International Journal of Molecular Sciences

Editorial

Jump to: Research, Review

5 pages, 176 KiB

Open AccessEditorial

Extracellular Matrix in Development and Disease

by Julia Thom Oxford, Jonathon C. Reeck and Makenna J. Hardy

Int. J. Mol. Sci. 2019, 20(1), 205; https://doi.org/10.3390/ijms20010205 - 8 Jan 2019

Cited by 27 | Viewed by 5529

Abstract

The evolution of multicellular metazoan organisms was marked by the inclusion of an extracellular matrix (ECM), a multicomponent, proteinaceous network between cells that contributes to the spatial arrangement of cells and the resulting tissue organization. [...] Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

Research

Jump to: Editorial, Review

13 pages, 29292 KiB

Open AccessArticle

Porcine Breast Extracellular Matrix Hydrogel for Spatial Tissue Culture

by Girdhari Rijal, Jing Wang, Ilhan Yu, David R. Gang, Roland K. Chen and Weimin Li

Int. J. Mol. Sci. 2018, 19(10), 2912; https://doi.org/10.3390/ijms19102912 - 25 Sep 2018

Cited by 22 | Viewed by 6304

Abstract

Porcine mammary fatty tissues represent an abundant source of natural biomaterial for generation of breast-specific extracellular matrix (ECM). Here we report the extraction of total ECM proteins from pig breast fatty tissues, the fabrication of hydrogel and porous scaffolds from the extracted ECM [...] Read more.

Porcine mammary fatty tissues represent an abundant source of natural biomaterial for generation of breast-specific extracellular matrix (ECM). Here we report the extraction of total ECM proteins from pig breast fatty tissues, the fabrication of hydrogel and porous scaffolds from the extracted ECM proteins, the structural properties of the scaffolds (tissue matrix scaffold, TMS), and the applications of the hydrogel in human mammary epithelial cell spatial cultures for cell surface receptor expression, metabolomics characterization, acini formation, proliferation, migration between different scaffolding compartments, and in vivo tumor formation. This model system provides an additional option for studying human breast diseases such as breast cancer. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

19 pages, 2889 KiB

Open AccessArticle

Decellularized Diaphragmatic Muscle Drives a Constructive Angiogenic Response In Vivo

by Mario Enrique Alvarèz Fallas, Martina Piccoli, Chiara Franzin, Alberto Sgrò, Arben Dedja, Luca Urbani, Enrica Bertin, Caterina Trevisan, Piergiorgio Gamba, Alan J. Burns, Paolo De Coppi and Michela Pozzobon

Int. J. Mol. Sci. 2018, 19(5), 1319; https://doi.org/10.3390/ijms19051319 - 28 Apr 2018

Cited by 25 | Viewed by 6038

Abstract

Skeletal muscle tissue engineering (TE) aims to efficiently repair large congenital and acquired defects. Biological acellular scaffolds are considered a good tool for TE, as decellularization allows structural preservation of tissue extracellular matrix (ECM) and conservation of its unique cytokine reservoir and the [...] Read more.

Skeletal muscle tissue engineering (TE) aims to efficiently repair large congenital and acquired defects. Biological acellular scaffolds are considered a good tool for TE, as decellularization allows structural preservation of tissue extracellular matrix (ECM) and conservation of its unique cytokine reservoir and the ability to support angiogenesis, cell viability, and proliferation. This represents a major advantage compared to synthetic scaffolds, which can acquire these features only after modification and show limited biocompatibility. In this work, we describe the ability of a skeletal muscle acellular scaffold to promote vascularization both ex vivo and in vivo. Specifically, chicken chorioallantoic membrane assay and protein array confirmed the presence of pro-angiogenic molecules in the decellularized tissue such as HGF, VEGF, and SDF-1α. The acellular muscle was implanted in BL6/J mice both subcutaneously and ortotopically. In the first condition, the ECM-derived scaffold appeared vascularized 7 days post-implantation. When the decellularized diaphragm was ortotopically applied, newly formed blood vessels containing CD31⁺, αSMA⁺, and vWF⁺ cells were visible inside the scaffold. Systemic injection of Evans Blue proved function and perfusion of the new vessels, underlying a tissue-regenerative activation. On the contrary, the implantation of a synthetic matrix made of polytetrafluoroethylene used as control was only surrounded by vWF⁺ cells, with no cell migration inside the scaffold and clear foreign body reaction (giant cells were visible). The molecular profile and the analysis of macrophages confirmed the tendency of the synthetic scaffold to enhance inflammation instead of regeneration. In conclusion, we identified the angiogenic potential of a skeletal muscle-derived acellular scaffold and the pro-regenerative environment activated in vivo, showing clear evidence that the decellularized diaphragm is a suitable candidate for skeletal muscle tissue engineering and regeneration. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

