JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2025
·
IF 4.3
Fan Yanan,An Caizhelin,Wang Zhihui,Luo Jia,Wang Wenbin,Luo Qing,Song Guanbin
Hepatocytes are the primary functional cells in the liver, and the malignant transformation of hepatocytes significantly contributes to hepatocellular carcinoma (HCC) progression. Liver fibrosis and cirrhosis caused by extracellular matrix (ECM) remodeling during liver lesions is a pivotal driver of HCC. However, the impact of matrix stiffness on hepatocytes and the underlying molecular mechanisms are not fully understood. Herein, using gelatin/sodium alginate hydrogels with different stiffnesses to simulate the change of matrix stiffness during liver lesions, we found that matrix stiffening leads to a notable decrease in the expression of hepatocyte nuclear factor 4α (HNF4α) and functional hepatocyte genes and a significant increase in the expression of interleukin 6 (IL‒6) in human hepatocyte line L‒02 cells, indicating obvious damage of hepatocyte function. In addition, matrix stiffening causes extensive DNA damage to L‒02 cells. Mechanistically, matrix stiffening upregulates piezo‒type mechanosensitive ion channel component 1 (Piezo1) expression and activates extracellular signal‒regulated kinase 1/2 (ERK1/2) signaling. Piezo1 knockdown suppresses matrix stiffening‒induced functional impairment and DNA damage in L‒02 cells. Moreover, Piezo1 knockdown blocks matrix stiffening‒activated ERK1/2 signaling in L‒02 cells. U0126 (a selective inhibitor of ERK1/2 activation) treatment could rescue matrix stiffening‒induced functional impairment and DNA damage. Taken together, these findings demonstrate that matrix stiffening induces functional impairment and DNA damage in L‒02 cells via the Piezo1‒ERK1/2 signaling pathway, which provides evidence for a better understanding of the hepatocyte function damage caused by tissue mechanical microenvironment change in liver diseases and the mechanotransduction in this process. Graphical abstract An increase in matrix stiffness inhibits HNF4α expression and promotes IL‒6 expression in L‒02 cells. Meanwhile, matrix stiffening induces L‒02 cell DNA damage and upregulates the expression of γ‒H2AX and 53BP1. These findings prove that matrix stiffness is a crucial mechanical regulator of cellular functional impairment and DNA damage and plays an important role in liver disease.
研究领域:
医学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Yue Chen,Dan Xue,Di Huang,Xinying Li,Yuyou Duan,Bin Chen
Matrix stiffness is a key factor in breast cancer progression, but its impact on cell function and response to treatment is not fully understood. Here, we developed a stiffness-tunable hydrogel-based three-dimensional system that recapitulates the extracellular matrix and physiological properties of human breast cancer in vitro. Adjusting the ratio of GelMA to PEGDA in the hydrogel formulation enabled the fine-tuning of matrix stiffness across a range of 7 to 52 kPa. Utilizing this three-dimensional (3D) hydrogel platform for a breast cancer cell culture has enabled precise functional evaluations. Variations in matrix stiffness resulted in significant changes in the morphology of breast cancer cells after 2 weeks of incubation. The analysis of transcriptomic sequencing revealed that the 3D microenvironment significantly changed the expression of a wide panel of transcriptomic profiles of breast cancer cells in various matrix stiffness. Gene Ontology analysis further suggested that specific biological functions could potentially be linked to the magnitude of the matrix stiffness. According to our findings, extracellular matrix rigidity modulates the sensitivity of breast cancer cells to paclitaxel and adriamycin. Notably, the expression of ABCB1 and YAP1 genes may be upregulated in the 3D culture environment, potentially contributing to the increased drug resistance observed in breast cancer cells. This work aims to establish facile adjustable hydrogels to deepen insights into matrix rigidity effects on breast cancer cells within 3D microenvironments, highlighting the critical role of extracellular matrix stiffness in modulating cell-matrix interactions.
