Tissue matrix arrays for high-throughput screening and systems analysis of cell function

Beachley, Vince; Wolf, Matthew T.; Hall, Matthew D.; Manda, Srikanth S.; Jacobs, Heather; Blatchley, Michael R.; Bader, Joel S.; Pandey, Akhilesh; Pardoll, Drew M.; Elisseeff, Jennifer H.

doi:10.1038/nmeth.3619

Cited by 143 publications

(129 citation statements)

References 42 publications

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“…ECM proteins, such as fibronectin and collagen I, constitute complex grid structures that support and connect surrounding connective tissues [33]. The overexpression of ECM proteins, combined with the obstruction of their degradation, contributes to the accumulation of the ECM, eventually leading to tissue fibrosis [34-38].…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

Chen

Yang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Transforming growth factor-β1 (TGF-β1) plays a crucial role in chronic inflammation in various tissues, and is related to inflammation-caused organ fibrogenesis associated with the epithelial-mesenchymal transition (EMT) and the deposition of the extracellular matrix (ECM). However, the effect of TGF-β1 on bovine mammary epithelial cells (BMECs) with mastitis, and its mechanism, remain unknown. Methods: We analyzed the level of TGF-β1 in inflamed mammary tissues and cells using western blotting. BMECs were treated with TGF-β1, and EMT-related gene and protein expression changes were evaluated using quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescence. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor, and analyzed EMT-related protein expression by western blotting. In addition, we injected TGF-β1 into mice mammary glands to investigate whether it can cause mammary fibrosis in vivo. Results: The TGF-β1 level was up-regulated in mammary tissues with mastitis and in inducible inflammatory BMECs. TGF-β1 treatment activated the TGF/ Smad signaling pathway in BMECs during their transition to the EMT phenotype, as indicated by morphological changes from a cobblestone-like shape to a spindle-like one. TGF-β1 treatment also up-regulated the expression of α-smooth muscle actin, vimentin, and collagen I, albumin, and down-regulated the expression of E-cadherin both in mRNA level and protein level. Furthermore, TGF-β1 enhanced the gene expressions of MMP2, MMP7, and fibronectin in BMECs. TGF-β1 injection induced mice mammary infection and fibrosis. Conclusion: These findings suggested that aberrant up-regulation of TGF-β1 in bovine mastitic mammary glands might play an important role in bovine mammary fibrosis caused by unresolved inflammation.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

Chen

Yang

Wang

et al. 2017

Cell Physiol Biochem

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“…Collagen is present in mammary carcinoma tissues at amounts 3 to 10 times higher than other ECM proteins such as HA and GAG [59, 60]. Markers of mammary carcinoma such as increased tissue density and stiffness are primarily due to overexpressed collagen in tumor ECM.…”

Section: Discussionmentioning

confidence: 99%

Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model

Özçelikkale

Shin

Noe-Kim

et al. 2017

Journal of Controlled Release

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Successful drug delivery and overcoming drug resistance are the primary clinical challenges for management and treatment of cancer. The ability to rapidly screen drugs and delivery systems within physiologically relevant environments is critically important; yet is currently limited due to lack of appropriate tumor models. To address this problem, we developed the Tumor-microenvironment-on-chip (T-MOC), a new microfluidic tumor model simulating the interstitial flow, plasma clearance, and transport of the drug within the tumor. We demonstrated T-MOC’s capabilities by assessing the delivery and efficacy of doxorubicin in small molecular form versus hyaluronic acid nanoparticle (NP) formulation in MCF-7 and MDA-MB-231, two cell lines representative of different molecular subtypes of breast cancer. Doxorubicin accumulated and penetrated similarly in both cell lines while the NP accumulated more in MDA-MB-231 than MCF-7 potentially due to binding of hyaluronic acid to CD44 expressed by MDA-MB-231. However, the penetration of the NP was less than the molecular drug due to its larger size. In addition, both cell lines cultured on the T-MOC showed increased resistance to the drug compared to 2D culture where MDA-MB-231 attained a drug-resistant tumor-initiating phenotype indicated by increased CD44 expression. When grown in immunocompromised mice, both cell lines exhibited cell-type-dependent resistance and phenotypic changes similar to T-MOC, confirming its predictive ability for in vivo drug response. This initial characterization of T-MOC indicates its transformative potential for in vitro testing of drug efficacy towards prediction of in vivo outcomes and investigation of drug resistance mechanisms for advancement of personalized medicine.

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“…Alternatively, decellularization of tissues yields native extracellular matrices that may have more representative physicochemical properties of the native niche. 50,51 However, decellularized tissues and native ECM often have poorly defined composition, and may contain many different biochemical and physical cues, making it difficult to test specific hypotheses. Raising the concentration of ECM proteins in hydrogels is often used to increase the stiffness to a limited range, but it also increases the density of adhesion ligands available for cellular receptors.…”

Section: Manipulating Mechanobiologymentioning

confidence: 99%

Mechanical forces direct stem cell behaviour in development and regeneration

Vining

Mooney

2017

Nat Rev Mol Cell Biol

1,168

958

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Stem cells and their local microenvironment, or niche, communicate through mechanical, cues to regulate cell fate and cell behaviour, and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their differentiation and self-renewal. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights on the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.

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Tissue matrix arrays for high-throughput screening and systems analysis of cell function

Cited by 143 publications

References 42 publications

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

TGF-β1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFβ1/Smad Signaling Pathway

Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model

Mechanical forces direct stem cell behaviour in development and regeneration

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