12 pages, 10216 KiB

Open AccessArticle

The ADAMTS5 Metzincin Regulates Zebrafish Somite Differentiation

by Carolyn M. Dancevic, Yann Gibert, Joachim Berger, Adam D. Smith, Clifford Liongue, Nicole Stupka, Alister C. Ward and Daniel R. McCulloch

Int. J. Mol. Sci. 2018, 19(3), 766; https://doi.org/10.3390/ijms19030766 - 7 Mar 2018

Cited by 3 | Viewed by 5162

Abstract

The ADAMTS5 metzincin, a secreted zinc-dependent metalloproteinase, modulates the extracellular matrix (ECM) during limb morphogenesis and other developmental processes. Here, the role of ADAMTS5 was investigated by knockdown of zebrafish adamts5 during embryogenesis. This revealed impaired Sonic Hedgehog (Shh) signaling during somite patterning [...] Read more.

The ADAMTS5 metzincin, a secreted zinc-dependent metalloproteinase, modulates the extracellular matrix (ECM) during limb morphogenesis and other developmental processes. Here, the role of ADAMTS5 was investigated by knockdown of zebrafish adamts5 during embryogenesis. This revealed impaired Sonic Hedgehog (Shh) signaling during somite patterning and early myogenesis. Notably, synergistic regulation of myod expression by ADAMTS5 and Shh during somite differentiation was observed. These roles were not dependent upon the catalytic activity of ADAMTS5. These data identify a non-enzymatic function for ADAMTS5 in regulating an important cell signaling pathway that impacts on muscle development, with implications for musculoskeletal diseases in which ADAMTS5 and Shh have been associated. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

14 pages, 2181 KiB

Open AccessArticle

Overexpression of the Vitronectin V10 Subunit in Patients with Nonalcoholic Steatohepatitis: Implications for Noninvasive Diagnosis of NASH

by Maria Del Ben, Diletta Overi, Licia Polimeni, Guido Carpino, Giancarlo Labbadia, Francesco Baratta, Daniele Pastori, Valeria Noce, Eugenio Gaudio, Francesco Angelico and Carmine Mancone

Int. J. Mol. Sci. 2018, 19(2), 603; https://doi.org/10.3390/ijms19020603 - 18 Feb 2018

Cited by 7 | Viewed by 4343

Abstract

Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, [...] Read more.

Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

17 pages, 2528 KiB

Open AccessArticle

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

by Salin A. Chakkalakal, Juliane Heilig, Ulrich Baumann, Mats Paulsson and Frank Zaucke

Int. J. Mol. Sci. 2018, 19(2), 541; https://doi.org/10.3390/ijms19020541 - 11 Feb 2018

Cited by 17 | Viewed by 5146

Abstract

Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the [...] Read more.

Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the X or Y position within the Gly-X-Y cause different phenotypes like Stickler syndrome and congenital spondyloepiphyseal dysplasia (SEDC). We investigated the consequences of arginine to cysteine substitutions (X or Y position within the Gly-X-Y) towards the N and C terminus of the triple helix. Protein expression and its secretion trafficking were analyzed. Substitutions R75C, R134C and R704C did not alter the thermal stability with respect to wild type; R740C and R789C proteins displayed significantly reduced melting temperatures (T_m) affecting thermal stability. Additionally, R740C and R789C were susceptible to proteases; in cell culture, R789C protein was further cleaved by matrix metalloproteinases (MMPs) resulting in expression of only a truncated fragment affecting its secretion and intracellular retention. Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

1951 KiB

Open AccessArticle

Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin

by Sara Stridh, Fredrik Palm, Tomoko Takahashi, Mayumi Ikegami-Kawai, Malou Friederich-Persson and Peter Hansell

Int. J. Mol. Sci. 2017, 18(12), 2701; https://doi.org/10.3390/ijms18122701 - 13 Dec 2017

Cited by 7 | Viewed by 4044

Abstract

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with [...] Read more.