研究领域:
生物医学工程
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2022
·
IF 12.91
Hua-Hua Liu,Yang Xu,Cao-Jie Li,Shu-Jung Hsu,Xia-Hui Lin,Rui Zhang,Jie Chen,Jun Chen,Dong-Mei Gao,Jie-Feng Cui,Xin-Rong Yang,Zheng-Gang Ren,Rong-Xin Chen
Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo . Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming.
研究领域:
肿瘤学
·
分子生物学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2022
·Vol. 8
·期 1
·e10375
·
IF 10.684
Long Yang,Jingwen Li,Guangchao Zang,Sijie Song,Zhengwen Sun,Xinyue Li,Yuanzhu Li,Zhenhong Xie,Guangyuan Zhang,Ni Gui,Shu Zhu,Tingting Chen,Yikui Cai,Yinping Zhao
Cervical cancer metastasis is an important cause of death in cervical cancer. Previous studies have shown that epithelial–mesenchymal transition (EMT) of tumors promotes its invasive and metastatic capacity. Alterations in the extracellular matrix (ECM) and mechanical signaling are closely associated with cancer cell metastasis. However, it is unclear how matrix stiffness as an independent cue triggers EMT and promotes cervical cancer metastasis. Using collagen-coated polyacrylamide hydrogel models and animal models, we investigated the effect of matrix stiffness on EMT and metastasis in cervical cancer. Our data showed that high matrix stiffness promotes EMT and migration of cervical cancer hela cell lines in vitro and in vivo. Notably, we found that matrix stiffness regulates yes-associated protein (YAP) activity via PPIase non-mitotic a-interaction 1 (Pin1) with a non-Hippo mechanism. These data indicate that matrix stiffness of the tumor microenvironment positively regulates EMT in cervical cancer through the Pin1/YAP pathway, and this study deepens our understanding of cervical cancer biomechanics and may provide new ideas for the treatment of cervical cancer.
研究领域:
癌症生物学
·
细胞生物学
·
生物力学
✓ 已验证
DOI
PubMed
高影响因子
Bioactive Materials
·
2020
·
IF 8.724
Mi Hu,Fan Jia,Wei-Pin Huang,Xu Li,Deng-Feng Hu,Jing Wang,Ke-Feng Ren,Guo-Sheng Fu,Yun-Bing Wang,Jian Ji
Stiffening of blood vessels is one of the most important characteristics in the process of many cardiovascular pathologies such as atherosclerosis, angiosteosis, and vascular aging. Increased stiffness of the vascular extracellular matrix drives artery pathology and alters phenotypes of vascular cell. Understanding how substrate stiffness impacts vascular cell behaviors is of great importance to the biomaterial design in tissue engineering, regenerative medicine, and medical devices. Here we report that changing substrate stiffness has a significant impact on the autophagy of vascular endothelial cells (VECs) and smooth muscle cells (VSMCs). Interestingly, our findings demonstrate that, with the increase of substrate stiffness, the autophagy level of VECs and VSMCs showed differential changes: endothelial autophagy levels reduced, leading to the reductions in a range of gene expression associated with endothelial function; while, autophagy levels of VSMCs increased, showing a transition from contractile to the synthetic phenotype. We further demonstrate that, by inhibiting cell autophagy, the expressions of endothelial functional gene were further reduced and the expression of VSMC calponin increased, suggesting an important role of autophagy in response of the cells to the challenge of microenvironment stiffness changing. Although the underlying mechanism requires further study, this work highlights the relationship of substrate stiffness, autophagy, and vascular cell behaviors, and enlightening the design principles of surface stiffness of biomaterials in cardiovascular practical applications.
