Craig A. Simmons

Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by the thickening of the heart muscle. Mutations in genes encoding contractile proteins, such MYBPC3 and MYH7 account for over half of patients with familial HCM. MicroRNAs (miRNAs) are pivotal regulators of gene expression that may influence disease progression. Despite their potential significance, there is a scarcity of published data on miRNAs in HCM. Induced pluripotent stem cells (iPSCs) have emerged as valuable tools for modeling various cardiovascular diseases, including HCM. However, the miRNA expression profiles associated with HCM remain largely unexplored within iPSC models. Investigating the differential expression of miRNAs in HCM patients offers a promising avenue to identify potential therapeutic targets for individuals affected by this condition. In this study, we performed an unbiased screen using a microarray (NanoString Technologies) that contained 798 miRNAs to identify differentially expressed miRNAs in iPSC-cardiomyocytes (CM) and myocardial tissues derived from healthy donors and HCM patients with MYBPC3 and MYH7 mutations, identifying miR-9-5p as significantly downregulated in all HCM iPSC-CM and myectomy tissue compared to control. KEGG pathway analysis of gene targets using miRTarBase and g:Profiler revealed that miR-9-5p regulates genes in the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance pathway, which is involved in hypercontractility associated with HCM. Modulation of miR-9-5p expression in vitro using mimics significantly reduced cardiomyocyte size and contractility of MYBPC3 mutant iPSC-CMs whereas healthy control iPSC-CMs treated with antagomiRs exhibited hypertrophy. Our findings identify miR-9-5p as a regulator of cardiomyocyte hypertrophy and contractility, and suggest the miR-9-5p/EGFR tyrosine kinase inhibitor resistance axis as a potential therapeutic target to mitigate hypertrophy and hypercontractility exhibited in HCM.

Pulmonary artery compliance and stiffness are increasingly recognized as contributors to outcomes in pulmonary arterial hypertension (PAH). We report significant associations between main pulmonary artery (MPA) pulsatility and gold standard measures of MPA stiffness, components of right ventricular (RV) afterload, function, and RV-PA coupling in experimental and in patients with iPAH. Our findings suggest that MPA pulsatility is a simple, accessible surrogate to MPA stiffness that may facilitate the assessment of prognostically important factors in PAH.

Burn injury remains a major clinical challenge, causing substantial morbidity, disability, and reconstructive burden. Although autografts remain the gold standard, their use is limited by donor-site scarcity, highlighting the need for patient-specific skin substitutes that combine structural support with regenerative bioactivity. Here, we developed a stem cell-laden 3D-bioprinted skin substitute comprising porcine skin-derived decellularized extracellular matrix (dECM) bioink loaded with autologous burn-derived mesenchymal stem cells (BDMSCs), an innovative and potent source isolated from discarded burn skin, together with a polyurethane/silver nanoparticle supportive layer. The dECM bioink retained extracellular matrix components and regenerative growth factors, supported high-fidelity bioprinting, promoted BDMSC survival, adhesion, migration, infiltration, and proliferation, and supported native-like cell–matrix interactions. In a porcine third-degree burn model, dECM-PU/Ag+BDMSC constructs enhanced epithelialization, collagen maturation, dermal organization, and vascular maturation while reducing contraction, inflammatory infiltration, and fibrotic remodeling. Overall, this platform advances a personalized stem cell-based bioengineered skin substitute for severe burn repair.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms, as well as testing drug safety and efficacy. However, current hiPSC-CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targeted culture media and organoid formats have been identified as potential high-yield contributors to improve CM maturation. This study presents an hiPSC-CM maturation medium formulation, designed using a differential evolutionary approach targeting metabolic functionality for iterative optimization. Relative to existing high-performing reference formulations, our medium significantly matured morphology, Ca²⁺ handling, electrophysiology, and metabolism, which was further validated by multi-omic screening, for cells in either pure or co-cultured microtissue formats. Together, these findings not only provide a reliable workflow for highly functional hiPSC-CMs for downstream use, but also demonstrate the power of high-dimensional optimization processes in evoking advanced biological function in vitro.

