Biologics and cardiac disease: challenges and opportunities

Biologics are revolutionizing the treatment of chronic diseases, such as cancer and monogenic disorders, by overcoming the limits of classic therapeutic approaches using small molecules. However, the clinical use of biologics is limited for cardiovascular diseases (CVDs) , which are the primary cause of morbidity and mortality worldwide. Here, we review the state-of-the-art use of biologics for cardiac disorders and provide a framework for understanding why they still struggle to enter the field. Some limitations are common and intrinsic to all biological drugs, whereas others depend on the complexity of cardiac disease. In our opinion, delineating these struggles will be valuable in developing and accelerating the approval of a new generation of biologics for CVDs

755 Rat engineered heart tissue is a novel in vitro model to evaluate cardiomyocyte proliferation and fibroblast activation after injury

Abstract Aims Adult mammals, including humans, fail to regenerate the majority of the lost cardiomyocytes (CMs) that are replaced with scar tissue after injury. This lack of regenerative response is due to the loss of proliferative capacity of adult CMs which in mice occurs 7 days after birth. An in vitro model that recapitulates these changes has not been developed yet. Using rat engineered heart tissues (rEHTs) we have developed a custom-made cryoinjury system to test the hypothesis that maturation of CMs in EHTs regulates the proliferative response of CMs after injury. Methods rEHT were generated using neonatal rat heart cells. A discrete lesion was produced on the mid-section of mature (Day 18) and immature (Day 6) EHTs using a custom-made system based on liquid nitrogen and a 23G needle and medium was supplemented with EdU for 48 h. Results Cryoinjury in mature EHTs produces a localized injury, preserving their residual contractile activity that does not recover over time. We observed a significant increase of EdU+CMs post injury (6.3 ± 1.9% vs. 10.1 ± 1.6%) without significant changes in Ki67+ and pH3+ CMs suggesting that cryoinjury in mature rEHTs induces DNA synthesis but not CM proliferation. Injury in mature EHTs induced also significant proliferation and activation of fibroblasts with collagen deposition. Interestingly, cryoinjury performed in immature EHTs stimulated a significant proliferative response in CMs Conclusions Similar to adult rodents, we show that cryoinjury induces DNA synthesis in CMs without proliferative response and contractile recovery. On the other hand, cryoinjury in immature EHTs leads to CMs proliferation. Moreover, mature EHT fibroblast response to injury retraces the activation progression of cardiac fibroblast after infarction characterized by proliferation, increase of activation markers, increase of collagen deposition suggesting EHTs as a novel model to investigate the biology of cardiac regeneration upon injury

Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis

Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung. Here, we show that lung endothelial cells secrete angiocrine factors that regulate alveolar cell differentiation. Specifically, we build on our previous data on the anti-fibrotic microRNA-200c and identify the Vascular Endothelial Growth Factor receptor 1, also named Flt1, as its main functional target in endothelial cells. Endothelial-specific knockout of Flt1 reproduces the anti-fibrotic effect of microRNA-200c against pulmonary fibrosis and results in the secretion of a pool of soluble factors and matrix components able to promote epithelial transdifferentiation in a paracrine manner. Collectively, these data indicate the existence of a complex endothelial-epithelial paracrine crosstalk in vitro and in vivo and position lung endothelial cells as a relevant therapeutic target in the fight against pulmonary fibrosis

Preliminary Report on the Second Season of the Italian Archeological Mission in the Eastern Desert of Egypt

International audienc

Preliminary Report on the Second Season of the Italian Archeological Mission in the Eastern Desert of Egypt

International audienc

Preliminary Report on the Second Season of the Italian Archeological Mission in the Eastern Desert of Egypt

International audienc

Role of circulating factors in cardiac aging

Worldwide increase in life expectancy is a major contributor to the epidemic of chronic degenerative diseases. Aging, indeed, simultaneously affects multiple organ systems, and it has been hypothesized that systemic alterations in regulators of tissue physiology may regulate this process. Cardiac aging itself is a major risk factor for cardiovascular diseases and, because of the intimate relationship with the brain, may contribute to increase the risk of neurodegenerative disorders. Blood-borne factors may play a major role in this complex and still elusive process. A number of studies, mainly based on the revival of parabiosis, a surgical technique very popular during the 70s of the 20th century to study the effect of a shared circulation in two animals, have indeed shown the potential that humoral factors can control the aging process in different tissues. In this article we review the role of circulating factors in cardiovascular aging. A better understanding of these mechanisms may provide new insights in the aging process and provide novel therapeutic opportunities for chronic age-related disorders

Engineered heart tissue maturation inhibits cardiomyocyte proliferative response to cryoinjury

The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines

Fulminant Myocarditis Unmasking Adult-Onset Still's Disease and Desmoplakin Truncation

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