Stiffness Assisted Cell-Matrix Remodeling Trigger Mechanotransduction Regulatory Programs to Induce Stem Cell Differentiation
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ABSTRACT:
PROVIDER: PRJNA940143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23677045_1.fastq.gz | Fastqsanger.gz | |||
| SRR23677045_2.fastq.gz | Fastqsanger.gz | |||
| SRR23677046_1.fastq.gz | Fastqsanger.gz | |||
| SRR23677046_2.fastq.gz | Fastqsanger.gz | |||
| SRR23677047_1.fastq.gz | Fastqsanger.gz |
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Project description:The interplay of transcription and epigenetics in response to biophysical factors is important in the design of engineered matrix platforms that seek to direct cellular fate. We present a nanoparticle crosslinker to reinforce hydrogels and study the impact on hMSC transcription through RNA-seq. The study provides insight into how environmental stiffness drives global intracellular signaling through PI3AKT transction and chromatin remodeling to enable YAP/TAZ activity.
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Project description:Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving cancer. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models which lack the major cell-cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. Using flow cytometry, we show that the expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 to sense changes in static extracellular matrix stiffness and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.
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Project description:In breast cancer, the increased stiffness of the extracellular matrix (ECM) is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of ECM mechanics. Here, we show in a 3D culture model of breast cancer that stiff ECM induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that Sp1 acts along with histone deacetylases (HDAC) 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction.
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Project description:Cells sense the biophysical properties of the surrounding microenvironment. In particular, the stiffness of the extracellular milieu can be interrogated by cells and integrated through mechanotransduction. Many cellular processes (like proliferation, migration, or differentiation) depend on the mechanical status of the cell (being largely dictated by actomyosin-dependent intracellular contractility), which in turn is influenced by the mechanical properties of the microenvironment. In this study, we explored the influence of substrate stiffness on the proteome of undifferentiated human umbilical cord matrix mesenchymal stem/stromal cells (hUCM-MSCs). The relative abundance of several identified proteins suffered significant changes when comparing between substrates. Interestingly, many of such proteins are related to the regulation of the actin cytoskeleton, a main player of mechanotransduction and cell physiology in response to mechanical cues.
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Project description:The transcriptional regulator YAP orchestrates important cell functions, determining tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin cytoskeleton-dependent and Hippo kinase-independent mechanisms. RHO activity is necessary but not sufficient for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based siRNA screenings provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective ECM remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications.
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Project description:In this study, we investigate how matrix stiffness regulates chromatin reorganization and cell reprogramming, and find that matrix stiffness acts as a biphasic regulator of epigenetic state and fibroblast-to-neuron conversion efficiency, maximized at an intermediate stiffness of 20 kPa. ATAC-sequencing analysis shows the same trend of chromatin accessibility to neuronal genes at these stiffness levels. Concurrently, we observe peak levels of histone acetylation and histone acetyltransferase (HAT) activity in the nucleus on matrices at 20 kPa, and inhibiting HAT activity abolishes matrix stiffness effects. G-actin and cofilin, the co-transporters shuttling HAT into the nucleus, rises with decreasing matrix stiffness; however, reduced importin-9 on soft matrices limits nuclear transport. These two factors result in a biphasic regulation of HAT transport into the nucleus, which is directly demonstrated on matrices with dynamically tunable stiffness. These findings unravel a mechanism of the mechano-epigenetic regulation that is valuable for cell engineering in disease modeling and regenerative medicine applications.
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Project description:In this study, we investigate how matrix stiffness regulates chromatin reorganization and cell reprogramming, and find that matrix stiffness acts as a biphasic regulator of epigenetic state and fibroblast-to-neuron conversion efficiency, maximized at an intermediate stiffness of 20 kPa. ATAC-sequencing analysis shows the same trend of chromatin accessibility to neuronal genes at these stiffness levels. Concurrently, we observe peak levels of histone acetylation and histone acetyltransferase (HAT) activity in the nucleus on matrices at 20 kPa, and inhibiting HAT activity abolishes matrix stiffness effects. G-actin and cofilin, the co-transporters shuttling HAT into the nucleus, rises with decreasing matrix stiffness; however, reduced importin-9 on soft matrices limits nuclear transport. These two factors result in a biphasic regulation of HAT transport into the nucleus, which is directly demonstrated on matrices with dynamically tunable stiffness. These findings unravel a mechanism of the mechano-epigenetic regulation that is valuable for cell engineering in disease modeling and regenerative medicine applications.
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Project description:Remodeling and increased stiffness of the extracellular matrix is a hallmark of solid cancers and contributes to tumor progression through increased proliferation, survival and migration. Mechanotransduction, the process in which cells sense and transduce mechanical signals, can result in transcriptional changes that in turn alter cellular behavior. In vitro culturing of MCF10ACA1a (CA1a) breast cancer cells on polyacrylamide-based hydrogels of variable stiffness revealed drastic changes in morphology, indicating a stiffness dependent induction of a malignant phenotype. We used DNA microarray to characterize the transcriptome of CA1a cells on low (400 Pa) and high (5000 Pa) stiffness, corresponding to the stiffness of normal breast and breast cancer, respectively.
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Project description:Remodeling and increased stiffness of the extracellular matrix is a hallmark of solid cancers and contributes to tumor progression through increased proliferation, survival and migration. Mechanotransduction, the process in which cells sense and transduce mechanical signals, can result in transcriptional changes that in turn alter cellular behavior. In vitro culturing of MCF10ACA1a (CA1a) breast cancer cells on polyacrylamide-based hydrogels of variable stiffness revealed drastic changes in morphology, indicating a stiffness dependent induction of a malignant phenotype. We used two different techniques, DNA microarray and RNA sequencing, to characterize the transcriptome of CA1a cells on low (500 Pa) and high (8000 Pa) stiffness, corresponding to the stiffness of normal breast and breast cancer, respectively.
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Project description: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.
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