The president Giulia Da Re interviews Vittoria Cenni, a researcher at the Institute of Molecular Genetics of CNR in Bologna (https://www.igm.cnr.it/istituto-2/organizzazione/personale/cenni-vittoria/).
Dear Vittoria, we had the fortune of meeting during the International Summit on collagen VI-related pathologies in San Sebastian, Spain. What is your work, and how did you come to study Collagen VI?
After graduating in molecular biology, I focused on protein biochemistry and cell biology, mainly training in Boston and at the University of Modena. Upon returning to Bologna, I applied these technologies to study some diseases of the musculoskeletal system. The laboratory is located at the Codivilla Putti Research Institute at the Rizzoli Orthopedic Institute – IOR, where various musculoskeletal pathologies are treated. This setting led to a true collaboration, allowing me to focus my research on bone and muscle tumors, as well as muscular dystrophies due to genetic mutations. Some years ago, a beautiful collaboration began with Patrizia Sabatelli, an excellent electron microscopist with a significant background in protein matrix deficiency diseases, including collagen VI. Together with Prof. Merlini and Prof. Bonaldo, Patrizia has become a reference in the field of these pathologies. Our collaboration fully exploits the complementarity of our skills. Patrizia, through microscopy investigations, identifies morphological alterations at the cellular and subcellular levels finely. On the other hand, through molecular biology studies, I try to identify the molecular mechanisms underlying these alterations.
Give us an example of how you apply your biomolecular knowledge in your work.
In practice, my studies aim to understand which signaling mechanisms are activated in the cell following the arrival of specific extracellular stimuli, whether chemical (hormones, cytokines, or pro-inflammatory substances) or mechanical (stretching of muscle cells, sliding and compression between cells in tissues, etc.). In the cell, these stimuli are converted into biochemical signals, leading to the controlled modification of specific proteins in a cascade manner. At the end of this cascade, known as “signal transduction,” specific genes responsible for the response to that particular stimulus are activated. This, for example, translates into the modulation of numerous cellular events, including proliferation, differentiation, migration, etc.
We know that you have been recognized for your excellence, and your studies have received significant funding from Cure CMD – Cure Congenital Muscular Disease, the association in the United States for fighting muscular dystrophies.
In the past, our and other laboratories observed alterations in the tendons of patients with collagen VI mutations, as well as in animal models where collagen VI is completely absent. These findings led us to hypothesize that the tendon, the organ connecting muscles to adjacent bones, could be directly involved in the onset of contractions and retractions that afflict patients with these pathologies daily, for which there are currently no definitive cures. In fact, the study funded by Cure CMD aims to determine the morphological and functional modifications of the tendon cells in patients with collagen VI pathologies when stimulated externally. Our hypothesis is that in the cells of Col6 patients, the mutated collagen VI, which is an extracellular protein, may introduce incorrect information into the cell. It’s a bit like not carefully reading the content of a letter delivered to us and making wrong decisions.
But the topic of your studies had never been addressed before?
Tendons are made up of fibers of different collagens, so the role of collagens in ensuring the proper functionality of the tendon and, of course, the muscles, has been known and described for a long time. However, there are no studies specifically highlighting the importance of collagen VI in this context.
But have there been studies on tendons for other neuromuscular pathologies?
No. Studies on tendons in neuromuscular syndromes are very rare, as it is preferable to focus on characterizing the muscle, which is severely compromised. In many myopathies, the shortening of the tendon is considered a consequence of reduced muscle activity. However, our studies on tendon cultures from Col6 patients show that tenocytes have altered motility in addition to a deficit in matrix organization. These studies demonstrate that tendon deficit is primary and is present independently of muscle activity. There are some studies suggesting a replacement of tendon cells with fibroblasts, but this has not been demonstrated in tendon biopsies, which appear unaffected.
In general, I believe it is crucial to study the origin of contractions because they represent a clinical aspect common to many muscle pathologies. Understanding the signaling mechanisms regulating tendon dysfunctions will provide the opportunity to modulate these pathways and start clinical trials to validate targeted therapies.
Tell us more about your presentation at the Col6 International Summit in Spain.
I presented the scientific evidence published so far on the morphological and functional alterations of the tendons in patients with collagen VI deficiency. In parallel, I shared some very promising results that we obtained thanks to the funding from Cure CMD, which are described in a manuscript under review.
What was the most interesting thing you learned from the summit that you didn’t expect?
In general, the activity of the Noelia Foundation. I imagine that initially, it started as a small group of patients and families, but over the years, it has gained a high level of credibility, attracting internationally renowned researchers who are funded through private donations and government entities. In San Sebastian, the Noelia Foundation created a beautiful event where patients and their relatives had the opportunity to interact with clinicians who, in turn, could engage with numerous researchers from various European and American laboratories with diverse expertise. This way of working is undoubtedly winning because it highlights the needs of patients and allows researchers to exchange ideas and perspectives. It is the true essence of scientific research.
Would you like to comment on genetic editing? What do you think?
Assuming it’s not my field of work, I can say that initially, I was very skeptical about the results promised by these technologies. When discussions about DNA or RNA editing started in the past, I couldn’t understand how it was possible to restore the “normal” phenotype in all cells of the organism that have a mutation. However, in recent years, things have changed a lot. Perhaps also because these technologies can be applied to all genetic pathologies, there are many projects on genetic editing currently funded by numerous governmental and/or private associations. This certainly suggests that sensational discoveries are on the horizon. I cannot make predictions about the timing because there are multiple factors to consider and challenges to overcome, but I am optimistic.
What are your plans for the future?
Certainly, to thoroughly investigate the effects of extracellular stimulation on the physiology of tendon cells in patients. We will also try to cross-reference these evaluations with other molecular and functional alterations related to collagen VI deficiency that have already been reported. Naturally, we will continue to seek the necessary funding, especially to hire other researchers who will help us pursue multiple research avenues simultaneously. This will allow us to validate experimental hypotheses more quickly and obtain results in a short time.
Can you explain the collaborative synergy between your CNR laboratory in Bologna and Professor Bonaldo’s laboratory at the University of Padua? How do you communicate and work together?
Prof. Bonaldo and his team of researchers in Padua have extensive experience in collagen VI deficiency diseases. They represent, for us, a constantly updated and fake-news-proof Wikipedia page! In addition to this, they were the first to develop knockout murine models of collagen VI (a murine model refers to a genetically modified mouse affected by collagenopathy) and are happy to share this tool to validate the evidence obtained on human biological samples.
Will you come to the Collagen VI gathering in Bologna next year? You are invited! I don’t know how to thank you; you are a treasure.
Certainly! I can’t wait to publish the data and share them with the community and all of you! See you in Bologna!