Antisenescence Therapy Improves Function in a Human Model of Cardiac Fibrosis-on-a-Chip.

Cardiac fibrosis is a significant contributor to heart failure and is characterized by abnormal ECM deposition and impaired contractile function. We have previously developed a model of cardiac fibrosis via TGF-β treatment of engineered microtissues using heart-on-a-chip technology which incorporates human induced pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts. Here, we describe that these cardiac fibrotic tissues expressed markers associated with cellular senescence via transcriptomic analysis.

Modeling Heart Diseases on a Chip: Advantages and Future Opportunities.

Heart disease is a significant burden on global health care systems and is a leading cause of death each year. To improve our understanding of heart disease, high quality disease models are needed. These will facilitate the discovery and development of new treatments for heart disease.

Isolation of ready-made rat microvessels and its applications in effective in vivo vascularization and in angiogenic studies in vitro.

Despite recent advances in the differentiation of human pluripotent stem cells into multiple cell types for application in replacement therapies, tissue vascularization remains a bottleneck for regenerative medicine. Fragments of primary microvessels (MVs) harvested from adipose tissue retain endothelialized lumens and perivascular cell coverage. We have used these MVs to support the survival and engraftment of transplanted human pluripotent stem cell-derived cardiomyocytes, pancreatic progenitors or primary human islets.

A human model of arteriovenous malformation (AVM)-on-a-chip reproduces key disease hallmarks and enables drug testing in perfused human vessel networks.

Brain arteriovenous malformations (AVMs) are a disorder wherein abnormal, enlarged blood vessels connect arteries directly to veins, without an intervening capillary bed. AVMs are one of the leading causes of hemorrhagic stroke in children and young adults. Most human sporadic brain AVMs are associated with genetic activating mutations in the KRAS gene.

A three-dimensional human adipocyte model of fatty acid-induced obesity.

Obesity prevalence has reached pandemic proportions, leaving individuals at high risk for the development of diseases such as cancer and type 2 diabetes. In obesity, to accommodate excess lipid storage, adipocytes become hypertrophic, which is associated with an increased pro-inflammatory cytokine secretion and dysfunction of metabolic processes such as insulin signaling and lipolysis. Targeting adipocyte dysfunction is an important strategy to prevent the development of obesity-associated disease.

Microvascular Dysfunction in Skeletal Muscle Precedes Myocardial Vascular Changes in Diabetic Cardiomyopathy: Sex-Dependent Differences.

Aim: To uncover sex-related microvascular abnormalities that underlie the early presentation of reduced perfusion in leg skeletal muscle in a type II rat model of diabetic cardiomyopathy.

Methods And Results: Diabetes was induced using a non-obese, diet-based, low-dose streptozotocin model in adult female (18 diabetic, 9 control) and male rats (29 diabetic, 11 control). Time-course monitoring over 12 months following diabetes induction was performed using echocardiography, treadmill exercise, photoacoustic imaging, flow-mediated dilation (FMD), histopathology, and immunohistochemistry.

GP2-enriched pancreatic progenitors give rise to functional beta cells in vivo and eliminate the risk of teratoma formation.

Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) can be differentiated into beta-like cells in vitro and in vivo and therefore have therapeutic potential for type 1 diabetes (T1D) treatment. However, the purity of PPs varies across different hPSC lines, differentiation protocols, and laboratories. The uncommitted cells may give rise to non-pancreatic endodermal, mesodermal, or ectodermal derivatives in vivo, hampering the safety of hPSC-derived PPs for clinical applications and their differentiation efficiency in research settings.

State of the field: cellular and exosomal therapeutic approaches in vascular regeneration.

Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis.

Cell-based therapies for vascular regeneration: Past, present and future.

Tissue vascularization remains one of the outstanding challenges in regenerative medicine. Beyond its role in circulating oxygen and nutrients, the vasculature is critical for organ development, function and homeostasis. Importantly, effective vascular regeneration is key in generating large 3D tissues for regenerative medicine applications to enable the survival of cells post-transplantation, organ growth, and integration into the host system.

Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models.

Islet transplantation is a promising treatment for type 1 diabetes (T1D), yet the low donor pool, poor islet engraftment, and life-long immunosuppression prevent it from becoming the standard of care. Human embryonic stem cell (hESC)-derived pancreatic cells could eliminate donor shortages, but interventions to improve graft survival are needed. Here, we enhanced subcutaneous engraftment by employing a unique vascularization strategy based on ready-made microvessels (MVs) isolated from the adipose tissue.

Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells.

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force.

Engineered human cardiac microtissues: The state-of-the-(he)art.

Due to the integration of recent advances in stem cell biology, materials science, and engineering, the field of cardiac tissue engineering has been rapidly progressing toward developing more accurate functional 3D cardiac microtissues from human cell sources. These engineered tissues enable screening of cardiotoxic drugs, disease modeling (eg, by using cells from specific genetic backgrounds or modifying environmental conditions) and can serve as novel drug development platforms. This concise review presents the most recent advances and improvements in cardiac tissue formation, including cardiomyocyte maturation and disease modeling.