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10⁻¹⁰ and 10⁻⁸ M) increased HA 3-fold. On the contrary, at a high concentration (10⁻⁶ M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

7731 KiB

Open AccessArticle

Glucocorticoids Improve Myogenic Differentiation In Vitro by Suppressing the Synthesis of Versican, a Transitional Matrix Protein Overexpressed in Dystrophic Skeletal Muscles

by Natasha McRae, Leonard Forgan, Bryony McNeill, Alex Addinsall, Daniel McCulloch, Chris Van der Poel and Nicole Stupka

Int. J. Mol. Sci. 2017, 18(12), 2629; https://doi.org/10.3390/ijms18122629 - 6 Dec 2017

Cited by 17 | Viewed by 6960

Abstract

In Duchenne muscular dystrophy (DMD), a dysregulated extracellular matrix (ECM) directly exacerbates pathology. Glucocorticoids are beneficial therapeutics in DMD, and have pleiotropic effects on the composition and processing of ECM proteins in other biological contexts. The synthesis and remodelling of a transitional versican-rich [...] Read more.

In Duchenne muscular dystrophy (DMD), a dysregulated extracellular matrix (ECM) directly exacerbates pathology. Glucocorticoids are beneficial therapeutics in DMD, and have pleiotropic effects on the composition and processing of ECM proteins in other biological contexts. The synthesis and remodelling of a transitional versican-rich matrix is necessary for myogenesis; whether glucocorticoids modulate this transitional matrix is not known. Here, versican expression and processing were examined in hindlimb and diaphragm muscles from mdx dystrophin-deficient mice and C57BL/10 wild type mice. V0/V1 versican (Vcan) mRNA transcripts and protein levels were upregulated in dystrophic compared to wild type muscles, especially in the more severely affected mdx diaphragm. Processed versican (versikine) was detected in wild type and dystrophic muscles, and immunoreactivity was highly associated with newly regenerated myofibres. Glucocorticoids enhanced C2C12 myoblast fusion by modulating the expression of genes regulating transitional matrix synthesis and processing. Specifically, Tgfβ1, Vcan and hyaluronan synthase-2 (Has2) mRNA transcripts were decreased by 50% and Adamts1 mRNA transcripts were increased three-fold by glucocorticoid treatment. The addition of exogenous versican impaired myoblast fusion, whilst glucocorticoids alleviated this inhibition in fusion. In dystrophic mdx muscles, versican upregulation correlated with pathology. We propose that versican is a novel and relevant target gene in DMD, given its suppression by glucocorticoids and that in excess it impairs myoblast fusion, a process key for muscle regeneration. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

1119 KiB

Open AccessArticle

Increased Serum Levels of Fetal Tenascin-C Variants in Patients with Pulmonary Hypertension: Novel Biomarkers Reflecting Vascular Remodeling and Right Ventricular Dysfunction?

by Ilonka Rohm, Katja Grün, Linda Marleen Müller, Daniel Kretzschmar, Michael Fritzenwanger, Atilla Yilmaz, Alexander Lauten, Christian Jung, P. Christian Schulze, Alexander Berndt and Marcus Franz

Int. J. Mol. Sci. 2017, 18(11), 2371; https://doi.org/10.3390/ijms18112371 - 8 Nov 2017

Cited by 17 | Viewed by 4259

Abstract

Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular [...] Read more.

