Séminaires et conférences

More information on Abigail Mackey ‘s webpage and CV.

In this seminar, the so-called overlap myositis will be highlighted.

I will first address, anti-synthestase syndromes as a classical example of this group where a typical form of myositis is associated with characteristic skin lesions and interstitial lung disease. This group is an entity on its own and can well be characterized based on the additional typical presence of t-RNA-synthetase autoantibodies like anti-Jo1. We have recently identified presence of plasma cells in the skeletal muscle tissue of these patients. Here I will present our recent results showing a highly specialized immunological niche as extra medullary immunological niche for plasma cells and activated B cells. It contains alkaline phosphatase-positive perimysial fibroblasts, CD138+ plasma cells and CXCL12+ and CXCL13+CD20+ B cells. We localize these cells close to CD68+MHC cl. II+CD169+ macrophages and define the MHC cl. I+ and MHC cl. II+ MxA negative type II interferon driven milieu of myofiber activation. Overall, we provide a conceptual framework for antibody producing cells residing in an extramedullary niche and self-perpetuating an autoimmune process in the skeletal muscle.

Second, I will focus briefly on Systemic sclerosis, a chronic disease of connective tissues characterized by fibosis, vasculopathy and autoimmunity. Affected patients show signs of the skin, internal organs and sometimes overlap myositis. The vasculopathy is considered obliterative but the pathogenic basis is not known to date.

We have applied a new electron microscopical technique called large scale electron microscopy allowing a ‘pan and zoom’ approach similar to ‘google earth’ viewing.

This analysis allows to study >1000 capillaries of patients and controls, highlighting reduplications of basement membranes endothelial activation and pericytes proliferations

We show that this type of ultrastructural changes is specific for a subtype of scleromyositis and discus possible pathogenic mechanisms.

Summary

WhiteLab Genomics is a company specialized in the development of an Artificial Intelligence platform dedicated to the field of genomic medicine. Today we use AI and our specialized Applications team to come up with optimized solutions to overcome both technical and scientific challenges. We have developed an AI platform dedicated to the field of gene and cell therapy, which helps our customers accelerate and optimize their R&D programs, along different phases. We have developed specific datasets in the field of AAV.
Having access to a wide spectrum of technologies, we also develop and execute customized molecular assays, assisting research teams in their genome engineering and gene and cell therapy programs.

Despite a massive body of knowledge which has been produced related to the mechanisms guiding muscle regeneration, great interest still moves the scientific community toward the study of different aspects of skeletal muscle homeostasis, plasticity, and regeneration. Indeed, the lack of effective therapies for several physio-pathologic conditions suggests that a comprehensive knowledge of the different aspects of cellular behavior and molecular pathways, regulating each regenerative stage, has to be still devised. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite cells, as well as other precursor cells, whose activity is strictly dependent on environmental signals. However, muscle regeneration is severely compromised in several pathological conditions due to either the progressive loss of stem cell populations or to missing signals that limit the damaged tissues from efficiently activating a regenerative program. It is, therefore, plausible that the loss of control over these cells fate might lead to pathological cell differentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. The basis of muscle regeneration and the impact of cytokines and growth factors on the physiopathology of skeletal muscle will be discussed.

Read more information on Antonio Musarò on his biosketch.

Marco Narici (PhD) is Professor in Physiology at the University of Padova, Italy. He worked as researcher at the Rodolfo Margaria Laboratory, University of Milan, Italy, and took up the position of Assistant Professor at the Medical Research Centre of Geneva University, CH (1994-96). In 1999 he moved back to the UK as Professor in Physiology of Ageing at Manchester Metropolitan University where he was Director of the Institute of Research into Human Movement. In 2012, he was appointed as Professor in Clinical  at the University of Nottingham to work at the MRC ARUK Centre for Musculoskeletal Ageing. In 2017 he moved back to Italy, to the University of Padova where he took the chair in Physiology at the School of Medicine. He has been coordinator of the EC FP5 project BETTER AGEING and leader of two WPs of FP7 Project MYOAGE, he has been part of EC Framework 7 Advisory Panels for Ageing Research (LinkAge, WhyWeAge) and was President of the European College of Sport Science (2013-15). He has published over 230 peer reviewed journal articles (H-factor 64) and book chapters. His present work and interests are focused on the mechanisms of remodeling of human neuromuscular system with exercise, inactivity (including spaceflight) and ageing. He is presently coordinating the NeuAge PRIN Project funded by the Italian Ministry of Education, University and Research (MIUR) focusing on the Mechanisms of Neuromuscular Ageing and its Functional Implications.

