Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.     

DNA synthesis in glial cells during nerve regeneration

Zusammenfassung Autoradiographie von Gliazellen, welche regenerierende motorische Nervenzellen umgeben, ergab eine stark erhöhte DNA-Synthese in den Gliazellen zwischen dem zweiten und sechsten Tag nach dem Nervenschaden. Morphologisch erscheinen typische Gliaveränderungen mit hochgradiger Hypertrophie der Astrocyten in der zweiten und dritten Woche nach der Operation.     

Inhibition of lens regeneration in the eye of the adult newt,Diemictylus viridescens

Résumé La comparaison immunoéléctrophorétique d'extrait du cristallin de salamandre avec de l'extrait du cristallin de poulet a montré que la différence essentielle réside dans le caractère antigénétique du-cristallin. La régénération du cristallin fut inhibée par les matières extraites du cristallin de salamandre mais non pas par celles qui provenaient du cristallin de poulet.

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This work was supported by a grant from the National Research Council of Canada toD. J. McCallion.     

Metabolism of the snailCryptozona ligulata during regeneration of optic tentacles

Summary The biochemical changes in the hemolymph and tissues were followed during regeneration of the optic tentacles of the snailCryptozona ligulata (Pulmonata-Stylommatophora). There is a remarkable increase in total carbohydrates in hemolymph and tissues and glycogen in tissues at the expense of free amino acids and fatty acids. It is clear that ablation of the optic tentacles stimulates carbohydrate synthesis through glyconeogenic routes. The optic tentacles regenerate completely in 18–21 days.     

RNA-induced biosynthesis of adult haemolobin in Coolye's disease

Riassunto L'introduzione nella cavità midollare dello sterno di soggetti affetti da morbo di Cooley di ARN II° estratto dalle cellule emopoiteiche normali, provoca un netto aumento della quota di HbA nelle cellule della serie eritroblastica.     

Muscle development, regeneration and laminopathies: how lamins or lamina-associated proteins can contribute to muscle development, regeneration and disease

The aim of this review article is to evaluate the current knowledge on associations between muscle formation and regeneration and components of the nuclear lamina. Lamins and their partners have become particularly intriguing objects of scientific interest since it has been observed that mutations in genes coding for these proteins lead to a wide range of diseases called laminopathies. For over the last 10 years, various laboratories worldwide have tried to explain the pathogenesis of these rare disorders. Analyses of the distinct aspects of laminopathies resulted in formulation of different hypotheses regarding the mechanisms of the development of these diseases. In the light of recent discoveries, A-type lamins—the main building blocks of the nuclear lamina—together with other key elements, such as emerin, LAP2α and nesprins, seem to be of great importance in the modulation of various signaling pathways responsible for cellular differentiation and proliferation.     

Cellular events in denervated limb stumps ofAmbystoma larvae during re-innervation and subsequent regeneration

Summary Amputated, denervatedAmbystoma forelimbs undergo cellular dedifferentiation and slight resorption through 12 days post-amputation. Subsequently, as limb stumps become re-innervated, there occur mitosis, blastema formation, and regeneration. The initial increase in the mitotic index in once-denervated limb stumps is closely correlated with the presence of ingrowing nerve fibres.This work was supported by grant PCM 76-11807 from the National Science Foundation.     

Autoradiographic study on incorporation of leucine-H3 in peripheral nerves during regeneration

Zusammenfassung Durch Gabe von radioaktivem Leucin wurde festgestellt, dass im regenerierenden peripheren Nerven die Proteinsynthese in den Schwannschen Zellen deutlich erhöht ist. Verglichen damit ist die Eiweißsynthese in den Axonstümpfen, von denen die Regeneration ausgeht, geringfügig.     