研究领域:
生物医学工程
·
细胞生物学
·
心血管科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2025
·Vol. 22
·期 14
·3454-3463
·
IF 3.2
Chen Jiahao,Chen Mengting,Xie Zhiwen,Shen Luheng,Jiang Juntao,Xia Shujie
Background: Prostate cancer (PCa) poses a significant health burden for men, with docetaxel constituting the primary therapeutic option for patients with metastatic PCa. However, the mechanisms governing docetaxel resistance remain incompletely understood. Several studies have implicated the role of the extracellular matrix (ECM) stiffness in cancer drug resistance, yet the precise role of ECM stiffness in docetaxel resistance in PCa remains elusive. The aim of this study was to explore the influence of ECM stiffness on docetaxel resistance in PCa and elucidate the underlying molecular mechanisms, thereby providing novel insights into PCa treatment.Methods: Polyacrylamide gels of varying stiffness were utilized to mimic different ECM stiffness conditions. The sensitivity of PCa cells to docetaxel was evaluated using CCK-8, TUNEL staining, flow cytometry, and western blotting. RNA-seq was employed to analyze the transcriptomic effects of different ECM stiffness on PC-3 cells. Western blotting, qPCR, and siRNA were utilized to validate the regulatory role of the key gene in the sensitivity of PCa cells to docetaxel under varying stiffness conditions.Results: Our findings indicate that high ECM stiffness enhances docetaxel resistance in PCa cells by inhibiting docetaxel-induced apoptosis. This process is mediated through the integrin-related mechanotransduction pathway. Specifically, high ECM stiffness upregulates the expression of PRRX1, thereby promoting docetaxel resistance in PCa cells.Conclusions: High ECM stiffness promotes docetaxel resistance in PCa, with PRRX1 identified as a pivotal gene in this process. These findings contribute to a deeper understanding of the mechanisms underlying docetaxel resistance in PCa and may inform the development of novel therapeutic strategies.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2023
·
IF 5.8
Yijie Wang,Hui Zhang,Shiyang Wu,Wanting Wan,Xueping Kang,Bei Gao,Haoyu Shi,Shuyang Zhao,Lin Niu,Rui Zou
The hallmark of orthodontic tooth movement (OTM) is time-consuming during clinical treatments. The acceleration of OTM through modulating proliferation and apoptosis of periodontal ligament cells (PDLCs) possesses the potential application in clinical treatments. Here, we established an in vitro model with a graded increase in substrate stiffness to investigate the underlying mechanism of proliferation and apoptosis of PDLCs. The role of the integrin-linked kinase (ILK) in response to substrate stiffness was investigated by the depletion model of PDLCs. We found that the proliferation and apoptosis of PDLCs show a stiffness-dependent property with stiffer substrates favoring increased bias at the transcript level. Depleting integrin-linked kinase diluted the correlation between PDLCs behaviors and substrate stiffness. Our results suggest that ILK plays a significant role in modulating PDLC proliferation and apoptosis and can serve as a potential target for accelerating OTM.
研究领域:
牙科
·
细胞生物学
·
生物力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Hong Li,Yuchuan Sun,Qing Li,Qing Luo,Guanbin Song
A hepatocellular carcinoma tissue has mechanical heterogeneity, where the stiffness gradually increases from the core to the invasion front. Furthermore, there is evidence that stem cells from liver cancer (LCSCs) preferentially enrich the invasion front, exhibiting the stiffest modulus in the tumor. LCSCs have the features of stem/progenitor cells and play a vital part in liver cancer development. However, whether matrix stiffness affects LCSC stemness remains unclear. Here, we established a three-dimensional hydrogel for culturing LCSCs to simulate the stiffness of the core and the invasion front of a liver cancer tissue. The results showed that a stiffer matrix (72.2 ± 0.90 kPa) significantly potentiated LCSC stemness as compared with a soft matrix (7.7 ± 0.41 kPa). Moreover, Yes-associated protein signaling might mediate this promotion. Together, our findings illustrate the relationship between matrix stiffness and LCSC stemness, which may aid the production of novel treatment approaches against liver cancer.
