Blog with our Expert - Anna Marsano
Author: Martina Konantz
Meet Anna Marsano from the Cardiac Surgery and Engineering Laboratory at the Department of Biomedicine. One of her main research areas is the development and investigation of engineered tissue patches to induce safe and effective cardiac revascularization after myocardial infarction. Her other focus is the development of 3D in vivo and in vitro models to study cardiac maturation and pathophysiology, which can be also used to develop patient-specific treatments. Today she shares her research and vision for in vitro engineered models of cardiac tissue.
Anna Marsano was born in Genova, Italy. She studied Biomedical Engineering at the University of Genova in Italy and then completed a PhD at the Swiss Federal Institute of Technology in Lausanne (EPFL). She then moved to New York City to do a postdoc at Columbia University. In 2014, she joined the Department of Biomedicine as a research group leader. Her work has received several awards, including the Dirk Schäfer Research Prize from the Surgery Department of Basel University Hospital. Among others, her seminal work generating a “heart-on-chip” model, published in 2016, paved the way for further developments in the field. Anna is not only an accomplished scientist but also a mentor who truly enjoys sharing her knowledge with her own students, postdocs and colleagues. She lives in Binningen and enjoys hiking and doing yoga
What is your personal vision of the direction of your field of research? In other words, why is it relevant and what are your main long-term goals?
Unfortunately, the potential of regeneration in the mammalian heart diminuishes soon after birth. Despite significant progress made in this field over the past decades, there is still no effective treatment for myocardial infarction that restores cardiac function or possibly prevents the progression to heart failure.There are three primary approaches in research to treating myocardial infarction. The first involves replacing the non-contractile scar tissue with functional cardiomyocytes. The second focuses on modulating inflammation and ventricular remodelling, promoting angiogenesis, and supporting cardiomyocyte survival to reduce or prevent further scar expansion. The last approach is to mechanically support the heart's pumping function.
To restore the regeneration potential of cardiomyocytes, one strategy involves stimulating them to re-enter the cell cycle, proliferate in large numbers, and then to re-differentiate into a fully functional adult-like cells. To achieve this, researchers are exploring methods such as administration of specific factors (e.g. exosomes or microRNA) or by gene editing techniques. These approaches are inspired by the regenerative abilities of cardiomyocytes in lower vertebrates (like zebrafish or newts) and young mice. Alternatively, researchers are trying to recruit cardiac progenitor cells from the pericardium or resident cells. However, several challenges must be overcome before these approaches can be translated into clinical applications. These include safe and effective delivery of the specific factor, recruitment of sufficient numbers of progenitor cells, and induction of enough cardiomyocytes to proliferate and differentiate into an adult phenotype.
Cardiomyocytes or cardiac progenitor cells can be administered as single cells or in the form of monolayers or three-dimensional cardiac patches. This approach faces major challenges, including the need to control the differentiation stage of pluripotent stem cells into specific cardiac lineages (e.g., pacemaker cells or ventricle cells), to upscale pluripotent stem cell-derived cardiomyocytes, and to achieve complete mechanical and electrical integration and vascularization of the cells/patches with the still-functioning heart. In this regard, significant advances have been made in recent years with respect to upscaling of differentiation protocols for pluripotent stem cells (e.g. by Prof. Eschenhagen and Prof. Zweigerdt), and differentiation into specific cardiac lineages (by Prof. G. Keller).
In my view, the second line of research is particularly relevant because although functional cardiac patches can be generated successfully, strategies to improve microcirculation, reduce fibrosis, and control inflammatory responses would be crucial to ensure the successful survival and integration of the implanted patch into the heart. My own research belongs to this second area.
I believe that in the future it will be essential to have reliable and functional cardiac models to further investigate the mechanisms of cardiac repair and regeneration. While in vitro models have been generated in the past, they often are limited in simulating the complexity and the maturity of the myocardium as a whole tissue and achieving a full adult cardiomyocyte phenotype. Although these models have proven to be valuable in certain applications such as cardiotoxicity testing and mimicking hereditary disease conditions (Prof. Vunijak-Novakovic and Prof. Radisic), they are limited in their ability to fully replicate diseases that affect the entire tissue, such as ventricle remodeling.
In light of these limitations, I am exploring ways to improve the quality of maturation and functionality of cardiomyocytes into the adult phenotype and tissue organization by applying various physical stimuli from clinically relevant cell sources, such as human induced pluripotent stem cell-derived cardiomyocytes. My goal is to create a fully matured engineered cardiac model that can be used to better mimic diseases affecting the entire tissue.
I believe that in the future it will be essential to have reliable and functional cardiac models to further investigate the mechanisms of cardiac repair and regeneration.Anna Marsano
Thinking about this vision - which are your main contributions to the field?
Regarding my contributions to the field, I am currently focused on developing cell-based treatments that can support the survival and restoration of mature and functional cardiomyocytes in the border zone of the infarction thereby, stabilizing cardiac function and potentially preventing the progression to heart failure. Specifically, my contribution is to advance our knowledge of a promising cell source, namely adipose tissue-derived stromal vascular fraction (SVF), which is known to have high angiogenic and repair potential. However, the heterogeneity of the cell composition of SVF and the high intra-donor variability pose challenges for its clinical translation. Therefore, my work aims to better understand and identify the individual components of the cell mixture in SVF that contribute to improve cardiac function. I am studying ways to reduce donor-to-donor variability and improve control of their angiogenic potential once the cell-based patch is implanted in vivo (Cerino et al., 2017; Mytsyk et al., 2021).
