Category: Scientific publications

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Glucocorticoids as a brake on cardiac regenerative factors: a novel therapeutic strategy

We are excited to announce our new publication in Nature Cardiovascular Research, in which we describe an innovative strategy to enhance heart regeneration through blockade of the glucocorticoid receptor.

In our study, we demonstrate that glucocorticoids—steroid hormones that are physiologically present in the circulation—play a key role in limiting the responsiveness of cardiomyocytes to major regenerative growth factors and cytokines. Specifically, we show that these hormones act as a true hormonal brake, contributing to the loss of the heart’s regenerative capacity during late postnatal stages and in adulthood.

A central finding of our work is the demonstration that pharmacological blockade of the glucocorticoid receptor can remove this brake, restoring the ability of cardiomyocytes to respond to proliferative stimuli. This approach substantially enhances the effectiveness of growth factor–based regenerative therapies, even in mature hearts.

In preclinical models, we further observed that the combination of a glucocorticoid receptor antagonist with a regenerative factor produces markedly superior results compared with single treatments. This effect is particularly relevant in settings of cardiac damage associated with anthracycline-based cancer therapies, where the combined approach improved cardiomyocyte survival and preserved cardiac function.

Overall, we believe that these findings open new avenues for the development of combined therapeutic strategies aimed at regenerating cardiac tissue and that, if clinically validated, they could have a significant impact on the treatment of heart failure.

Congratulations to Silvia Da Pra and Stefano Boriati, a postdoctoral researcher and a PhD student in our group, who carried out the majority of the experimental work, and thanks to all team members Carmen Miano, Francesca Sacchi, Chiara Bongiovanni, Irene Del Bono and Nicola Pianca for their contributions. We also thank the collaborators who were instrumental to the success of this project, in particular the research groups led by Eldad Tzahor (Weizmann Institute of Science, Israel), Catherine Wilson (University of Cambridge, United Kingdom), and Mattia Lauriola and Carlo Ventura (University of Bologna, Italy).

Go to the full article: : Da Pra S, Boriati S, Miano M, Sacchi F,  Batho C,  Bongiovanni C, Del Bono I, Aharonov A, Pianca N, Tassinari R, Dahir R, Ventura C, Lauriola M, Tzahor E, Wilson C & D’Uva G. Harnessing glucocorticoid receptor antagonism to enhance the efficacy of cardiac regenerative growth factors and cytokines : Nature Cardiovascular Research 2026

Read-only access to the article (no subscription required): https://rdcu.be/e2EN0

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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).

Go to the full article: : Bongiovanni C, Bueno-Levy H, Posadas Pena D, Del Bono I, Miano C, Boriati S, Da Pra S, Sacchi F, Redaelli S, Bergen M, Romaniello D, Pontis F, Tassinari R, Kellerer L, Petraroia I, Mazzeschi M, Lauriola M, Ventura C, Heermann S, Weidinger G, Tzahor E, D’Uva G and BMP7 promotes cardiomyocyte regeneration in zebrafish and adult mice. Cell Reports 2024

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Our review on cardiotoxicity of anticancer therapies is online!

Unfortunately, anticancer drugs can induce side effects on heart tissue. This phenomenon, known as cardiotoxicity, in severe cases, can reduce the quality and life expectancy of cancer patients, regardless of the oncological prognosis.

The good news is that the complex molecular mechanisms responsible for these effects in different classes of anticancer drugs are beginning to emerge, and as a result, potential therapeutic approaches to protect the heart from these effects are beginning to be proposed.

#cardiotossicità #farmaciantitumorali #ricercascientifica #medicina #salute #unibo #irccsmultimedica #conFondazioneCariplo

 

Abstract: Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies.

Go to the original article: Morelli MB, Miano C, Bongiovanni C, Sacchi F, Da Pra S, Lauriola M and D’Uva G. Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection. Frontiers in Cardiovascular Medicine, 2022

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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

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Our article on heart development is out in Nature!

Glad we could be part of this international project on heart development! Congratulations to Gonzalo del Monte Nieto and Richard Harvey!

Abstract: In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction. Defective trabeculation leads to embryonic lethality or non-compaction cardiomyopathy (NCC). There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium, whereas in chicks, chamber wall thickening occurs before overt trabeculation. In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs. Endocardium–myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch and Neuregulin (NRG). Late disruption of the Notch pathway causes NCC5. Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice and the matrix metalloprotease ADAMTS1 promotes trabecular termination, the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Vegfa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease.

Go to the full article: Del Monte-Nieto G, Ramialison M, Adam AAS, Wu B, Aharonov A, D’Uva G, Bourke LM, Pitulescu ME, Chen H, de la Pompa JL, Shou W, Adams RH, Harten SK, Tzahor E, Zhou B and Harvey RP. Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature, 2018

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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

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Our review on the role of CYP1B1 in cancer development is out in Cancer Treatment Reviews!

Abstract: Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.

Highlights:
•CYP1B1 triggers carcinogenesis by activating exogenous and endogenous molecules to reactive species.
•Other CYP1 family members play protecting roles against tumor formation by detoxifying carcinogenic compounds.
•CYP1B1 regulates multiple cell types within the cancer microenvironment, supporting a loop of inflammatory angiogenesis.
•Several chemopreventive phytochemicals are potent and specific CYP1B1 inhibitors.
•Specific CYP1B1 inhibition may translate into clinical chemoprevention/angioprevention approaches.

Go to the full article: D’Uva G, Baci D, Albini A and Noonan DM. Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. Cancer Treatment Reviews, 2017

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Our article on inflammation and cancer resistance to EGFR-targeted therapy is out!

Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A, IL1B and IL8, which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro. This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.

Go to the full article: Gelfo V, Rodia MT, Pucci M, Dall’Ora M, Santi S, Solmi R, Roth L, Lindzen M, Bonafè M, Bertotti A, Caramelli E, Lollini PL, Trusolino L, Yarden Y, D’Uva G* and Lauriola M. A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors. Oncotarget 2016 (*co-last author)

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Our review on steroid hormones and growth factor crosstalk is out in Seminars in Cell & Developmental Biology!

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones (SH) acting through nuclear receptors (NRs), are critical signalling mediators of cellular processes. Deregulations of ERBB and steroid hormone receptors are responsible for several diseases, including cancer, thus demonstrating the central role played by both systems.
This review will summarize and shed light on an emerging crosstalk between these two important receptor families. How this mutual crosstalk is attained, such as through extensive genomic and non-genomic interactions, will be addressed. In light of recent studies, we will describe how steroid hormones are able to fine-tune ERBB feedback loops, thus impacting on cellular output and providing a new key for understanding the complexity of biological processes in physiological or pathological conditions.
In our understanding, the interactions between steroid hormones and RTKs deserve further attention. A system biology approach and advanced technologies for the analysis of RTK-SH crosstalk could lead to major advancements in molecular medicine, providing the basis for new routes of pharmacological intervention in several diseases, including cancer.

Go to the full article: D’Uva G* and Lauriola M*. Towards the emerging crosstalk: ERBB family and steroid hormones. Seminars in Cell & Developmental Biology, 2016 (*co-corresponding authors)

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