研究领域:
癌症生物学
·
细胞生物学
·
组织工程
✓ 已验证
DOI
PubMed
高影响因子
Cell Regeneration
·
2020
·Vol. 9
·期 1
·1-16
·
IF 0
Guo Anqi,Wang Bingjie,Lyu Cheng,Li Wenjing,Wu Yaozu,Zhu Lu,Bi Ran,Huang Chenyu,Li Jiao Jiao,Du Yanan
Apparent Young’s modulus (AYM), which reflects the fundamental mechanical property of live cells measured by atomic force microscopy and is determined by substrate stiffness regulated cytoskeletal organization, has been investigated as potential indicators of cell fate in specific cell types. However, applying biophysical cues, such as modulating the substrate stiffness, to regulate AYM and thereby reflect and/or control stem cell lineage specificity for downstream applications, remains a primary challenge during in vitro stem cell expansion. Moreover, substrate stiffness could modulate cell heterogeneity in the single-cell stage and contribute to cell fate regulation, yet the indicative link between AYM and cell fate determination during in vitro dynamic cell expansion (from single-cell stage to multi-cell stage) has not been established.Here, we show that the AYM of cells changed dynamically during passaging and proliferation on substrates with different stiffness. Moreover, the same change in substrate stiffness caused different patterns of AYM change in epithelial and mesenchymal cell types. Embryonic stem cells and their derived progenitor cells exhibited distinguishing AYM changes in response to different substrate stiffness that had significant effects on their maintenance of pluripotency and/or lineage-specific characteristics. On substrates that were too rigid or too soft, fluctuations in AYM occurred during cell passaging and proliferation that led to a loss in lineage specificity. On a substrate with ‘optimal’ stiffness (i.e., 3.5 kPa), the AYM was maintained at a constant level that was consistent with the parental cells during passaging and proliferation and led to preservation of lineage specificity. The effects of substrate stiffness on AYM and downstream cell fate were correlated with intracellular cytoskeletal organization and nuclear/cytoplasmic localization of YAP.In summary, this study suggests that optimal substrate stiffness regulated consistent AYM during passaging and proliferation reflects and contributes to hESCs and their derived progenitor cells lineage specificity maintenance, through the underlying mechanistic pathways of stiffness-induced cytoskeletal organization and the downstream YAP signaling. These findings highlighted the potential of AYM as an indicator to select suitable substrate stiffness for stem cell specificity maintenance during in vitro expansion for regenerative applications.
研究领域:
干细胞生物学
·
生物物理学
·
再生医学
✓ 已验证
DOI
PubMed
Cancer Cell International
·
2022
·Vol. 22
·期 1
·1-18
·
IF 6.429
Wang Shunxi,Chen Long,Liu Wanqian
Background Ferroptosis have been implicated in tumorigenesis, tumor progression, and chemo- and immuno-therapy in cirrhotic hepatocellular carcinoma (HCC), indicating its association with matrix stiffness and clinical benefit of targeting drugs or immune checkpoint inhibitor. Here, we postulated that increased matrix stiffness reduces ferroptosis and impairs tumor immunity by regulating the expression of ferroptosis- and immune-related genes in HCC, which might be a robust predictor of therapeutic efficacy. Methods Using publicly available tissue microarray datasets, liver cancer rat model, and clinical specimen, ferroptosis-related differential genes in HCV-infected cirrhotic HCC and its mechanical heterogeneous pattern of expression were screened and identified. Further investigation on the underlying mechanism of matrix stiffness-regulated ferroptosis and the expression of immune mediator were performed. Finally, threshold analysis of HCC cases with sorafenib treatment revealed the value of clinical applications of these potential predictors. Results STEAP3 was identified as the ferroptosis-related differential genes in HCV-infected cirrhotic HCC. Stiffer matrix decreased STEAP3 in the invasive front area of HCC and the liver cirrhotic tissue. Contrarily, softer matrix induced STEAP3 in the central area of HCC and the normal liver tissue. Immunological correlation of STEAP3 in cirrhotic HCC showed that