation is essential for the maintenance of bone mass. The aim of this study was to characterize the DNA methylation marks, gene expression (coding and nonprotein-coding) and the ability to differentiate bone marrow stem cells (BMSCs) from patients with osteoporotic hip fractures. The BMSCs of patients with fractures showed greater proliferation and an altered differentiation capacity. DNA methylation analysis revealed that most differentially methylated sites are in genomic regions with enhancer activity. These enhancer regions were associated with differentially expressed genes, and these genes were enriched in bone related pathways, such as, osteogenic differentiation. Our results suggest that epigenetic mechanisms play an important role in the regulation of gene expression of BMSCs derived from patients with osteoporosis. A better knowledge of these pathways will permit us to improve bone metabolism in osteoporosis.Research carried out in this thesis was mainly developed in the Department of Medicine and Psychiatry of the Faculty of Medicine, University of Cantabria/ Mineral and lipid metabolism group of IDIVAL. The research was funded with grants from the Instituto de Salud Carlos III (PI12/615 and PI16/915). I have been funded by a predoctoral fellowship from the University of Cantabria and the Research Institute of Marques de Valdecilla Hospital (IDIVAL) (CVE-2016-11669)

Cord and cord blood stem cell tissue engineering for therapeutic intervention in liver disease

Liver cirrhosis and/or liver malignancies have been nominated as the 5th leading cause of death worldwide. The WHO reported, in 2006, that 20 million people around the globe suffer from some form or other of severe liver illness. The ultimate fate of end-stage liver disorders is hepatic dysfunction and eventually organ failure. The only curative mode of management for liver failure is liver transplantation, which is subject to many limitations. Novel alternatives, such as artificial and bio-artificial support devices only aid in temporary replacement of some liver function until an organ is available for transplantation. These newer modalities also have drawbacks or remain experimental and still demand further controlled trials to allow proof of concept and safety before transferring them to the bedside. Regenerative medicine and stem cell therapy has recently shown promise in the management of various human diseases. Recent reports of stem cell plasticity and its multipotentiality has raised hopes of stem cell therapy offering exciting therapeutic possibilities for patients with chronic liver disease. With the understanding that stem cells might not just be about making organs ex vivo, but also regenerating a patients own tissues; a concept is now developing to use stem cells to treat patients with serious disease conditions that are terminal or where conventional modes of treatment are insufficient. There exists a choice of stem cells that have been reported to be capable of self-renewal and differentiation to hepato-biliary cell lineages both in vitro and in vivo. These include: rodent and human embryonic stem cells, bone marrow haematopoietic stem cells, mesenchymal stem cells, umbilical cord blood stem cells, foetal liver progenitor cell and adult liver progenitor cells. It may, however, be argued that with a global population of 6 billion people and a global birth rate in access of 130 million per year, the products of birth ,umbilical cord and cord blood, possibly provide the most readily accessible and ethically sound alternative source of stem cells. The differentiated stem cells can be potentially exploited for gene therapy, cellular transplant, bio-artificial liver-assisted devices, drug toxicology testing and use as an in vitro model to understand the developmental biology of the liver. In this study UCB-derived nucleated cells and umbilical cord-derived Mesenchymal stem cells were exploited for liver differentiation ex vivo. These cells were cultured on extracellular matrix (ECM) protein-coated dishes and inserted into ECM incorporated scaffold 3D culture systems. Stimulation with exogenous mitogens and morphogens to induce hepatic histogenesis was experimented. Immunofluorescence analysis revealed the expression of markers specific for: hepatic stem cells (CK-19), hepatoblasts (AFP) and 4 mature hepatic and biliary epithelium markers including: albumin (ALB), and cytokeratin- 18 (CK-18) and cytokeratin-19 (CK-19) and cytokeratin-7 (CK-7) respectively. The differentiated cells displayed several features of hepatic cell kinetics and metabolic activities, including glycogen synthesis, uptake of Indocyanine green dye and cytochrome P450 activity. These cells may prove to have potential in developing cellular therapy for various liver disorders for which the current mode of therapy is inadequate and also provide an adequate in vitro model of parenchymal liver cells in toxicology and in bioartificial liver research.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Biotechnology to Combat COVID-19

