Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Mechanisms of physiological and pathological cardiac hypertrophy

Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD105+, CD73+, CD90+, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications. © 2017 International Society for Advancement of Cytometry.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.a.23239

Mammalian MSC from selected species: Features and applications.

Perhaps the most important advance in the field of cell therapy for heart disease has been the recognition that all stem/progenitor cells (both adult and embryonic) fail to engraft in the heart to a significant extent and thus work via paracrine mechanisms. This fundamental advance has led to 4 new paradigms that are discussed in this review and that may importantly shape, or even revolutionize, the future of the field: (1) repeated cell therapy, (2) intravenous cell therapy, (3) immunomodulatory actions of cell therapy, and (4) new cell types. Because virtually all of our current knowledge of cell therapy is predicated on the effects of a single cell dose, the idea that the full therapeutic effects of a cell product require repeated doses is disruptive and has far-reaching implications. For example, inadequate dosing (single-dose protocols) may be responsible, at least in part, for the borderline or disappointing results obtained to date in clinical trials; furthermore, future studies (both preclinical and clinical) may need to incorporate repeated cell administrations. Another disruptive idea, supported by emerging preclinical and clinical evidence, is that intravenously injected cells can produce beneficial effects on the heart, presumably via release of paracrine factors in extracardiac organs or endocrine factors into the systemic circulation. Intravenous administration would obviate the need for direct delivery of cells to the heart, making cell therapy simpler, cheaper, safer, more scalable, and more broadly available, even on an outpatient basis. Although the mechanism of action of cell therapy remains elusive, there is compelling in vitro evidence that transplanted cells modulate the function of various immune cell types via release of paracrine factors, such as extracellular vesicles, although in vivo evidence is still limited. Investigation of the new paradigms reviewed herein should be a top priority because it may profoundly transform cell therapy and finally make it a reality.

New Paradigms in Cell Therapy: Repeated Dosing, Intravenous Delivery, Immunomodulatory Actions, and New Cell Types.

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling.

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development.

Rationale:Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure. Objective:To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials. Methods and Results:CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surfa...

Unique Features of Cortical Bone Stem Cells Associated with Repair of the Injured Heart

Extracellular vesicles (EVs) derived from stem /progenitor cells harbor immense potential to promote cardiomyocyte survival and neovascularization, and to mitigate ischemic injury. However, EVs' parental stem/progenitor cells showed modest benefits in clinical trials, suggesting autologous stem cell/EV quality might have been altered by stimuli associated with the co-morbidities such as hyperglycemia associated with diabetes. Hyperglycemia is a characteristic of diabetes and a major driving factor in cardiovascular disease. The functional role of stem/progenitor cell-derived EVs and the molecular signature of their secreted EV cargo under hyperglycemic conditions remain elusive. Therefore, we hypothesized that hyperglycemic stress causes transcriptome changes in stem/progenitor cell-derived EVs that may compromise their reparative function. In this study, we performed an unbiased analysis of EV transcriptome signatures from 3 different stem/progenitor cell types by RNA sequencing. The analysis revealed differential expression of a variety of RNA species in EVs. Specifically, we identified 241 common-dysregulated mRNAs, 21 ncRNAs, and 16 miRNAs in three stem cell-derived EVs. Gene Ontology revealed that potential function of common mRNAs mostly involved in metabolism and transcriptional regulation. This study provides potential candidates for preventing the adverse effects of hyperglycemia-induced stem/progenitor cell-derived EV dysfunction, and reference data for future biological studies and application of stem/progenitor cell-derived EVs.

https://www.mdpi.com/2073-4409/9/9/2098/pdf

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells.

Rationale: G protein–coupled receptor kinases (GRKs) are dynamic regulators of cellular signaling. GRK5 is highly expressed within myocardium and is upregulated in heart failure. Although GRK5 is a critical regulator of cardiac G protein–coupled receptor signaling, recent data has uncovered noncanonical activity of GRK5 within nuclei that plays a key role in pathological hypertrophy. Targeted cardiac elevation of GRK5 in mice leads to exaggerated hypertrophy and early heart failure after transverse aortic constriction (TAC) because of GRK5 nuclear accumulation. Objective: In this study, we investigated the role of GRK5 in physiological, swimming-induced hypertrophy (SIH). Methods and Results: Cardiac-specific GRK5 transgenic mice and nontransgenic littermate control mice were subjected to a 21-day high-intensity swim protocol (or no swim sham controls). SIH and specific molecular and genetic indices of physiological hypertrophy were assessed, including nuclear localization of GRK5, and compared with TAC. Unlike after TAC, swim-trained transgenic GRK5 and nontransgenic littermate control mice exhibited similar increases in cardiac growth. Mechanistically, SIH did not lead to GRK5 nuclear accumulation, which was confirmed in vitro as insulin-like growth factor-1, a known mediator of physiological hypertrophy, was unable to induce GRK5 nuclear translocation in myocytes. We found specific patterns of altered gene expression between TAC and SIH with GRK5 overexpression. Further, SIH in post-TAC transgenic GRK5 mice was able to preserve cardiac function. Conclusions: These data suggest that although nuclear-localized GRK5 is a pathological mediator after stress, this noncanonical nuclear activity of GRK5 is not induced during physiological hypertrophy.

/pdf/differential-role-of-g-protein-coupled-receptor-kinase-5-in-1vp215e3tn.pdf

Differential Role of G Protein-Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy.

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Unique Features of Cortical Bone Stem Cells Associated with Repair of the Injured Heart

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells.

Differential Role of G Protein-Coupled Receptor Kinase 5 in Physiological Versus Pathological Cardiac Hypertrophy.