STEAP3-mediated immune infiltration of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells and HCC prognosis, predicting to regulate immune infiltration. Overexpression of STEAP3 induced ferroptosis and inhibited the expression of immune mediator of PD-L2 on a stiff matrix. Especially, the ferroptosis- and immune-related gene predictive biomarker (FIGPB), including STEAP3 and PD-L2, predicts better clinical benefit of sorafenib in HCC patients. Conclusions This finding identifies matrix stiffness impairs ferroptosis and anti-tumor immunity by mediating STEAP3 and PD-L2. More importantly, coordinated with PD-L2, matrix stiffness-dependent STEAP3 could be applied as the independent predictors to favorable sorafenib response, and thus targeting it could be a potential diagnosis and treatment strategy for HCC.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2023
·
IF 5.8
Jialin Chen,Qingyun Mo,Qiuzi Long,Renwang Sheng,Zhixuan Chen,Yifan Luo,Chuanquan Liu,Ludvig J. Backman,Yanan Zhang,Wei Zhang
Corneal fibrosis is a common outcome of inappropriate repair associated with trauma or ocular infection. Altered biomechanical properties with increased corneal stiffness is a feature of fibrosis that cause corneal opacities, resulting in severe visual impairment and even blindness. The present study aims to determine the effect of hydroxycamptothecin (HCPT) and matrix stiffness on transforming growth factor-β1 (TGF-β1)-induced fibrotic processes in human corneal fibroblasts (HTK cells). HTK cells were cultured on substrates with different stiffnesses (“soft”, ∼261 kPa; “stiff”, ∼2.5 × 103 kPa) and on tissue culture plastic (TCP, ∼106 kPa) and simultaneously treated with or without 1 μg/mL HCPT and 10 ng/mL TGF-β1. We found that HCPT induced decreased cell viability and antiproliferative effects on HTK cells. TGF-β1-induced expression of fibrosis-related genes (FN1, ACTA2) was reduced if the cells were simultaneously treated with HCPT. Substrate stiffness did not affect the expression of fibrosis-related genes. The TGF-β1 induced expression of FN1 on both soft and stiff substrates was reduced if cells were simultaneously treated with HCPT. However, this trend was not seen for ACTA2, i.e., the TGF-β1 induced expression of ACTA2 was not reduced by simultaneous treatment of HCPT in either soft or stiff substrate. Instead, HCPT treatment in the presence of TGF-β1 resulted in increased gene expression of keratocyte phenotype makers (LUM, KERA, AQP1, CHTS6) on both substrate stiffnesses. In addition, the protein expression of keratocyte phenotype makers LUM and ALDH3 was increased in HTK cells simultaneously treated with TGF-β1 and HCPT on stiff substrate as compared to control, i.e., without HCPT. In conclusion, we found that HCPT can reduce TGF-β1-induced fibrosis and promote the keratocyte phenotype in a substrate stiffness dependent manner. Thus, HCPT stimulation might be an approach to stimulate keratocytes in the appropriate healing stage to avoid or reverse fibrosis and achieve more optimal corneal wound healing.
研究领域:
眼科学
·
细胞生物学
·
生物力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Chuanchuan Lin,Bailong Tao,Yiman Deng,Ye He,Xinkun Shen,Rong Wang,Lu Lu,Zhihong Peng,Zengzilu Xia,Kaiyong Cai
Bone marrow derived mesenchymal stromal cells (BMSCs) migration to injury site is a prevalent event in tissue repair process after damage occurrence. The migration process is always accompanied with matrix stiffness change. In this study, sodium alginate hydrogels with different stiffness and Transwell chambers with gradient chemical factors were employed to mimic tissue repair in vivo . In this work, in the stiffness range of 1–20 kPa, BMSCs in stiffer matrix showed higher migration speed compared to those in softer matrix. Moreover, stiffer matrix decreased the nuclear stiffness of BMSCs and reduced the expression of lamin A/C, which playing a main role in the regulation of nuclear stiffness. Furthermore, it was found that BMSCs fitted environment by selecting migration strategy. This study provides a novel platform for the investigation of BMSCs migration to mimic the natural tissue repair process.
研究领域:
细胞生物学
·
组织工程
·
生物力学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）