This book provides an inclusive and comprehensive discussion of the transmission, science, biology, genome sequencing, diagnostics, and therapeutics of COVID-19. It also discusses public and government health measures and the roles of media as well as the impact of society on the ongoing efforts to combat the global pandemic. It addresses almost every topic that has been studied so far in the research on SARS-CoV-2 to gain insights into the fundamentals of the disease and mitigation strategies. This volume is a useful resource for virologists, epidemiologists, biologists, medical professionals, public health and government professionals, and all global citizens who have endured and battled against the pandemic

Pameran Reka Cipta, Penyelidikan dan Inovasi (PRPI) 2009

PRPI 2009 kini telah memasuki tahun penganjurannya yang ke-7. Pameran penyelidikan di UPM telah bermula sejak tahun 1997 semasa Exhibition & Seminar Harnessing for Industry Advantage. Pada tahun 2002, Pameran Reka Cipta dan Penyelidikan (PRP) buat pertama kali telah diadakan dengan menggunakan konsep pertandingan hasil projek penyelidikan yang telah dijalankan oleh para penyelidik UPM. Kejayaan penganjuran PRP 2002 telah merintis usaha untuk menjadikannya sebagai aktiviti tahunan UPM dan ianya terus berkembang sejajar dengan nama baharunya yang ditukar kepada Pameran Reka Cipta, Penyelidikan dan Inovasi yang bermula penganjurannya pada tahun 2005. Sebagai kesinambungan daripada kejayaan penganjuran PRPI 2006, 2007 dan 2008 yang lalu dan status UPM sebagai salah sebuah Universiti Penyelidikan, PRPI 2009 kali ini yang merupakan pameran penyelidikan yang terbesar di UPM terus dilaksanakan dengan aspirasi dan semangat yang lebih jitu. Pameran ini juga menjadi pelantar kepada para penyelidik untuk mengenengahkan hasil penyelidikan yang dijalankan dan penemuan baharu kepada umum. Di samping itu ianya juga menjadi penanda aras terhadap kualiti sesuatu projek penyelidikan bagi melayakkan para penyelidik UPM untuk menyertai pameran di peringkat kebangsaan dan seterusnya antarabangsa. Adalah diharapkan pelaksanaan PRPI 2009 ini akan dapat menyemarakkan budaya penyelidikan di kalangan staf dan juga pelajar UPM sekaligus menjadikan UPM sebagai Universiti Penyelidikan yang cemerlang di negara ini

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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Conserved temporal ordering of promoter activation implicates common mechanisms governing the immediate early response across cell types and stimuli

The promoters of immediate early genes (IEGs) are rapidly activated in response to an external stimulus. These genes, also known as primary response genes, have been identified in a range of cell types, under diverse extracellular signals and using varying experimental protocols. Genomic dissection on a case-by-case basis has not resulted in a comprehensive catalogue of IEGs. I completed a rigorous meta-analysis of eight genome-wide FANTOM5 CAGE (cap analysis of gene expression) time-course datasets, and it revealed successive waves of promoter activation in IEGs, recapitulating known relationships between cell types and stimuli. I found a set of 57 (42 protein-coding) candidate IEGs possessing promoters that consistently drive a rapid but transient increase in expression following external stimulation. These genes show significant enrichment for known IEGs reported previously, pathways associated with the immediate early response, and include a number of non-coding RNAs with roles in proliferation and differentiation. There was strong conservation of the ordering of activation for these genes, such that 77 pairwise promoter activation orderings were conserved. Leveraging comprehensive CAGE time series data across cell types, I also observed extensive alternative promoter usage by such genes, which is likely to hinder their discovery from previous, smaller-scale studies. The common activation ordering of the core set of early-responding genes I identified may indicate conserved underlying regulatory mechanisms. By contrast, the considerably larger number of transiently activated genes that are specific to each cell type and stimulus illustrates the breadth of the primary response

Advances in Nanomaterials in Biomedicine

Advances in Nanomaterials in Biomedicine” provided a platform for more than 110 researchers from different countries to present their latest investigations in various fields of nanotechnology, new methods and nanomaterials intended for medical applications. Modern achievements in the field of nanoparticle-based diagnostics, drug delivery and the use of various nanomaterials in the treatment of diseases are presented in 11 original articles. The published reviews provide a comprehensive analysis of the current information on the use of nanomedicine in the treatment and diagnosis of cancer and liver fibrosis, in the field of solid tissue engineering and in drug delivery systems