Read more information on Marco Narici’s research group.

Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Therefore, we developed an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrated different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients’ cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Finally, additional optimization of therapeutic transgene, CRISPR-Cas9 tools and donor DNA delivery further improve efficiency and safety of the approach.

Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.

You can find more information on Mario Amendola on his  Biosketech.

Skeletal muscle and bone exhibit great capacities to regenerate due to tissue-specific stem cells, i.e. satellite cells and skeletal stem cells from periosteum and bone marrow. However, bone fails to heal properly in 10% of bone injuries and delayed healing is increased to 40% in patients with soft tissue damage associated with bone fracture. The role of skeletal muscle in bone repair is well recognized clinically but the underlying cellular and molecular mechanisms are poorly understood. Muscle regulates the inflammatory environment of fracture and muscle satellite cells are providing a source of growth factors for bone repair.

We show that mesenchymal progenitors residing in skeletal muscle adjacent to bone also participate in cartilage and bone formation during bone regeneration. We used single cell RNAseq analyses to characterize the skeletal muscle mesenchymal progenitors, their response to bone injury and the impact of musculoskeletal trauma on the cellular response to injury. The results elucidate the role skeletal muscle during bone repair as a source of mesenchymal progenitors contributing to bone repair, and as a mediator of initial fibrotic response and fibrotic remodelling in bone repair. The findings suggest that new pharmacological and cell-based approaches can be developed to improve musculoskeletal regeneration by targeting skeletal muscle adjacent to bone.

Read more information on Céline Colnot’s research group and on her biosktech.

You can find more information on Rashmi Khotary on his  Biosketech and on his website.

Summary

In response to injury, Muscle Stem Cells (MuSCs) exit quiescence, proliferate and differentiate to form new myofibers, while also repopulating the stem cell niche in preparation for future injuries. The transitioning between cell fates that allow MuSCs to regenerate the muscle fibers involves temporal ordered changes in gene expression that occur in response to environmental cues. The environmental cues are interpreted by the epigenetic machinery in the cell to establish transcriptional permissive or transcriptional repressive states at individual genes. The Dilworth lab is working to understand the role for different epigenetic enzymes in regulating the transitions between MuSC cell fates. In this seminar, characterization of the role for the H3K27me3 demethylase JMJD3 and the transcription elongation factor NELF in regulating MuSC-mediated regeneration will be presented.

Read more on Jeffrey Dilworth’s biosketch

Our lab aims to identify the mechanisms controlling cell fate decisions during cellular differentiation, conversion and reprogramming, and how such processes are affected by genetic mutations of key regulatory proteins including transcription factors. To achieve this goal he proposes to integrate descriptive, functional and single-cell genomics to  dissect how genetic elements and their variants impinge on the temporal and spatial control of gene expression.

Short CV:

Academics:

• Oct 07 – Jul 11 Microsoft Research PhD student – Lab of Irene Bozzoni
• Oct 11 – Feb 17 Research Fellow (Human Frontier Science Program) – Lab of Alex Meissner and Eric Lander
• Feb 17 – TIGEM Assistant Investigator / Armenise/Harvard Fellow / Rita-Levi Montalcini Assistant Professor of Molecular Biology at the University of Naples « Federico II »

Research Grants:

• 2017 – Rita Levi-Montalcini Assistant Professorship Grant (Tenure-Track)
• 2017 – European Research Council (ERC) Starting Grant
• 2017 – Telethon Foundation Start-up Grant
• 2017 – Armenise/Harvard Career Development Award

Research Topics:

• Single Cell Genomics
• Stem Cell Reprogramming and Transdifferentiation
• High-Throughput dissection of CIS regulatory elements and TFs

More information on his website