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Matrix stiffness-dependent regulation of immunomodulatory genes in human MSCs is associated with the lncRNA CYTOR

ABSTRACT: Previous studies have demonstrated that the physical properties of biomaterials can be adjusted to program therapeutically relevant functions in encapsulated mesenchymal stromal cells (MSCs). However, the intracellular pathways affected by mechanical cues in this cell type are not well understood. An understanding of the pertinent factors involved would not only aid in the rational design of substrates but also uncover targetable mechanisms that can facilitate the engineering of MSCs for cell therapies. Here, a bone marrow-mimetic hydrogel is employed to systematically explore the stiffness-responsive transcriptome of MSCs. High matrix rigidity impedes integrin-collagen adhesions which yields changes in cell morphology that are characterized by a contractile network of actin proximal to the cell membrane. This results in a suppression of ECM-regulatory genes involved in the remodeling of collagen fibrils and an upregulation of secreted immunomodulatory factors. Moreover, an investigation of long non-coding RNAs reveals that CYTOR contributes to these stiffness-driven changes in gene abundance. A robust knockdown of CYTOR using antisense oligonucleotides enhances the expression of numerous mechanoresponsive cytokines and chemokines to levels exceeding what is achievable by modulating matrix stiffness alone. Taken together, these findings emphasize the utility in studying previously unexplored mechanisms of mechanotransduction to inform novel strategies for enhancing the efficacy of MSC-based therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255574 | GEO | 2024/08/21

REPOSITORIES: GEO

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ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation [ChIP-seq]

Project description:Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly-isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known pro-fibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue-fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and pro-fibrotic transcriptional regulators. Using loss and gain of function studies we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis and contractile function. Together these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.

2020-11-14 | GSE161446 | GEO

ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation [ATAC-seq]

2020-11-14 | GSE161434 | GEO

Cell elasticity determines macrophage function.

Project description:We report that macrophage elasticity plays a dominant role in bacterial phagocytosis, release of TNF-alpha, and production of reactive oxygen species. We show that macrophage elasticity is modulated by mechanical factors including substrate rigidity and substrate stretch. Changes in macrophage elasticity are dependent upon the degree of actin polymerization, and mediated in part through small rhoGTPase activity. Moreover, the functional effects of macrophage elasticity are not predicted by gene expression profiles. Murine RAW 267.4 macrophages were separately grown on 2 matrix stiffness levels (1200, 150000 Pascals) for 0, 2, 6, 18 hours with 3 replicate sample experiments per condition. Total RNA extracted from the cells and profiled by microarrays. Keywords: Murine RAW 267.4 macrophage, matrix stiffness, phagocytosis, cell elasticity.

2012-03-28 | E-GEOD-36878 | biostudies-arrayexpress

Delineating the heterogeneity of matrix-directed differentiation towards soft and stiff tissue lineages via single-cell profiling.

Project description:Mesenchymal stromal/stem cells (MSCs) are a heterogeneous population of multipotent progenitors that contribute to tissue regeneration and homeostasis. MSCs assess extracellular elasticity by probing resistance to applied forces via adhesion, cytoskeletal, and nuclear mechanotransducers, that direct differentiation toward soft or stiff tissue lineages. Even under controlled conditions, MSC differentiation exhibits substantial cell-to-cell variation that remains poorly characterized. By single-cell transcriptional profiling of naïve, matrix-conditioned, and early differentiation state cells, we identified distinct MSC subpopulations with distinct mechanosensitivities, differentiation capacities, and cell cycling. We showed that soft matrices support adipogenesis of multipotent cells and endochondral ossification of non-adipogenic cells, whereas intramembranous ossification and pre-osteoblast proliferation are enhanced by stiff matrices. Using diffusion pseudotime mapping, we delineated hierarchical matrix-directed differentiation and identified mechanoresponsive genes. We found that tropomyosin-1 (TPM1) is highly sensitive to stiffness cues both at RNA and protein levels and that changes in expression of TPM1 determine adipogenic or osteogenic fates. Thus, cell-to-cell variation in tropomyosin-mediated matrix-sensing contributes to impaired differentiation with implications to the biomedical potential of MSCs.

2021-05-01 | GSE166824 | GEO

Next-generation sequencing facilitates quantitative analysis of rat BMSCs in soft or stiff SA hydrogel

Project description:Purpose: To identify genes and the molecular pathways involved in the MSCs response to extracellular matrix stiffness, we performed RNA-sequencing of MSCs which cultured in soft (2 kPa) and stiff (18 kPa) SA hydrogels. Methods: mRNA profiles of MSCs cultured in soft (2 kPa) and stiff (18 kPa) SA hydrogel for 48 h were generated by deep sequencing, in quadruplicate, using Illumina HiSeq 2000. Results: Using an optimized data analysis workflow, we identified 33950 transcripts in MSCs with BWA workflow. Conclusions: Our results present the detailed analysis of MSCs transcriptomes cultured in soft (2 kPa) and stiff (18 kPa) matrix, and found that matrix stiffness dominated multiple mRNA pathways in MSCs.

