Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts

Walker, Cierra J.; Crocini, Claudia; Ramirez, Daniel M. Carter; Killaars, Anouk R.; Grim, Joseph C.; Aguado, Brian A.; Clark, Kyle; Allen, Mary A.; Dowell, Robin; Leinwand, Leslie A.; Anseth, Kristi S.

doi:10.1038/s41551-021-00709-w

Cited by 109 publications

(97 citation statements)

References 83 publications

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“…Surprisingly, these cells not only determine ECM changes but also dictate the functions of resident cells within tissues. The ECM supplies cells with proper chemical and mechanical signals to regulate cell proliferation, migration, and differentiation to maintain tissue homeostasis ( 36 , 39 ). In SF, collagen I exhibit a disorganized structure and enhanced cross-linking, while collagen III is crucial for appropriate collagen I fibrillogenesis and tissue functionality ( 39 ).…”

Section: Introductionmentioning

confidence: 99%

“…The ECM supplies cells with proper chemical and mechanical signals to regulate cell proliferation, migration, and differentiation to maintain tissue homeostasis ( 36 , 39 ). In SF, collagen I exhibit a disorganized structure and enhanced cross-linking, while collagen III is crucial for appropriate collagen I fibrillogenesis and tissue functionality ( 39 ). Petersen et al believed that markers of type I or III collagen turnover may reflect the severity of synovitis and SF, which is highly correlated with OA pain sensitivity.…”

Section: Introductionmentioning

confidence: 99%

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Synovial Fibrosis Involvement in Osteoarthritis

et al. 2021

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Bone changes have always been the focus of research on osteoarthritis, but the number of studies on synovitis has increased only over the last 10 years. Our current understanding is that the mechanism of osteoarthritis involves all the tissues that make up the joints, including nerve sprouting, pannus formation, and extracellular matrix environmental changes in the synovium. These factors together determine synovial fibrosis and may be closely associated with the clinical symptoms of pain, hyperalgesia, and stiffness in osteoarthritis. In this review, we summarize the consensus of clinical work, the potential pathological mechanisms, the possible therapeutic targets, and the available therapeutic strategies for synovial fibrosis in osteoarthritis to gain insight and provide a foundation for further study.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synovial Fibrosis Involvement in Osteoarthritis

et al. 2021

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“…In some cases, this reprogrammed state can be maladaptive and can aggravate diseases such as fibrosis 4,7,9 , influence cellular behavior of cancer metastasis 10 , or limit tissue regeneration procedures [4][5][6] . However, mechanisms of mechanical memory are not well understood, and investigating how to disrupt maladaptive mechanical memory for translational applications is critical.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Scott

Casas

Schneider

et al. 2021

Preprint

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Understanding how cells remember previous mechanical environments to influence their fate, or mechanical memory, informs the design of biomaterials and therapies in medicine. Current regeneration therapies require two-dimensional (2D) cell expansion processes to achieve large cell populations critical for the repair of damaged (e.g. connective and musculoskeletal) tissues. However, the influence of mechanical memory on cell fate following expansion is unknown, and mechanisms defining how physical environments influence the therapeutic potential of cells remain poorly understood. Here, we show that the organization of histone H3 trimethylated at lysine 9 (H3K9me3) and expression of tissue-identifying genes in primary cartilage cells (chondrocytes) transferred to three-dimensional (3D) hydrogels depends on the number of previous population doublings on tissue culture plastic during 2D cell expansion. Decreased levels of H3K9me3 occupying promoters of dedifferentiation genes after the 2D culture were also retained in 3D culture. Suppression of H3K9me3 during expansion of cells isolated from a murine model similarly resulted in the loss of the chondrocyte phenotype and global remodeling of nuclear architecture. In contrast, increasing levels of H3K9me3 through inhibiting H3K9 demethylases partially rescued the chondrogenic nuclear architecture and gene expression, which has important implications for tissue repair therapies, where expansion of large numbers of phenotypically-suitable cells is required. Overall, our findings indicate mechanical memory in primary cells is encoded in the chromatin architecture, which impacts cell fate and the phenotype of expanded cells.SIGNIFICANCE STATEMENTTissue regeneration procedures, such as cartilage defect repair (e.g. Matrix-induced Autologous Chondrocyte Implantation) often require cell expansion processes to achieve sufficient cells to transplant into an in vivo environment. However, the chondrocyte cell expansion on 2D stiff substrates induces epigenetic changes that persist even when the chondrocytes are transferred to a different (e.g. 3D) or in vivo environment. Treatments to alter epigenetic gene regulation may be a viable strategy to improve existing cartilage defect repair procedures and other tissue engineering procedures that involve cell expansion.

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“…Although non-sarcomeric in nature, antifibrotic therapy could affect titin isoform composition. Advances in biomaterial sciences to control the extracellular stiffness (Walker et al 2021;Jian et al 2014;Crocini et al 2020;Shimkunas et al 2021), could help dissecting the crosstalk between the cardiac sarcomere and the extracellular matrix and their relative contribution to cardiac passive tension.…”

Section: Targeting Passive Forcesmentioning

confidence: 99%

Cardiac sarcomere mechanics in health and disease

Crocini

Gotthardt

2021

Biophys Rev

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The sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of striated muscle. In the heart, mutations in sarcomeric proteins are responsible for the majority of genetically inherited cardiomyopathies. Here, we review the major determinants of cardiac sarcomere mechanics including the key structural components that contribute to active and passive tension. We dissect the molecular and structural basis of active force generation, including sarcomere composition, structure, activation, and relaxation. We then explore the giant sarcomere-resident protein titin, the major contributor to cardiac passive tension. We discuss sarcomere dynamics exemplified by the regulation of titin-based stiffness and the titin life cycle. Finally, we provide an overview of therapeutic strategies that target the sarcomere to improve cardiac contraction and filling.

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Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts

Cited by 109 publications

References 83 publications

Synovial Fibrosis Involvement in Osteoarthritis

Synovial Fibrosis Involvement in Osteoarthritis

Epigenetic remodeling during monolayer cell expansion reduces therapeutic potential

Cardiac sarcomere mechanics in health and disease

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