Pulmonary vascular remodeling is a pathophysiological feature that common to all classes of pulmonary hypertension (PH) and right ventricular dysfunction, which is the major prognosis-limiting factor. Vascular, as well as cardiac tissue remodeling are associated with a re-expression of fetal variants of cellular adhesion proteins, including tenascin-C (Tn-C). We analyzed circulating levels of the fetal Tn-C splicing variants B⁺ and C⁺ Tn-C in serum of PH patients to evaluate their potential as novel biomarkers reflecting vascular remodeling and right ventricular dysfunction. Serum concentrations of B⁺ and C⁺ Tn-C were determined in 80 PH patients and were compared to 40 healthy controls by enzyme-linked immunosorbent assay. Clinical, laboratory, echocardiographic, and functional data were correlated with Tn-C levels. Serum concentrations of both Tn-C variants were significantly elevated in patients with PH (p < 0.05). Significant correlations could be observed between Tn-C and echocardiographic parameters, including systolic pulmonary artery pressure (B⁺ Tn-C: r = 0.31, p < 0.001, C⁺ Tn-C: r = 0.26, p = 0.006) and right atrial area (B⁺ Tn-C: r = 0.46, p < 0.001, C⁺ Tn-C: r = 0.49, p < 0.001), and laboratory values like BNP (B⁺ Tn-C: r = 0.45, p < 0.001, C⁺ Tn-C: r = 0.42, p < 0.001). An inverse correlation was observed between Tn-C variants and 6-minute walk distance as a functional parameter (B⁺ Tn-C: r = −0.54, p < 0.001, C⁺ Tn-C: r = −0.43, p < 0.001). In a multivariate analysis, B⁺ Tn-C, but not C⁺ Tn-C, was found to be an independent predictor of pulmonary hypertension. Both fetal Tn-C variants may represent novel biomarkers that are capable of estimating both pulmonary vascular remodeling and right ventricular load. The potential beneficial impact of Tn-C variants for risk stratification in patients with PH needs further investigation. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

31 pages, 3702 KiB

Open AccessReview

Role of Extracellular Matrix in Development and Cancer Progression

by Cameron Walker, Elijah Mojares and Armando Del Río Hernández

Int. J. Mol. Sci. 2018, 19(10), 3028; https://doi.org/10.3390/ijms19103028 - 4 Oct 2018

Cited by 728 | Viewed by 28483

Abstract

The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM’s composition and [...] Read more.

The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM’s composition and organization are spatiotemporally regulated to control cell behaviour and differentiation, but dysregulation of ECM dynamics leads to the development of diseases such as cancer. The chemical cues presented by the ECM have been appreciated as key drivers for both development and cancer progression. However, the mechanical forces present due to the ECM have been largely ignored but recently recognized to play critical roles in disease progression and malignant cell behaviour. Here, we review the ways in which biophysical forces of the microenvironment influence biochemical regulation and cell phenotype during key stages of human development and cancer progression. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

11 pages, 200 KiB

Open AccessReview

Decellularized Tissue for Muscle Regeneration

by Anna Urciuolo and Paolo De Coppi

Int. J. Mol. Sci. 2018, 19(8), 2392; https://doi.org/10.3390/ijms19082392 - 14 Aug 2018

Cited by 58 | Viewed by 7381

Abstract

Several acquired or congenital pathological conditions can affect skeletal muscle leading to volumetric muscle loss (VML), i.e., an irreversible loss of muscle mass and function. Decellularized tissues are natural scaffolds derived from tissues or organs, in which the cellular and nuclear contents are [...] Read more.

Several acquired or congenital pathological conditions can affect skeletal muscle leading to volumetric muscle loss (VML), i.e., an irreversible loss of muscle mass and function. Decellularized tissues are natural scaffolds derived from tissues or organs, in which the cellular and nuclear contents are eliminated, but the tridimensional (3D) structure and composition of the extracellular matrix (ECM) are preserved. Such scaffolds retain biological activity, are biocompatible and do not show immune rejection upon allogeneic or xenogeneic transplantation. An increase number of reports suggest that decellularized tissues/organs are promising candidates for clinical application in patients affected by VML. Here we explore the different strategies used to generate decellularized matrix and their therapeutic outcome when applied to treat VML conditions, both in patients and in animal models. The wide variety of VML models, source of tissue and methods of decellularization have led to discrepant results. Our review study evaluates the biological and clinical significance of reported studies, with the final aim to clarify the main aspects that should be taken into consideration for the future application of decellularized tissues in the treatment of VML conditions. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

36 pages, 1012 KiB

Open AccessReview

From Structure to Phenotype: Impact of Collagen Alterations on Human Health

by Lavinia Arseni, Anita Lombardi and Donata Orioli

Int. J. Mol. Sci. 2018, 19(5), 1407; https://doi.org/10.3390/ijms19051407 - 8 May 2018

Cited by 119 | Viewed by 20509

Abstract

The extracellular matrix (ECM) is a highly dynamic and heterogeneous structure that plays multiple roles in living organisms. Its integrity and homeostasis are crucial for normal tissue development and organ physiology. Loss or alteration of ECM components turns towards a disease outcome. In [...] Read more.

