Curi Cytostretcher — Peer-Reviewed Publications

Combinatorial extracellular matrix cues with mechanical strain induce differential effects on myogenesis in vitro

Abstract: Skeletal muscle regeneration remains a clinical unmet need for volumetric muscle loss and atrophy where muscle function cannot be restored to prior capacity. Current experimental approaches do not account for the complex microenvironmental factors that modulate myogenesis. In this study we developed a biomimetic tissue chip platform to systematically study the combined effects of the extracellular matrix (ECM) microenvironment and mechanical strain on myogenesis of murine myoblasts. Using stretchable tissue chips composed of collagen I (C), fibronectin (F) and laminin (L), as well as their combinations thereof, we tested the addition of mechanical strain regimens on myogenesis at the transcriptomic and translational levels. Our results show that ECMs have a significant effect on myotube formation in C2C12 murine myoblasts. Under static conditions, laminin substrates induced the longest myotubes, whereas fibronectin produced the widest myotubes. Combinatorial ECMs showed non-intuitive effects on myotube formation. Genome-wide analysis revealed the upregulation in actin cytoskeletal related genes that are suggestive of myogenesis. When mechanical strain was introduced to C + F + L combinatorial ECM substrates in the form of constant or intermittent uniaxial strain at low (5%) and high (15%) levels, we observed synergistic enhancements in myotube width, along with transcriptomic upregulation in myosin heavy chain genes. Together, these studies highlight the complex role of microenvironmental factors such as ECM interactions and strain on myotube formation and the underlying signaling pathways.

Originally Published in: Biomaterials Science (2023) (Link to Paper)

Curi CytostretcherArianna KieserJuly 21, 2023Skeletal Muscle Cells

Passive-Stretch Induced Skeletal Muscle Injury Platform for Duchenne Muscular Dystrophy Modeling

Inactivity following skeletal muscle dysfunction in DMD usually causes compromised soft tissue and decreased joint range of motion. Passive stretch techniques in combination with an exercise program are used as interventions to prevent musculoskeletal complications in children with DMD. However, the exact role of stretch-based rehabilitation methods is not well established in children with DMD. In fact, the underlying molecular and cellular mechanisms of how stretch-based rehabilitation methods in dystrophin-deficient muscle fibers might worsen the disease phenotype have not been fully explained. Therefore, the purpose was to establish an in vitro stretch-induced injury model in normal and dystrophic rat skeletal muscle fibers.

Originally Published in: Archives of Physical Medicine and Rehabilitation - V103, Issue 3 (2022) (Link to Paper)

Curi CytostretcherArianna KieserMarch 1, 2022Skeletal Muscle Cells

Combining stretching and gallic acid to decrease inflammation indices and promote extracellular matrix production in osteoarthritic human articular chondrocytes

Osteoarthritis (OA) patients undergo cartilage degradation and experience painful joint swelling. OA symptoms are caused by inflammatory molecules and the upregulation of catabolic genes leading to the breakdown of cartilage extracellular matrix (ECM). Here, we investigate the effects of gallic acid (GA) and mechanical stretching on the expression of anabolic and catabolic genes and restoring ECM production by osteoarthritic human articular chondrocytes (hAChs) cultured in monolayers. hAChs were seeded onto conventional plates or silicone chambers with or without 100 μM GA. A 5% cyclic tensile strain (CTS) was applied to the silicone chambers and the deposition of collagen and glycosaminoglycan, and gene expressions of collagen types II (COL2A1), XI (COL11A2), I (COL1A1), and X (COL10A1), and matrix metalloproteinases (MMP-1 and MMP-13) as inflammation markers, were quantified. CTS and GA acted synergistically to promote the deposition of collagen and glycosaminoglycan in the ECM by 14- and 7-fold, respectively. Furthermore, the synergistic stimuli selectively upregulated the expression of cartilage-specific proteins, COL11A2 by 7-fold, and COL2A1 by 47-fold, and, in contrast, downregulated the expression of MMP-1 by 2.5-fold and MMP-13 by 125-fold. GA supplementation with CTS is a promising approach for restoring osteoarthritic hAChs ECM production ability making them suitable for complex tissue engineering applications.

Originally Published in: Experimental Cell Research - V408, Issue 2 (2021) (Link to Paper)

BRAF Modulates Stretch-Induced Intercellular Gap Formation through Localized Actin Reorganization

Mechanical forces acting on cell–cell adhesion modulate the barrier function of endothelial cells. The actively remodeled actin cytoskeleton impinges on cell–cell adhesion to counteract external forces. We applied stress on endothelial monolayers by mechanical stretch to uncover the role of BRAF in the stress-induced response. Control cells responded to external forces by organizing and stabilizing actin cables in the stretched cell junctions. This was accompanied by an increase in intercellular gap formation, which was prevented in BRAF knockdown monolayers. In the absence of BRAF, there was excess stress fiber formation due to the enhanced reorganization of actin fibers. Our findings suggest that stretch-induced intercellular gap formation, leading to a decrease in barrier function of blood vessels, can be reverted by BRAF RNAi. This is important when the endothelium experiences changes in external stresses caused by high blood pressure, leading to edema, or by immune or cancer cells in inflammation or metastasis.

Originally Published in: International Journal of Molecular Sciences (2021) (Link to Paper)

Curi CytostretcherArianna KieserAugust 17, 2021Human Endothelial Cells

Enhanced Matrix Production by Cocultivated Human Stem Cells and Chondrocytes Under Concurrent Mechanical Strain

A popular treatment for osteoarthritis is chondrocyte implantation. However, that treatment relies on cell survival and extracellular matrix production under high mechanical stress post-injection into patients' knees. In this study, adipose-derived stem cells and articular chondrocytes were cultured separately, or co-cultivated, at various ratios and exposed to mechanical stress to mimic forces that would be applied in patients' joints. This figure shows an increase in glycosaminoglycan (GAG) production which is an essential component of the extracellular matrix that lines articulating joints. Use of Curi Bio's Cytostretcher platform allowed researchers to identify the optimum culture conditions for cartilaginous ECM production under physiologically relevant conditions.

Originally Published in: In Vitro Cellular & Developmental Biology - Animal (2021) (Link to Paper)

Curi CytostretcherArianna KieserJune 30, 2021Stem Cells

Regional Differences and Physiologic Behaviors in Peripapillary Scleral Fibroblasts

Described cellular alignment in scleral stroma and showed that extracellular topography affects fibroblast activity in vitro. Specifically, demonstrated that extracellular topographic cues alter cellular response to mechanical strain and can stabilize fibroblasts by preventing a change in cellular orientation in the presence of mechanical strain.

Originally Published in: Investigative Ophthalmology and Visual Science (2021)

Curi CytostretcherArianna KieserFebruary 8, 2021

Dasatinib Inhibits Peripapillary Scleral Myofibroblast Differentiation

This study identified dasatinib as a potent inhibitor of cyclic mechanical stretch-induced myofibroblast differentiation in vitro.

Originally Published in: Experimental Eye Research (2020) (Link to Paper)

Curi CytostretcherArianna KieserMarch 13, 2020Eye Tissue

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