cardiac regeneration Archives

May 28, 2024September 8, 2024

BMP7 as a Key to Heart Regeneration: Our Progress

We are thrilled to announce our latest publication in Cell Reports! Our research indicates that a decrease in the production of growth factors, particularly BMP7, during early postnatal development contributes to the loss of regenerative capacity of the mammalian heart.
We demonstrate that BMP7 supports cardiomyocyte proliferation during the neonatal stage, and its administration boosts cardiomyocyte proliferation in postnatal life, even in adulthood, and especially after myocardial infarction. These findings suggest that BMP7 administration holds promise as a therapeutic approach for heart regeneration. Moreover, our study finds support from the zebrafish model, which naturally regenerates injured hearts. In this regard, inhibiting BMP7 impeded cardiomyocyte regeneration post-cardiac injury, while its induction accelerated the process. We believe our findings pave the way for heart regenerative therapies based on the administration of BMP7.
Congratulations to Chiara Bongiovanni for leading the project, and congratulations to the other lab team members Irene Del Bono, Carmen Miano, Stefano Boriati, Silvia Da Pra, Francesca Sacchi, Francesca Pontis, and Ilaria Petraroia for their help and support in experimental activities. We express our gratitude to collaborators who were instrumental in the success of this project, particularly the research groups led by Eldad Tzahor(Weizmann Institute of Science, Israel), Gilbert Weidinger (University of Ulm, Germany), Stephan Heermann (University of Friburg, Germany), Mattia Lauriola, and Carlo Ventura (University of Bologna, Italy).

Original Article Link (open access): https://dx.doi.org/10.1016/j.celrep.2024.114162

October 8, 2021April 15, 2022

Our publication (review) on “direct cardiogenesis” strategies for heart regeneration is online!

Is it possible to reawaken the intrinsic cardiac regenerative potential after major injuries, for example induced by myocardial infarction? We are happy to share our publication (review) on an emerging, promising and rapidly evolving approach for heart regeneration based on stimulating the proliferation of endogenous cardiac muscle cells.

Abstract: Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

Go to the full article: : Bongiovanni C, Sacchi F, Da Pra S, Pantano E, Miano C, Morelli MB and D’Uva G. Reawakening the intrinsic cardiac regenerative potential: molecular strategies to boost dedifferentiation and proliferation of endogenous cardiomyocytes. Frontiers in Cardiovascular Medicine – Cardiovascular Biologics and Regenerative Medicine, 2021

#research #heart #regeneration #cardiomyocyte #proliferation #myocardialinfarction #duvalab

April 13, 2018April 13, 2018

Fellowship opportunity in our lab

We are recruiting a research fellow at MultiMedica ONLUS Foundation (Milan). The contract is for 1 year, starting from June 2018, and potentially renewable for a total of three years.
The project is funded by Cariplo Foundation and the research will be conducted in our laboratory, which forms a bridge between the fields of cancer, cardiotoxicity of anticancer therapies and cardiac regeneration.

The selected research fellow will develop a project on the cardiotoxicity of anti-cancer therapies. Cardio-toxicity is a common side effect of chemotherapy and targeted anti-cancer therapies, strongly impacting on the quality of life and the overall survival, regardless of the oncological prognosis. The goal is to develop strategies for reducing the cardiotoxic side effects of current anti-cancer therapies, while simultaneously improving their efficacy. By employing both breast cancer cells and primary mouse cardiomyocytes cultures in vitro, the research activities will be focused on the role of specific growth factors and receptors on cell differentiation status, and the impact on tumour growth and cardiotoxic side effects. In vivo analysis on mouse models will also be conducted.

Applicants requirements: Applicants must have a molecular-, cell- and biochemistry backgrounds, such as a Master Degree in Biotechnology, Biology or related field. Candidates must have at least one year of experience in a research laboratory. Familiarity with standard molecular biology techniques (Real Time PCR, Western Blot, Immunofluorescence analysis…), as well as the expertise in cardiac and/or tumour biology, are required. Passion for science as well as a positive attitude towards solving problems is required in order to pursue technically challenging and intellectually stimulating projects in the lab.

Other criteria: PhD Degree is not required, but is positively evaluated. Expertise in procedures for the induction of cardiac damage (by cardiotoxic drugs or myocardial infarction) as well as in the analysis of microarray o RNA-seq datasets is a plus factor for the selection process.