2021-08-06 | GSE181512 | GEO

Matrix rigidity and cardiac reprogramming

Project description:Matrix rigidity and cardiac reprogramming

| PRJNA517614 | ENA

Tunable three-dimensional engineered prostate cancer tissues for in vitro recapitulation of heterogeneous in vivo prostate tumor stiffness

Project description:In this study we report the establishment and characterization of a three-dimensional in vitro, coculture engineered prostate cancer tissue (EPCaT) disease model based upon and informed by our characterization of in vivo prostate cancer (PCa) xenograft tumor stiffness. In prostate cancer, tissue stiffness is known to impact changes in gene and protein expression, alter therapeutic response, and be positively correlated with an aggressive clinical presentation. To inform an appropriate stiffness range for our in vitro model, PC-3 prostate tumor xenografts were established. Tissue stiffness ranged from 95 to 6,750 Pa. Notably, xenograft cell seeding density significantly impacted tumor stiffness; a two-fold increase in the number of seeded cells not only widened the tissue stiffness range throughout the tumor, but also resulted in significant spatial heterogeneity. To fabricate our in vitro EPCaT model, PC-3 castration-resistant prostate cancer cells were co-encapsulated with BJ-5ta fibroblasts within a poly(ethylene glycol)-fibrinogen matrix augmented with excess poly(ethylene glycol)-diacrylate to modulate the matrix mechanical properties. Encapsulated cells temporally remodeled their in vitro microenvironment and enrichment of gene sets associated with tumorigenic progression was observed in response to increased matrix stiffness. Through variation of matrix composition and culture duration, EPCaTs were tuned to mimic the wide range of biomechanical cues provided to PCa cells in vivo; collectively, a range of 50 to 10,000 Pa was achievable. Markedly, this also encompasses published clinical PCa stiffness data. Overall, this study serves to introduce our bioinspired, tunable EPCaT model and provide the foundation for future PCa progression and drug development studies.

2022-05-24 | GSE203495 | GEO

Surface topography enhances differentiation of mesenchymal stem cells towards osteogenic and adipogenic lineages

Project description:Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ridge structures. Micro- and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 um ridges increased adipogenic differentiation whereas 2 um ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces - e.g. by multi beam laser interference in sub-micrometer scale - do not induce differentiation of MSCs per se, but support their directed differentiation.

2018-09-20 | E-MTAB-7177 | biostudies-arrayexpress

Mechanotransduction regulates adipose estrogen output and its impact on tumor cell growth

Project description:Adipose stromal cells (ASCs) are the primary source of local estrogens in adipose tissue, aberrant production of which promotes estrogen receptor-positive (ER+) breast cancer. Here we show that extracellular matrix (ECM) rigidity and cell contractility are two opposing determinants for estrogen output of ASCs. Using synthetic ECMs and elastomeric micropost arrays with tunable rigidity, we find that increasing matrix compliance induces transcription of aromatase, a rate-limiting enzyme in estrogen biosynthesis. This mechanical cue is transduced sequentially by Discoidin Domain Receptor 1 (DDR1), c-Jun N-terminal kinase 1 (JNK1), and phosphorylated JunB, which binds to and activates two breast cancer-associated aromatase promoters. In contrast, elevated cell contractility due to actin stress fiber formation dampens aromatase transcription. Mechanically stimulated stromal estrogen production enhances estrogen-dependent transcription in ER+ tumor cells and promotes their growth. This novel mechanotransduction pathway underlies communications between ECM, stromal hormone output, and cancer cell growth within the same microenvironment. Total RNA was isolated from primary adipose stromal cells after 2d culture or 3d Collagen gel for 21 hours. Triplicates for each conditioned were analyzed

2013-03-04 | E-GEOD-44811 | biostudies-arrayexpress

Ascorbic acid and TGF-B differentially effect on ECM elaborated by the corneal endothelial cells

Project description:Fuchs endothelial corneal dystrophy FECD is a progressive corneal disease that impacts the structure and stiffness of the Descemets membrane DM, a protein layer that serves as a matrix for the corneal endothelial cells CECs. These structural alterations of the DM contribute to the loss of the CECs resulting in corneal edema and blindness. Oxidative stress and TGF-b pathways have been implicated in endothelial cell loss and endothelial to mesenchymal transition of CECs in FECD. Ascorbic acid AA is found at high concentrations in FECD and its impacts on CECs survival has been investigated. However, TGF-b and AA effects on the composition and rigidity of the CECs matrix remain unknown. In this study, we investigated the effect of AA, TGF-b1 and TGF-b3 on the deposition, ultrastructure, stiffness, and composition of the extracellular matrix ECM secreted by primary bovine corneal endothelial cells BCECs. Immunofluorescence and electron microscopy post-decellularization demonstrated a robust deposition and distinct structure of ECM in response to treatments. AFM measurements showed that the modulus of the matrix in BCECs treated with TGF-b1 and TGF-b3 was significantly lower than the controls. There was no difference in the stiffness of the matrix between the AA-treated cell and controls. Gene Ontology analysis of the proteomics results revealed that AA modulates the oxidative stress pathway in the matrix while TGF-b induces the expression of matrix proteins collagen IV, laminin and lysyl oxidase homolog 1. Molecular pathways identified in this study demonstrate the differential role of soluble factors in pathogenesis of the FECD.

| MSV000088172 | MassIVE

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