In addition to her work in the lab, Anna is also an active reviewer in numerous bioengineering journals and an external scientific expert, e.g. for the European Commission. She is a member of the organizing committee of the Cardioascona EMBO Workshop on Cardiomyocyte Biology (http://www.cardioascona.ch/), the Swiss Society of Biomaterials and Regenerative Medicine (https://ssbrm.ch/).
My other line of research, which aims at developing complex three-dimensional functional cardiac tissue models, is also highly relevant to the development of effective treatment of myocardial (cardiac) infarction (Marsano et al, 2016; Occhetta, et al., 2018; Mainardi et al, 2021; Pisanu et al., 2022). In fact, the generation of reliable and functional in vitro of cardiac engineered tissue is essential for simulating diseases such as myocardial ischemia, studying mechanisms of cardiac repair and regeneration, as well as cardiac maturation.
What are the main challenges in your field of research?
Understanding the mechanisms underlying the observed benefits of cell-based treatments during preclinical studies, and gaining insight into the fate, phenotype, and therapeutic potential of cells or factors delivered to ischemic heart tissue present significant challenges.
Another crucial aspect of cell-based treatments is the successful integration of cardiac cells or patches into the heart, which requires both mechanical and electrical connections with the surrounding healthy heart tissue to form an optimally functional cardiac network. To this end, it is also crucial to induce a dense capillary network to allow survival of the cell-based patch after implantation.
Another significant challenge is to precisely control the differentiation stage of pluripotent stem cells into specific cardiac phenotypes and enhance their maturation to a functional adult-like level. This aspect is of utmost importance not only for generating trustworthy and scientifically sound in vitro cardiac tissue models but also for producing cardiac patches for heart implantation. Healthy and disease models based on poorly differentiated cardiomyocytes can lead to misleading conclusions. To address relevant biological questions about regeneration and damage mechanisms, it is crucial to induce reliable cardiac differentiation into cardiac lineage and a fully contractile adult-like phenotype.
What part of your work as a group leader do you enjoy/appreciate the most?
I truly enjoy interacting with students and scientists. I find their enthusiasm and dedication admirable, especially when confronted with challenging situations. It is incredibly fulfilling to witness their scientific knowledge and critical thinking skills develop over time, and I take great pride in observing their progress.
Last but not least? If we could grant you a scientific “wish”, apart from enough resources to perform your research, what would that be? The sky is the limit…
I would like to see all scientists, especially the younger ones, not having such a hard time and having a fairer, more constructive and supportive work environment where everyone feels valued and is highly motivated to give their best. For instance, I believe that an important step towards achieving these working conditions would be the implementation of shared parental leave policies that better meet the changing societal and family needs.
- Zweigerdt, R., Olmer, R., Singh, H., & Haverich, A. (2014). Scalable expansion of human pluripotent stem cells in suspension culture. Nature Protocols, 9(12), 2743-2757.
- Querdel E, Reinsch M, Castro L, Köse D, Bähr A, Reich S, Geertz B, Ulmer B, Schulze M, Lemoine MD, Krause T, Lemme M, Sani J, Shibamiya A, Stüdemann T, Köhne M, Bibra CV, Hornaschewitz N, Pecha S, Nejahsie Y, Mannhardt I, Christ T, Reichenspurner H, Hansen A, Klymiuk N, Krane M, Kupatt C, Eschenhagen T, Weinberger F. (2021) Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner. Circulation, 18;143(20):1991-2006. doi: 10.1161/CIRCULATIONAHA.120.047904.
- Yang D, Gomez-Garcia J, Funakoshi S, Tran T, Fernandes I, Bader GD, Laflamme MA, Keller GM. Modeling human multi-lineage heart field development with pluripotent stem cells. Cell Stem Cell. 2022 Sep 1;29(9):1382-1401.e8. doi: 10.1016/j.stem.2022.08.007.
- Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, Aggarwal P, Zhang B, Conant G, Ronaldson-Bouchard K, Pahnke A, Protze S, Lee JH, Davenport Huyer L, Jekic D, Wickeler A, Naguib HE, Keller GM, Vunjak-Novakovic G, Broeckel U, Backx PH, Radisic M. A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling. Cell. 2019 Feb 7;176(4):913-927.e18. doi: 10.1016/j.cell.2018.11.042.
- Pisanu A. Reid G, Fusco D, Sileo A, Robles Diaz D, Tahrini H., Putame G. Massai D, Isu G, Marsano A, Bi-zonal cardiac engineered tissues with differential maturation features in a mid-throughput multimodal bioreactor, iScience, 2022
- Mainardi A, Carminati F, Ugolini GS, Occhetta P, Isu G, Robles Diaz D, Reid G, Visone R, RasponiM, Marsano A. A dynamic microscale mid-throughput fibrosis model to investigate the effects of cardiomyocytes on fibroblast activation. Lab on a Chip, 2021
- Occhetta P, Isu G, Lemme M, Conficconi C, Oertle P, Räz C, Visone R, Cerino G, Plodinec M, Rasponi M, Marsano A. A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation. Integr Biol (Camb). 2018.
- Marsano A*, Conficconi C, Lemme M, Occhetta P, Gaudiello E, Votta E, Cerino G, Redaelli A, Rasponi M*. Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues. Lab Chip. 2016. *Corresponding authors.
- Cerino G, Gaudiello E, Muraro MG, Eckstein F, Martin I, Scherberich A, Marsano A. Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells. Sci Rep. 2017