Publications by authors named "Janna K Mouw"

15 Publications

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Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning.

Sci Adv 2020 Jul 24;6(30):eaaz6197. Epub 2020 Jul 24.

Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.

Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor as a critical gene at the intersection of epigenetic heterogeneity and three-dimensional (3D) collective invasion. We further identified JAG1 signaling as a previously unknown upstream activator of expression in leader cells. Using live-cell imaging, we found that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1 signaling jointly drive collective cancer invasion through MYO10 up-regulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning.
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http://dx.doi.org/10.1126/sciadv.aaz6197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439406PMC
July 2020

Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.

J Clin Invest 2020 11;130(11):5721-5737

Department of Surgery.

Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness-repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density. Culture studies demonstrated that ZNF217 mediates a matrix stiffness- and collagen density-induced increase in Akt activity and mammary epithelial cell proliferation. Manipulation of the epithelium in a mouse model of mammographic density supported a causal relationship between stromal stiffness, reduced miR-203, higher levels of the murine homolog Zfp217, and increased Akt activity and mammary epithelial proliferation. ZNF217 was also increased in the normal breast epithelium of women with high mammographic density, correlated positively with epithelial proliferation and density, and inversely with miR-203. The findings identify ZNF217 as a potential target toward which preexisting therapies, such as the Akt inhibitor triciribine, could be used as a chemopreventive agent to reduce cancer risk in women with high mammographic density.
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http://dx.doi.org/10.1172/JCI129249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598051PMC
November 2020

Feeling Stress: The Mechanics of Cancer Progression and Aggression.

Front Cell Dev Biol 2018 28;6:17. Epub 2018 Feb 28.

Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, CA, United States.

The tumor microenvironment is a dynamic landscape in which the physical and mechanical properties evolve dramatically throughout cancer progression. These changes are driven by enhanced tumor cell contractility and expansion of the growing tumor mass, as well as through alterations to the material properties of the surrounding extracellular matrix (ECM). Consequently, tumor cells are exposed to a number of different mechanical inputs including cell-cell and cell-ECM tension, compression stress, interstitial fluid pressure and shear stress. Oncogenes engage signaling pathways that are activated in response to mechanical stress, thereby reworking the cell's intrinsic response to exogenous mechanical stimuli, enhancing intracellular tension via elevated actomyosin contraction, and influencing ECM stiffness and tissue morphology. In addition to altering their intracellular tension and remodeling the microenvironment, cells actively respond to these mechanical perturbations phenotypically through modification of gene expression. Herein, we present a description of the physical changes that promote tumor progression and aggression, discuss their interrelationship and highlight emerging therapeutic strategies to alleviate the mechanical stresses driving cancer to malignancy.
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http://dx.doi.org/10.3389/fcell.2018.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835517PMC
February 2018

Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

Mol Cancer Res 2018 05 5;16(5):777-790. Epub 2018 Feb 5.

Department of Neurology, University of California, San Francisco, San Francisco, California.

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. , the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932284PMC
May 2018

Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.

Nat Cell Biol 2016 Dec 7;18(12):1336-1345. Epub 2016 Nov 7.

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, California 94143, USA.

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.
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http://dx.doi.org/10.1038/ncb3429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361403PMC
December 2016

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

Nat Med 2016 05 18;22(5):497-505. Epub 2016 Apr 18.

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.
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http://dx.doi.org/10.1038/nm.4082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860133PMC
May 2016

Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness.

J Cell Biol 2016 Mar;212(6):707-19

Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064

Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence.
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http://dx.doi.org/10.1083/jcb.201507054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792073PMC
March 2016

The extracellular matrix modulates the hallmarks of cancer.

EMBO Rep 2014 Dec 8;15(12):1243-53. Epub 2014 Nov 8.

Department of Surgery, Center for Bioengineering and Tissue Regeneration UCSF, San Francisco, CA, USA Departments of Anatomy, Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, USA Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research UCSF, San Francisco, CA, USA UCSF Helen Diller Comprehensive Cancer Center UCSF, San Francisco, CA, USA

The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer-associated stromal cells. Hanahan and Weinberg defined the hallmarks of cancer to encompass key biological capabilities that are acquired and essential for the development, growth and dissemination of all human cancers. These capabilities include sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction and chronic inflammation. Here, we argue that biophysical and biochemical cues from the tumor-associated extracellular matrix influence each of these cancer hallmarks and are therefore critical for malignancy. We suggest that the success of cancer prevention and therapy programs requires an intimate understanding of the reciprocal feedback between the evolving extracellular matrix, the tumor cells and its cancer-associated cellular stroma.
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http://dx.doi.org/10.15252/embr.201439246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264927PMC
December 2014

Extracellular matrix assembly: a multiscale deconstruction.

Nat Rev Mol Cell Biol 2014 Dec 5;15(12):771-85. Epub 2014 Nov 5.

1] Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco. [2] Department of Anatomy, University of California, San Francisco. [3] Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco. [4] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco. [5] UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.
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http://dx.doi.org/10.1038/nrm3902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682873PMC
December 2014

The cancer glycocalyx mechanically primes integrin-mediated growth and survival.

Nature 2014 Jul 25;511(7509):319-25. Epub 2014 Jun 25.

1] Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, California 94143, USA [2] Bay Area Physical Sciences-Oncology Program, University of California, Berkeley, California 94720, USA [3] Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA [4] Departments of Anatomy and Bioengineering and Therapeutic Sciences and Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA.