A 3-D human model of complex cardiac arrhythmias.

Cardiac arrhythmias impact over 12 million people globally, with an increasing incidence of acquired arrhythmias. Although animal models have shed light onto fundamental arrhythmic mechanisms, species-specific differences and ethical concerns remain. Current human models using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) either lack the higher order tissue organization of the heart or implement unreliable arrhythmia induction techniques.

Transplanted microvessels improve pluripotent stem cell-derived cardiomyocyte engraftment and cardiac function after infarction in rats.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies have shown that most hiPSC-CMs do not survive after transplantation into the ischemic myocardial environment, limiting their regenerative potential and clinical application. We established a method to improve hiPSC-CM survival by cotransplanting ready-made microvessels obtained from adipose tissue.

Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing.

While interstitial fibrosis plays a significant role in heart failure, our understanding of disease progression in humans is limited. To address this limitation, we have engineered a cardiac-fibrosis-on-a-chip model consisting of a microfabricated device with live force measurement capabilities using co-cultured human cardiac fibroblasts and pluripotent stem cell-derived cardiomyocytes. Transforming growth factor-β was used as a trigger for fibrosis.

Endothelium-mediated contributions to fibrosis.

Fibrosis, characterized by abnormal and excessive deposition of extracellular matrix, results in compromised tissue and organ structure. This can lead to reduced organ function and eventual failure. Although activated fibroblasts, called myofibroblasts, are considered the central players in fibrosis, the contribution of endothelial cells to the inception and progression of fibrosis has become increasingly recognized.

Correction to: Type I Diabetes Delays Perfusion and Engraftment of 3D Constructs by Impinging on Angiogenesis; Which can be Rescued by Hepatocyte Growth Factor Supplementation.

[This corrects the article DOI: 10.1007/s12195-019-00574-3.].

Type I Diabetes Delays Perfusion and Engraftment of 3D Constructs by Impinging on Angiogenesis; Which can be Rescued by Hepatocyte Growth Factor Supplementation.

Introduction: The biggest bottleneck for cell-based regenerative therapy is the lack of a functional vasculature to support the grafts. This problem is exacerbated in diabetic patients, where vessel growth is inhibited. To address this issue, we aim to identify the causes of poor vascularization in 3D engineered tissues in diabetes and to reverse its negative effects.

Human Stem Cell-Derived Cardiac Model of Chronic Drug Exposure.

Animal models have been instrumental in providing insight into the molecular basis of disease. While such information has been successfully applied to the study of human disease, this translation would be significantly strengthened by the availability of models based on human cells. This would be particularly important for cardiovascular disease, as the physiology of human cardiomyocytes (CMs) differs significantly from rodents.

Maturation of Human Stem Cell-derived Cardiomyocytes in Biowires Using Electrical Stimulation.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been a promising cell source and have thus encouraged the investigation of their potential applications in cardiac research, including drug discovery, disease modeling, tissue engineering, and regenerative medicine. However, cells produced by existing protocols display a range of immaturity compared with native adult ventricular cardiomyocytes. Many efforts have been made to mature hPSC-CMs, with only moderate maturation attained thus far.

Bioengineering Approaches to Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) represent a potential unlimited cell supply for cardiac tissue engineering and possibly regenerative medicine applications. However, hPSC-CMs produced by current protocols are not representative of native adult human cardiomyocytes as they display immature gene expression profile, structure and function. In order to improve hPSC-CM maturity and function, various approaches have been developed, including genetic manipulations to induce gene expression, delivery of biochemical factors, such as triiodothyronine and alpha-adrenergic agonist phenylephrine, induction of cell alignment in 3D tissues, mechanical stress as a mimic of cardiac load and electrical stimulation/pacing or a combination of these.

Diabetes impairs arterio-venous specification in engineered vascular tissues in a perivascular cell recruitment-dependent manner.

Cell-based tissue engineering is a potential treatment alternative for organ replacement. However, the lack of a robust vasculature, especially in the context of diseases such as diabetes, is a major hindrance to its success. Despite extensive research on the effects of diabetes in angiogenic sprouting, its effects on vessel arterio-venous (AV) specification have not been addressed.

Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis.

We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation.

Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes.

Human pluripotent stem cells (hPSCs)-derived cardiomyocytes (hPSC-CMs) represent a potential indefinite cell supply for cardiac tissue engineering and possibly regenerative medicine applications. However, these cells are immature compared with adult ventricular cardiomyocytes. In order to overcome this limitation, an engineered platform, called biowire, was devised to provide cultured cardiomyocytes important biomimetic cues present during embryo development, such as three-dimensional cell culture, extracellular matrix composition, soluble factors and pacing through electrical stimulation, to induce the maturation of hPSC-CMs in vitro.