The extracellular matrix (ECM) is a highly dynamic and heterogeneous structure that plays multiple roles in living organisms. Its integrity and homeostasis are crucial for normal tissue development and organ physiology. Loss or alteration of ECM components turns towards a disease outcome. In this review, we provide a general overview of ECM components with a special focus on collagens, the most abundant and diverse ECM molecules. We discuss the different functions of the ECM including its impact on cell proliferation, migration and differentiation by highlighting the relevance of the bidirectional cross-talk between the matrix and surrounding cells. By systematically reviewing all the hereditary disorders associated to altered collagen structure or resulting in excessive collagen degradation, we point to the functional relevance of the collagen and therefore of the ECM elements for human health. Moreover, the large overlapping spectrum of clinical features of the collagen-related disorders makes in some cases the patient clinical diagnosis very difficult. A better understanding of ECM complexity and molecular mechanisms regulating the expression and functions of the various ECM elements will be fundamental to fully recognize the different clinical entities. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

15 pages, 615 KiB

Open AccessReview

Human Cancer and Platelet Interaction, a Potential Therapeutic Target

by Shike Wang, Zhenyu Li and Ren Xu

Int. J. Mol. Sci. 2018, 19(4), 1246; https://doi.org/10.3390/ijms19041246 - 20 Apr 2018

Cited by 62 | Viewed by 8317

Abstract

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect [...] Read more.

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce cancer-related thrombosis. Here, we discuss the potential function of platelets in regulating cancer progression and summarize the factors and signaling pathways that mediate the cancer cell-platelet interaction. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

14 pages, 9238 KiB

Open AccessReview

Microfabrication-Based Three-Dimensional (3-D) Extracellular Matrix Microenvironments for Cancer and Other Diseases

by Kena Song, Zirui Wang, Ruchuan Liu, Guo Chen and Liyu Liu

Int. J. Mol. Sci. 2018, 19(4), 935; https://doi.org/10.3390/ijms19040935 - 21 Mar 2018

Cited by 13 | Viewed by 6115

Abstract

Exploring the complicated development of tumors and metastases needs a deep understanding of the physical and biological interactions between cancer cells and their surrounding microenvironments. One of the major challenges is the ability to mimic the complex 3-D tissue microenvironment that particularly influences [...] Read more.

Exploring the complicated development of tumors and metastases needs a deep understanding of the physical and biological interactions between cancer cells and their surrounding microenvironments. One of the major challenges is the ability to mimic the complex 3-D tissue microenvironment that particularly influences cell proliferation, migration, invasion, and apoptosis in relation to the extracellular matrix (ECM). Traditional cell culture is unable to create 3-D cell scaffolds resembling tissue complexity and functions, and, in the past, many efforts were made to realize the goal of obtaining cell clusters in hydrogels. However, the available methods still lack a precise control of cell external microenvironments. Recently, the rapid development of microfabrication techniques, such as 3-D printing, microfluidics, and photochemistry, has offered great advantages in reconstructing 3-D controllable cancer cell microenvironments in vitro. Consequently, various biofunctionalized hydrogels have become the ideal candidates to help the researchers acquire some new insights into various diseases. Our review will discuss some important studies and the latest progress regarding the above approaches for the production of 3-D ECM structures for cancer and other diseases. Especially, we will focus on new discoveries regarding the impact of the ECM on different aspects of cancer metastasis, e.g., collective invasion, enhanced intravasation by stress and aligned collagen fibers, angiogenesis regulation, as well as on drug screening. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

33 pages, 2321 KiB

Open AccessReview

Beyond the Matrix: The Many Non-ECM Ligands for Integrins

by Bryce LaFoya, Jordan A. Munroe, Alison Miyamoto, Michael A. Detweiler, Jacob J. Crow, Tana Gazdik and Allan R. Albig

Int. J. Mol. Sci. 2018, 19(2), 449; https://doi.org/10.3390/ijms19020449 - 2 Feb 2018

Cited by 49 | Viewed by 14077

Abstract

The traditional view of integrins portrays these highly conserved cell surface receptors as mediators of cellular attachment to the extracellular matrix (ECM), and to a lesser degree, as coordinators of leukocyte adhesion to the endothelium. These canonical activities are indispensable; however, there is [...] Read more.