How to apply: Applicants should send their CV by email with subject line “Research fellowships at Fondazione MultiMedica ONLUS” to Dr. Gabriele D’Uva (gabriele.duva@multimedica.it). One or more letters of recommendation are welcome, although not strictly required. Interviews will be conducted for selected candidates until the position is filled.

Previous publications relevant to the project:
• D’Uva G et al., ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology, 2015
• D’Uva G and Tzahor E, The key roles of ERBB2 in cardiac regeneration. Cell Cycle. 2015
• Yutzey KE. Regenerative biology: Neuregulin 1 makes heart muscle. Nature, 2015 (News & Views on our article)
• D’Uva G and Lauriola M, Towards the emerging cross-talk: ERBB family and steroid hormones. Seminars in Cell and Developmental Biology, 2016

March 13, 2018May 10, 2018

Our article on heart regeneration is out in Stem Cell Reports!

Happy to have collaborated to this international project on mammalian heart regeneration! Congratulations to Diana Nascimento and her team!

Abstract: So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth. However, thickening of the left ventricle wall, explained by an upsurge in cardiomyocyte proliferation during the initial response to injury, compensated cardiomyocyte loss and supported normal systolic function. Thus, apex resection triggers both regenerative and reparative mechanisms, endorsing this injury model for studies aimed at promoting cardiomyocyte proliferation and/or downplaying fibrosis.

Go to the full article: Sampaio-Pinto V, Rodrigues S, Laúndos T, Silva E, Nóvoa F, Silva A, Cerqueira R, Resende T, Pianca N, Leite-Moreira A, D’Uva G, Thorsteinsdóttir S, Pinto-do-Ó P, Nascimento DS. Neonatal Apex Resection Triggers Cardiomyocyte Proliferation, Neovascularization and Functional Recovery Despite Local Fibrosis. Stem Cell Report, 2018

May 1, 2017January 15, 2018

D’Uva lab receives ERA-CVD grant award on cardiovascular disease

We are very happy to receive a research grant “ERA-CVD Call 2016 for Transnational Research Projects on Cardiovascular Diseases” of European Union’s Horizon 2020 Framework Programme. This grant gives us the opportunity to establish our lab in Italy, in IRCCS MultiMedica (Milan)!

The project, in collaboration with Hubrecht Institute (Netherlands), Ulm University (Germany) and Weizmann Institute of Science (Israel), will investigate heart regeneration using a comparative approach between different species.

Ischemic heart disease, such as myocardial infarction, causes a massive loss of cardiomyocytes and leads to the formation of fibrotic scar tissue, resulting in impaired cardiac function and ultimately, heart failure. Recently, it has been demonstrated that myocardium is naturally regenerated in the human heart. However, the rate of replacement is too low to repair large areas of damaged myocardium. Stimulating the very low intrinsic proliferation rate of cardiomyocytes is a promising strategy for cardiac repair in patients with heart failure. To identify such repair signals, this project will use zebrafish, where cardiomyocyte regeneration occurs naturally, and mice, where it does not. Different possible reasons for the difference in the regenerative capacity of lower vertebrate versus mammals will be explored. The goal is to develop regenerative medicine strategies based on endogenous cardiomyocyte capacities.

June 13, 2015July 13, 2017

Our editorial article on cardiac regeneration is out in Cell Cycle!

Heart injuries such as those induced by acute ischemia can lead to heart failure, the most common cardiac ailment and a serious health problem worldwide. This occurs mainly due to the inability of the mammalian heart to regenerate after injury. Developing strategies to boost cardiac regeneration processes in humans is therefore clinically imperative.

Go to the full article: D’Uva G and Tzahor E. The key roles of ERBB2 in cardiac regeneration. Cell Cycle, 2015

April 6, 2015July 13, 2017

Our article on heart regeneration is out in Nature Cell Biology!

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 ( NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (ca ERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/ β-catenin signalling pathways. Transient induction of ca ERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

Go to the full article: Gabriele D’Uva, Alla Aharonov, Mattia Lauriola, David Kain, Yfat Yahalom-Ronen, Silvia Carvalho, Karen Weisinger, Elad Bassat, Dana Rajchman, Oren Yifa, Marina Lysenko, Tal Konfino, Julius Hegesh, Ori Brenner, Michal Neeman, Yosef Yarden, Jonathan Leor, Rachel Sarig, Richard P Harvey and Eldad Tzahor. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology, 2015