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.
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http://dx.doi.org/10.1038/nature13535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487551PMC
July 2014

Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.

Nat Med 2014 Apr 16;20(4):360-7. Epub 2014 Mar 16.

1] Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. [2] Department of Anatomy and Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA. [4] UCSF Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA.

Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.
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http://dx.doi.org/10.1038/nm.3497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981899PMC
April 2014

HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype.

J Clin Invest 2010 May 12;120(5):1535-50. Epub 2010 Apr 12.

Department of Pathology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications.
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http://dx.doi.org/10.1172/JCI39534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860938PMC
May 2010

Tensile loading modulates bone marrow stromal cell differentiation and the development of engineered fibrocartilage constructs.

Tissue Eng Part A 2010 Jun;16(6):1913-23

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.

Mesenchymal progenitors such as bone marrow stromal cells (BMSCs) are an attractive cell source for fibrocartilage tissue engineering, but the types or combinations of signals required to promote fibrochondrocyte-specific differentiation remain unclear. The present study investigated the influences of cyclic tensile loading on the chondrogenesis of BMSCs and the development of engineered fibrocartilage. Cyclic tensile displacements (10%, 1 Hz) were applied to BMSC-seeded fibrin constructs for short (24 h) or extended (1-2 weeks) periods using a custom loading system. At early stages of chondrogenesis, 24 h of cyclic tension stimulated both protein and proteoglycan synthesis, but at later stages, tension increased protein synthesis only. One week of intermittent cyclic tension significantly increased the total sulfated glycosaminoglycan and collagen contents in the constructs, but these differences were lost after 2 weeks of loading. Constraining the gels during the extended culture periods prevented contraction of the fibrin matrix, induced collagen fiber alignment, and increased sulfated glycosaminoglycan release to the media. Cyclic tension specifically stimulated collagen I mRNA expression and protein synthesis, but had no effect on collagen II, aggrecan, or osteocalcin mRNA levels. Overall, these studies suggest that the combination of chondrogenic stimuli and tensile loading promotes fibrochondrocyte-like differentiation of BMSCs and has the potential to direct fibrocartilage development in vitro.
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http://dx.doi.org/10.1089/ten.TEA.2009.0561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949230PMC
June 2010

Dynamic compression regulates the expression and synthesis of chondrocyte-specific matrix molecules in bone marrow stromal cells.

Stem Cells 2007 Mar 22;25(3):655-63. Epub 2006 Nov 22.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.

The overall objective of the present study was to investigate the mechanotransduction of bovine bone marrow stromal cells (BMSCs) through the interactions between transforming growth factor beta1 (TGF-beta1), dexamethasone, and dynamic compressive loading. Overall, the addition of TGF-beta1 increased cell viability, extracellular matrix (ECM) gene expression, matrix synthesis, and sulfated glycosaminoglycan content over basal construct medium. The addition of dexamethasone further enhanced extracellular matrix gene expression and protein synthesis. There was little stimulation of ECM gene expression or matrix synthesis in any medium group by mechanical loading introduced on day 8. In contrast, there was significant stimulation of ECM gene expression and matrix synthesis in chondrogenic media by dynamic loading introduced on day 16. The level of stimulation was also dependent on the medium supplements, with the samples treated with basal medium being the least responsive and the samples treated with TGF-beta1 and dexamethasone being the most responsive at day 16. Both collagen I and collagen II gene expressions were more responsive to dynamic loading than aggrecan gene expression. Dynamic compression upregulated Smad2/3 phosphorylation in samples treated with basal and TGF-beta1 media. These findings suggest that interactions between mechanical stimuli and TGF-beta signaling may be an important mechanotransduction pathway for BMSCs, and they indicate that mechanosensitivity may vary during the process of chondrogenesis.
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http://dx.doi.org/10.1634/stemcells.2006-0435DOI Listing
March 2007

Dynamic compression of chondrocyte-seeded fibrin gels: effects on matrix accumulation and mechanical stiffness.

Osteoarthritis Cartilage 2004 Feb;12(2):117-30

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, USA.

Objective: Various strategies have been tested to direct and control matrix synthesis in tissue engineered cartilage, including mechanical stimulation of the construct both before and after implantation. This study examined the effects of oscillatory compression on chondrocytes in a fibrin-based tissue engineered cartilage.

Design: Chondrocyte-seeded fibrin gels were cultured under unconfined mechanical compression for 10 or 20 days (free-swelling, 10% static, or 10+/-4% at 0.1 or 1Hz). During the culture period, accumulation of nitrite, sGAG, and proteolytic enzymes in the culture media were monitored. Following culture, the mechanical stiffness and biochemical content of the gels (DNA, sGAG, and hydroxyproline content and GAG Delta-disaccharide composition) were assessed.

Results: Compared to free-swelling conditions, static compression had little effect on the mechanical stiffness or biochemical content of the gels. Compared to static compression, oscillatory compression produced softer gels, inhibited sGAG and hydroxyproline accumulation in the gels, and stimulated accumulation of nitrite and sGAG in the culture media. Minimal differences were observed in DNA content and Delta-disaccharide composition across treatment conditions.

Conclusions: In this study, oscillatory compression inhibited formation of cartilage-like tissues by chondrocytes in fibrin gels. These results suggest that the effects of mechanical stimuli on tissue engineered cartilage may vary substantially between different scaffold systems.
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http://dx.doi.org/10.1016/j.joca.2003.08.009DOI Listing
February 2004
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