Background: Aortic microstructure-function relationships and the pathophysiology of how medial degeneration leads to aortic dissection remain poorly defined. We aimed to determine how degeneration of individual components of the extracellular matrix (ECM), namely elastin, collagen, and proteoglycans, influence biomechanical properties of aortic tissue through an improved, disease-motivated enzymatic digestion framework. Methods: Porcine aortic tissue was sectioned into 200 µm thick samples in the media, and progressively digested with elastase or collagenase for selective degradation of these ECM components. Full thickness human aortic tissues were treated with chondroitinase, hyaluronidase, and heparinase to completely remove proteoglycans. Biomechanical characterization was performed using planar biaxial tensile testing, from which low- and high-strain modulus, transition-zone behaviour, strain-energy density, and energy loss were derived. Degree of elastin fiber degradation was analyzed using two photon excitation fluorescence imaging. Analysis of collagen degradation was performed using picrosirius red staining under brightfield and polarized light. Alcian blue staining was used to evaluate proteoglycan content. Results: Induced fragmentation and disorganization of elastin fibers reduced low-strain load bearing capacity, evidenced by reduced low-strain modulus, strain-energy density, and transition zone stress, along with reduced energy loss. Targeted collagen disorganization similarly reduced strain-energy density and decreased strain at the onset of transition, consistent with premature collagen recruitment, and was accompanied by reductions in high strain modulus and energy loss with increasing collagen degradation. Proteoglycan removal decreased energy loss and was found to modulate low- and high-strain behaviour, including reduced strain-energy density and strain at onset of transition, and increased high strain modulus. Conclusions: Through targeted modelling of ECM degenerative features on aortic tissue mechanics, we have identified distinct disease-associated biomechanical roles for major matrix constituents, with overlapping effects. These findings delineate mechanical consequences of component-specific matrix degeneration while underscoring the complex, multifactorial nature of structure-function relationships in aortic disease.

Heart failure is a leading cause of morbidity and mortality, and fluid congestion complicates its management. Conventional home-monitoring methods, such as

The function of the heart is intrinsically linked to its mechanical properties and the contractile force generated by cardiac muscle cells (cardiomyocytes). Contractility is the composite ability to functionally contract, especially in a coordinated fashion on a tissue and organ scale, and to modulate the force and velocity of this contraction in accordance with the paced rate, as well as the applied preload and afterload. Reduced contractility is a major concern in clinical contexts, such as heart failure and cardiomyopathy. Despite significant advances in research and therapeutic interventions, controlling cardiomyocyte contractility remains a substantial challenge. A growing body of research highlights that biophysical cues, particularly microenvironment stiffness, play a crucial role in regulating myocardial contractility at both cellular and tissue levels. Here, we explore the tissue forming cardiac contractile, and specifically that of the ventricles, detailing the roles of excitation–contraction coupling and the role of mechano-electric feedback, as well as mechanisms of loss of function in relevant examples of hereditary or acquired disease. We further integrate how sarcomeric structure and its dynamic remodeling contribute to these regulatory processes, emphasizing their importance in both physiological load adaptation and disease-associated dysfunction. We then review methods of measurement of myocardial stiffness and modeling across different species and experimental setups. Finally, we examine the cellular and molecular mechanisms that integrate these processes and their potential applications in regulating cardiac contraction. This review aims to foster interdisciplinary approaches to advancing cardiac physiology and disease research.

Drug discovery efforts in neurological diseases, such as Alzheimer’s disease (AD), have had particularly poor outcomes due to the lack of models that recapitulate drug interactions at the cerebral vasculature. There is an unmet need to develop physiologically relevant models to study the impacts of blood flow-induced shear stress. In this work, we use a microfluidic platform to model the cerebral vasculature in AD using patient-derived brain endothelial-like cells (BECs). Induced pluripotent stem cells derived from a patient with familial AD (PSEN-2 N141I) and an unaffected control line were differentiated into BECs (AD2-BEC and fControl-BEC, respectively). BECs were exposed to static conditions or 12 dynes/cm ² of shear stress for 72 h prior to assessment of barrier permeability using fluorescent tracer assays, monocyte adhesion, and efflux transport function using receptor-inhibition assays. Upon shear conditioning, BECs demonstrated shear responsiveness through greater cell alignment in the direction of flow. AD2-BECs demonstrated reduced capacity for efflux transport by p-glycoprotein (P-gp), breast cancer resistant protein (BCRP), and multidrug resistant protein (MRP1) compared to controls (fControl-BECs, p = 0.0017, p = 0.0004, p = 0.0002, respectively). Upon application of shear conditioning, impairments to efflux transport in AD2-BECs were ameliorated. AD2-BECs also exhibited increased monocyte adhesion (2.2 ± 0.4-fold; p < 0.0001) which was further reduced by the application of shear stress in both lines. Taken together, these observations suggest the lack of shear stress exacerbates altered BEC phenotype in fAD. To our knowledge, we present the first in depth functional characterization of in vitro AD patient-derived BECs in both static and physiologically relevant shear conditions in which lack of shear reveals dysfunction of the cerebral endothelium in AD relevant to drug transport and immune cell trafficking.