Nucleolar changes in spinal ganglion neurons during the course of axon regeneration

Résumé L'écrasement du nerf sciatique du rat modifie de plusieurs manières les nucléoles des neurones ganglionnaires rachidiens correspondants. Tandis que le volume de la pars amorpha augmente considérablement, le filament nucléolaire ou nucleolonema s'allonge, sa disposition est plus lâche, et sa coloration devient moins évidente. Ce processus atteint son maximum 15 jours après le résection du nerf et il est négligeable 60 jours plus tard. Les changements du nucleolonema et de la pars amorpha pourraient être en rapport avec la synthèse cytoplasmatique.

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Supported by grant No. AF 313-64 of the U.S. Air Force Office of Scientific Research.     

The transverse-axial tubular system of cardiomyocytes

A characteristic histological feature of striated muscle cells is the presence of deep invaginations of the plasma membrane (sarcolemma), most commonly referred to as T-tubules or the transverse-axial tubular system (TATS). TATS mediates the rapid spread of the electrical signal (action potential) to the cell core triggering Ca²⁺ release from the sarcoplasmic reticulum, ultimately inducing myofilament contraction (excitation–contraction coupling). T-tubules, first described in vertebrate skeletal muscle cells, have also been recognized for a long time in mammalian cardiac ventricular myocytes, with a structure and a function that in recent years have been shown to be far more complex and pivotal for cardiac function than initially thought. Renewed interest in T-tubule function stems from the loss and disorganization of T-tubules found in a number of pathological conditions including human heart failure (HF) and dilated and hypertrophic cardiomyopathies, as well as in animal models of HF, chronic ischemia and atrial fibrillation. Disease-related remodeling of the TATS leads to asynchronous and inhomogeneous Ca²⁺-release, due to the presence of orphan ryanodine receptors that have lost their coupling with the dihydropyridine receptors and are either not activated or activated with a delay. Here, we review the physiology of the TATS, focusing first on the relationship between function and structure, and then describing T-tubular remodeling and its reversal in disease settings and following effective therapeutic approaches.     

Influenza infection induces host DNA damage and dynamic DNA damage responses during tissue regeneration

Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of 2 weeks in vivo. We show that influenza induces DNA damage to both, when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci). We show that DNA damage, as well as responses to DNA damage persist in vivo until long after virus has been cleared, at times when there are inflammation associated RONS (measured by xanthine oxidase activity and oxidative products). The frequency of lung epithelial and immune cells with increased γH2AX foci is elevated in vivo, especially for dividing cells (Ki-67-positive) exposed to oxidative stress during tissue regeneration. Additionally, we observed a significant increase in apoptotic cells as well as increased levels of DNA double strand break (DSB) repair proteins Ku70, Ku86 and Rad51 during the regenerative phase. In conclusion, results show that influenza induces DNA damage both in vitro and in vivo, and that DNA damage responses are activated, raising the possibility that DNA repair capacity may be a determining factor for tissue recovery and disease outcome.     

Variations in DNA synthesis and the activities of acid and alkaline deoxyribonucleases during regeneration of planaria (Polycelis tenuis)

Variations of DNA synthesis were established for the first time during planarian regeneration by 32P phosphoric acid incorporation. A first peak of DNA synthesis occurred between the 10th and the 18th hour after sectioning (maximum at 12 hrs.). Subsequently, DNA synthesis increased again progressively after the 24th hour to a plateau between 48 and 72 hrs. after regeneration. Simultaneously, variations of alkaline and acid DNases were determined.     

Carcinogenesis and regeneration in newts

Zusammenfassung Bei Untersuchungen an MolchenTriturus (Diemictylus) viridescens über Carcinogenese und Regeneration ergibt sich, dass während Schwanzregeneration die mit Dibenzanthracen oder Methylcholanthren behandelten Tiere im Unterschied zu nicht regenerierenden keine Geschwulstbildung zeigen. Andererseits hemmen aber carcinogene Stoffe den Regenerationsprozess bedeutend. Carcinogenese und Regeneration sind also verwandte, aber antagonistische Prozesse.