Auswahl der wissenschaftlichen Literatur zum Thema „Direct cardiac reprogramming“

Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate bothin vitroandin vivo. Several experiments show functional improvements in mouse models of myocardial infarction followingin situgeneration of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.

In vivo cardiac reprogramming is a potential therapeutic strategy to replace cardiomyocytes in patients with myocardial infarction. However, low conversion efficiency is a limitation of In vivo cardiac reprogramming for heart failure. In this study, we showed that graphene nanosheets mediated efficient direct reprogramming into induced cardiomyocytes In vivo. We observed that the administration of graphene nanosheets led to the accumulation of H3K4me3, which resulted in direct cardiac reprogramming. Importantly, the administration of graphene nanosheets combined with cardiac reprogramming factors in a mouse model of myocardial infarction enhanced the effectiveness of directly reprogrammed cell-based cardiac repair. Collectively, our findings suggest that graphene nanosheets can be used as an excellent biomaterial to promote cardiac cell fate conversion and provide a robust reprogramming platform for cardiac regeneration in ischemic heart disease.

Forced expression of core cardiogenic transcription factors can directly reprogram fibroblasts to induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. This cardiac reprogramming approach provides a proof of concept for induced heart regeneration by converting a fibroblast fate to a cardiomyocyte fate. However, it remains elusive whether chamber-specific cardiomyocytes can be generated by cardiac reprogramming. Therefore, we assessed the ability of the cardiac reprogramming approach for chamber specification in vitro and in vivo. We found that in vivo cardiac reprogramming post-myocardial infarction exclusively induces a ventricular-like phenotype, while a major fraction of iCMs generated in vitro failed to determine their chamber identities. Our results suggest that in vivo cardiac reprogramming may have an inherent advantage of generating chamber-matched new cardiomyocytes as a potential heart regenerative approach.

The human adult heart lacks a robust endogenous repair mechanism to fully restore cardiac function after insult; thus, the ability to regenerate and repair the injured myocardium remains a top priority in treating heart failure. The ability to efficiently generate a large number of functioning cardiomyocytes capable of functional integration within the injured heart has been difficult. However, the ability to directly convert fibroblasts into cardiomyocyte-like cells both in vitro and in vivo offers great promise in overcoming this problem. In this review, we describe the insights and progress that have been gained from the investigation of direct cardiac reprogramming. We focus on the use of key transcription factors and cardiogenic genes as well as on the use of other biological molecules such as small molecules, cytokines, noncoding RNAs, and epigenetic modifiers to improve the efficiency of cardiac reprogramming. Finally, we discuss the development of safer reprogramming approaches for future clinical application.

L’objectif principal de cette thèse est de développer un nouveau matériau naturel à base de ‎gélatine modifiée par méthacrylation (GelMA) nanofonctionnalisé par l’incorporation de ‎nanoliposomes ou de nanoparticules hybrides molles de type exosome-liposome. Ces ‎matrices hydrogel sont caractérisées d’un point de vue physicochimique et biologique afin ‎d'évaluer leur potentiel en ingénierie tissulaire. Le GelMA est préparé par modification ‎chimique de la gélatine, lorsque des groupements méthacrylate sont fixés sur des groupes ‎latéraux contenant des fonctions amine. Dans une première partie de ce travail, l’influence de ‎la source de la gélatine utilisée (porc ou poisson) et du degré de méthacrylation sur les ‎propriétés physicochimiques et biologiques des hydrogels a été étudiée. Dans une deuxième ‎partie de ce travail, la matrice GelMA a été nanofonctionnalisée par l’incorporation de nanoliposomes, ‎nanoparticules molles et naturelles présentant des propriétés d’auto-assemblage remarquables. Ces vecteurs utilisés notamment dans le domaine médical sont formés de bicouches lipidiques et peuvent transporter et libérer des molécules hydrophobes, hydrophiles ou amphiphiles. Dans ‎cette étude la naringine, une molécule active qui peut guider le processus de différenciation des cellules souches vers la lignée ostéoblastique, a été encapsulée dans les nanoliposomes ‎avant leur incorporation dans la matrice polymérique afin de développer un hydrogel d’intérêt ‎pour des applications en régénération osseuse. Ce matériau nanocomposite a été caractérisé ‎d’un point de vue physicochimique, biologique et le profil de libération de la naringine est ‎étudié. Dans une troisième et dernière partie de ce travail, la matrice GelMA a été nanofonctionnalisée par l’incorporation de nanoparticules hybrides molles de type exosome-liposome. Les exosomes, nanovésicules naturelles sécrétées par les cellules, présentent un intérêt croissant pour l'administration ciblée de médicaments en raison de la présence de récepteurs spécifiques aux cellules sur leur surface. L’hydrogel GelMA-‎nanoparticules hybrides a été caractérisée d’un point de vue physicochimique et biologique pour des applications en ‎reprogrammation cardiaque et a été bioimprimé et microfabriqué avec succès. Les hydrogels GelMA biofabriqués et nanofonctionnalisés avec des nanoliposomes ou ‎des nanoparticules hybrides molles de type exosome-liposome sont des systèmes prometteurs ‎pour la libération contrôlée de molécules bioactives et pour des applications en ingénierie tissulaire
The main objective of this thesis is to develop a new natural material based on methacrylated gelatin (GelMA) nanofunctionalized by the incorporation of nanoliposomes or soft hybrid exosome-liposome nanoparticles. The physicochemical and biological properties of these hydrogel matrices were characterized in order to evaluate their potential use for tissue engineering applications. GelMA is prepared by the chemical modification of gelatin when methacrylate groups are attached to side groups containing amine functions. In a first part of this work, the influence of the gelatin source (pork or fish) and the degree of methacrylation on the physicochemical and biological properties of hydrogels was studied. In a second part of this work, the GelMA matrix was nanofunctionalized by the incorporation of nanoliposomes, which are soft and natural nanoparticles with remarkable self-assembly properties. These well-established drug delivery systems‎ are formed of lipid bilayers and can transport and release hydrophobic, hydrophilic, and amphiphilic molecules. In this study, naringin, an active molecule that can guide the differentiation process of stem cells to the osteoblastic lineage, was encapsulated in nanoliposomes before their incorporation into the GelMA polymeric matrix in order to develop a system of interest for bone regeneration applications. This nanocomposite material was physicochemically and biologically characterized and the release profile of naringin was investigated. In a third and final part of this work, the GelMA matrix was nanofunctionalized by the incorporation of exosome-liposome soft hybrid nanoparticles. Exosomes, natural nanovesicles secreted by cells, are of increasing interest for targeted drug delivery applications due to the presence of cell specific receptors on their surface. The hybrid GelMA hydrogels were physicochemically and biologically characterized for applications in cardiac reprogramming and was successfully bioprinted and microfabricated. Biofabricated GelMA hydrogels nanofunctionalized with nanoliposomes or hybrid exosome-liposome nanoparticles are promising platforms for the controlled release of bioactive molecules and for tissue engineering applications