Vascular endothelial cells derived from transgene-free pig induced pluripotent stem cells for vascular tissue engineering.

Induced pluripotent stem cells (iPSCs) hold great promise for the treatment of cardiovascular diseases through cell-based therapies, but these therapies require extensive preclinical testing that is best done in species-in-species experiments. Pigs are a good large animal model for these tests due to the similarity of their cardiovascular system to humans. However, a lack of adequate pig iPSCs (piPSCs) that are analogous to human iPSCs has greatly limited the potential usefulness of this model system.

Fully biologic endothelialized-tissue-engineered vascular conduits provide antithrombotic function and graft patency.

Tissue-engineered vascular conduits (TEVCs), often made by seeding autologous bone marrow cells onto biodegradable polymeric scaffolds, hold promise toward treating single-ventricle congenital heart defects (SVCHDs). However, the clinical adoption of TEVCs has been hindered by a high incidence of graft stenosis in prior TEVC clinical trials. Herein, we developed endothelialized TEVCs by coating the luminal surface of decellularized human umbilical arteries with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs), followed by shear stress training, in flow bioreactors.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues.

De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis-Brief Report.

Background: A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of , is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin.

Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy.

Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear.

Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.

Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics.

Epigallocatechin gallate facilitates extracellular elastin fiber formation in induced pluripotent stem cell derived vascular smooth muscle cells for tissue engineering.

Tissue engineered vascular grafts possess several advantages over synthetic or autologous grafts, including increased availability and reduced rates of infection and thrombosis. Engineered grafts constructed from human induced pluripotent stem cell derivatives further offer enhanced reproducibility in graft production. One notable obstacle to clinical application of these grafts is the lack of elastin in the vessel wall, which would serve to endow compliance in addition to mechanical strength.

Methods for Differentiating hiPSCs into Vascular Smooth Muscle Cells.

Despite numerous efforts to generate vascular tissues that recapitulate the physiological characteristics of native vessels, vascular cell source remains one of the principal challenges in the construction of tissue-engineered vascular grafts (TEVGs). Human pluripotent stem cells, therefore, represent an indispensable source to supply a large production of vascular smooth muscle cells (VSMCs) for cell-based therapy. In particular, human induced pluripotent stem cells (hiPSCs) generated from the same individual have opened up new avenues of achieving patient specificity through the derivation of autologous and immunocompatible VSMCs.

An ex vivo physiologic and hyperplastic vessel culture model to study intra-arterial stent therapies.

Conventional in vitro methods for biological evaluation of intra-arterial devices such as stents fail to accurately predict cytotoxicity and remodeling events. An ex vivo flow-tunable vascular bioreactor system (VesselBRx), comprising intra- and extra-luminal monitoring capabilities, addresses these limitations. VesselBRx mimics the in vivo physiological, hyperplastic, and cytocompatibility events of absorbable magnesium (Mg)-based stents in ex vivo stent-treated porcine and human coronary arteries, with in-situ and real-time monitoring of local stent degradation effects.

Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia.

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing.

Efficient Differentiation of Human Induced Pluripotent Stem Cells into Endothelial Cells under Xenogeneic-free Conditions for Vascular Tissue Engineering.

Tissue engineered vascular grafts (TEVGs) represent a promising therapeutic option for emergency vascular intervention. Although the application of small-diameter TEVGs using patient-specific primary endothelial cells (ECs) to prevent thrombosis and occlusion prior to implantation could be hindered by the long time course required for in vitro endothelialization, human induced pluripotent stem cells (hiPSCs) provide a robust source to derive immunocompatible ECs (hiPSC-ECs) for immediate TEVG endothelialization. To achieve clinical application, hiPSC-ECs should be derived under culture conditions without the use of animal-derived reagents (xenogeneic-free conditions), to avoid unwanted host immune responses from xenogeneic reagents.

Xenogeneic-free generation of vascular smooth muscle cells from human induced pluripotent stem cells for vascular tissue engineering.

Development of mechanically advanced tissue-engineered vascular grafts (TEVGs) from human induced pluripotent stem cell (hiPSC)-derived vascular smooth muscle cells (hiPSC-VSMCs) offers an innovative approach to replace or bypass diseased blood vessels. To move current hiPSC-TEVGs toward clinical application, it is essential to obtain hiPSC-VSMC-derived tissues under xenogeneic-free conditions, meaning without the use of any animal-derived reagents. Many approaches in VSMC differentiation of hiPSCs have been reported, although a xenogeneic-free method for generating hiPSC-VSMCs suitable for vascular tissue engineering has yet to be established.

Induced pluripotent stem cell-derived smooth muscle cells increase angiogenesis and accelerate diabetic wound healing.

To assess the potential of human induced pluripotent stem cell-derived smooth muscle cells (hiPSC-SMC) to accelerate diabetic wound healing. hiPSC-SMC were embedded in 3D collagen scaffolds and cultured for 72 h; scaffolds were then applied to diabetic, nude mouse, splinted back wounds to assess healing. Cultured medium after scaffold incubation was collected and analyzed for expression of pro-angiogenic cytokines.

Tissue-Engineered Vascular Grafts with Advanced Mechanical Strength from Human iPSCs.

Vascular smooth muscle cells (VSMCs) can be derived in large numbers from human induced pluripotent stem cells (hiPSCs) for producing tissue-engineered vascular grafts (TEVGs). However, hiPSC-derived TEVGs are hampered by low mechanical strength and significant radial dilation after implantation. Here, we report generation of hiPSC-derived TEVGs with mechanical strength comparable to native vessels used in arterial bypass grafts by utilizing biodegradable scaffolds, incremental pulsatile stretching, and optimal culture conditions.

Extracellular Matrix From Hypertrophic Myocardium Provokes Impaired Twitch Dynamics in Healthy Cardiomyocytes.

Hypertrophic cardiomyopathy (HCM) is often caused by single sarcomeric gene mutations that affect muscle contraction. Pharmacological correction of mutation effects prevents but does not reverse disease in mouse models. Suspecting that diseased extracellular matrix is to blame, we obtained myocardium from a miniature swine model of HCM, decellularized thin slices of the tissue, and re-seeded them with healthy human induced pluripotent stem cell-derived cardiomyocytes.

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a novel missense desmoplakin variant (p.