Mechanical loading plays a critical
role in cardiac pathophysiology.
Engineered heart tissues derived from human induced pluripotent stem
cells (iPSCs) allow rigorous investigations of the molecular and pathophysiological
consequences of mechanical cues. However, many engineered heart muscle
models have complex fabrication processes and require large cell numbers,
making it difficult to use them together with iPSC-derived cardiomyocytes
to study the influence of mechanical loading on pharmacology and genotype–phenotype
relationships. To address this challenge, simple and scalable iPSC-derived
micro-heart-muscle arrays (μHM) have been developed. “Dog-bone-shaped”
molds define the boundary conditions for tissue formation. Here, we
extend the μHM model by forming these tissues on elastomeric
substrates with stiffnesses spanning from 5 to 30 kPa. Tissue assembly
was achieved by covalently grafting fibronectin to the substrate.
Compared to μHM formed on plastic, elastomer-grafted μHM
exhibited a similar gross morphology, sarcomere assembly, and tissue
alignment. When these tissues were formed on substrates with different
elasticity, we observed marked shifts in contractility. Increased
contractility was correlated with increases in calcium flux and a
slight increase in cell size. This afterload-enhanced μHM system
enables mechanical control of μHM and real-time tissue traction
force microscopy for cardiac physiology measurements, providing a
dynamic tool for studying pathophysiology and pharmacology.
The microRNA miR-133a is dysregulated in many types of cancer, but the underlying mechanism remains largely unknown. In this study, we showed that the expression level of miR-133a was reduced in ovarian cancer tissues compared with normal ovaries. Ectopic expression of miR-133a significantly inhibited ovarian cancer cell proliferation and colony formation, and induced G1-phase cell cycle arrest, whereas decreased miR-133a expression dramatically enhanced cell proliferation and colony formation. Importantly, miR-133a overexpression suppressed in vivo tumor growth in nude mice models. Through in silico search, we found that the 3'-untranslated region (UTR) of insulin-like growth factor 1 receptor (IGF1R) contains an evolutionarily conserved miR-133a binding site. miR-133a overexpression repressed IGF1R-3'UTR reporter activity, and reduced the mRNA and protein levels of endogenous IGF1R. Rescue experiments showed that ectopic expression of IGF1R significantly promoted the proliferation of ovarian cancer cells stably overexpressing miR-133a. Taken together, these findings indicate that miR-133a is an important regulator in ovarian cancer, and that its suppressive effects are mediated by targeting IGF1R.
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