human-neural-organoids-for-studying-brain-cancer-neurodegenerative

Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases

The lack of relevant in vitro neural models is an important obstacle on medical progress for neuropathologies. Establishment of relevant cellular models ...

Geneva University Hospitals

Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowledge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinson's disease is of particular interest. It is one of the most prevalent neurodegenerative diseases caused by the loss of dopaminergic neurons in the Substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from the progressive decline of efficacy as the disease progresses. Cell therapy application has emerged about two decades ago as a valid therapeutic alternative and recent advances in stem cell research suggest that pluripotent stem cell transplantation may be a promising approach to replace degenerated neurons in Parkinson's disease. Various sources of pluripotent stem cells (PSC) currently tested in animal models of Parkinson's disease have proven their efficacy in relieving symptoms and restoring damaged brain function. This review summarizes and discusses the important challenges that actually must be solved before the first studies of PSC transplantation can be undertaken into humans.

Pluripotent stem cells as new drugs? The example of Parkinson's disease.

The pathogenesis of pulmonary fibrosis is linked to oxidative stress, possibly generated by the reactive oxygen species (ROS) generating NADPH oxidase NOX4. Epithelial cell death is a crucial early step in the development of the disease, followed only later by the fibrotic stage. We demonstrate that in lungs of patients with idiopathic lung fibrosis, there is strong expression of NOX4 in hyperplastic alveolar type II cells.

A key role for NOX4 in epithelial cell death during development of lung fibrosis.

Glioblastoma is a deadly malignant brain tumor and one of the most incurable forms of cancer in need of new therapeutic targets. As some cancers are known to be caused by a virus, the discovery of viruses could open the possibility to treat, and perhaps prevent, such a disease. Although an association with viruses such as cytomegalovirus or Simian virus 40 has been strongly suggested, involvement of these and other viruses in the initiation and/or propagation of glioblastoma remains vague, controversial and warrants elucidation. To exhaustively address the association of virus and glioblastoma, we developed and validated a robust metagenomic approach to analyze patient biopsies via high-throughput sequencing, a sensitive tool for virus screening. In addition to traditional clinical diagnostics, glioblastoma biopsies were deep-sequenced and analyzed with a multistage computational pipeline to identify known or potentially discover unknown viruses. In contrast to the studies reporting the presence of viral signatures in glioblastoma, no common or recurring active viruses were detected, despite finding an antiviral-like type I interferon response in some specimens. Our findings highlight a discrete and non-specific viral signature and uncharacterized short RNA sequences in glioblastoma. This study provides new insights into glioblastoma pathogenesis and defines a general methodology that can be used for high-resolution virus screening and discovery in human cancers. 

Comprehensive metagenomic analysis of glioblastoma reveals absence of known virus despite antiviral-like type I interferon gene response.

While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma.

Extracellular nucleic acids circulate in plasma. They are expected to be present in manufactured blood products eligible for transfusion, but little is known about their biological activity on human cells. The aim of this study is to investigate whether cell-free nucleic acids (CFNAs) are present and biologically active in red blood cell units (RBCUs), fresh frozen plasmas, and platelet concentrates.

Cell-free nucleic acids are present in blood products and regulate genes of innate immune response.

Transfusion-transmitted infections remain a permanent threat in medicine. It keeps the burden of the past, marked by serious infections transmitted by transfusion, and is constantly threatened by emerging viruses. The global rise of immunosuppression among patients undergoing frequent transfusions exacerbates this problem. Over the past decade, criteria for donor selection have become increasingly more stringent. Although routine nucleic acid testing (NAT) for virus-specific detection has become more sensitive, these safety measures are only valuable for a limited number of select viruses. The scientific approach to this is however changing, with the goal of trying to identify infectious agents in donor units as early as possible to mitigate the risk of a clinically relevant infection. To this end, and in addition to an epidemiological surveillance of the general population, researchers are adopting new methods to discover emerging infectious agents, while simultaneously screening for an extended number of viruses in donors. Next-generation sequencing (NGS) offers the opportunity to explore the entire viral landscape in blood donors, the so-called metagenomics, to investigate severe transfusion reactions of unknown etiology. In the not too distant future, one could imagine this platform being used for routine testing of donated blood products.

Article	Year
Pluripotent stem cells as new drugs? The example of Parkinson's disease. International journal of pharmaceutics\| PubMed ID: 19782880	2009
A key role for NOX4 in epithelial cell death during development of lung fibrosis. Antioxidants & redox signaling\| PubMed ID: 21391892	2011
Comprehensive metagenomic analysis of glioblastoma reveals absence of known virus despite antiviral-like type I interferon gene response. International journal of cancer\| PubMed ID: 24347514	2014
Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. Cancer cell\| PubMed ID: 29198914	2017
Cell-free nucleic acids are present in blood products and regulate genes of innate immune response. Transfusion\| PubMed ID: 29664127	2018
Viral Metagenomics of Blood Donors and Blood-Derived Products Using Next-Generation Sequencing. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie\| PubMed ID: 31191194	2019

Olivier Preynat-Seauve

Biography

JoVE Journal Publications

Other Publications