The traditional view of integrins portrays these highly conserved cell surface receptors as mediators of cellular attachment to the extracellular matrix (ECM), and to a lesser degree, as coordinators of leukocyte adhesion to the endothelium. These canonical activities are indispensable; however, there is also a wide variety of integrin functions mediated by non-ECM ligands that transcend the traditional roles of integrins. Some of these unorthodox roles involve cell-cell interactions and are engaged to support immune functions such as leukocyte transmigration, recognition of opsonization factors, and stimulation of neutrophil extracellular traps. Other cell-cell interactions mediated by integrins include hematopoietic stem cell and tumor cell homing to target tissues. Integrins also serve as cell-surface receptors for various growth factors, hormones, and small molecules. Interestingly, integrins have also been exploited by a wide variety of organisms including viruses and bacteria to support infectious activities such as cellular adhesion and/or cellular internalization. Additionally, the disruption of integrin function through the use of soluble integrin ligands is a common strategy adopted by several parasites in order to inhibit blood clotting during hematophagy, or by venomous snakes to kill prey. In this review, we strive to go beyond the matrix and summarize non-ECM ligands that interact with integrins in order to highlight these non-traditional functions of integrins. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

14 pages, 248 KiB

Open AccessReview

The Biological Role of Hyaluronan-Rich Oocyte-Cumulus Extracellular Matrix in Female Reproduction

by Eva Nagyova

Int. J. Mol. Sci. 2018, 19(1), 283; https://doi.org/10.3390/ijms19010283 - 18 Jan 2018

Cited by 27 | Viewed by 7774

Abstract

Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte. This review focuses on key molecules that play an important role in the formation of the cumulus ECM, generated by the oocyte-cumulus complex. In [...] Read more.

Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte. This review focuses on key molecules that play an important role in the formation of the cumulus ECM, generated by the oocyte-cumulus complex. In particular, the specific inhibitors (AG1478, lapatinib, indomethacin and MG132) and progesterone receptor antagonist (RU486) exerting their effects through the remodeling of the ECM of the cumulus cells surrounding the oocyte have been described. After gonadotropin stimulus, cumulus cells expand and form hyaluronan (HA)-rich cumulus ECM. In pigs, the proper structure of the cumulus ECM depends on the interaction between HA and serum-derived proteins of the inter-alpha-trypsin inhibitor (IαI) protein family. We have demonstrated the synthesis of HA by cumulus cells, and the presence of the IαI, tumor necrosis factor-alpha-induced protein 6 and pentraxin 3 in expanding oocyte-cumulus complexes (OCC). We have evaluated the covalent linkage of heavy chains of IαI proteins to HA, as the principal component of the expanded HA-rich cumulus ECM, in porcine OCC cultured in medium with specific inhibitors: AG1478 and lapatinib (both inhibitors of epidermal growth factor receptor tyrosine kinase activity); MG132 (a specific proteasomal inhibitor), indomethacin (cyclooxygenase inhibitor); and progesterone receptor antagonist (RU486). We have found that both RU486 and indomethacin does not disrupt the formation of the covalent linkage between the heavy chains of IαI to HA in the expanded OCC. In contrast, the inhibitors AG1478 and lapatinib prevent gonadotropin-induced cumulus expansion. Finally, the formation of oocyte-cumulus ECM relying on the covalent transfer of heavy chains of IαI molecules to HA has been inhibited in the presence of MG132. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

18 pages, 2450 KiB

Open AccessReview

Mast Cells: Key Contributors to Cardiac Fibrosis

by Scott P. Levick and Alexander Widiapradja

Int. J. Mol. Sci. 2018, 19(1), 231; https://doi.org/10.3390/ijms19010231 - 12 Jan 2018

Cited by 39 | Viewed by 6072

Abstract

Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac [...] Read more.

Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

998 KiB

Open AccessReview

Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases

by Yao Ye, Aurelia Vattai, Xi Zhang, Junyan Zhu, Christian J. Thaler, Sven Mahner, Udo Jeschke and Viktoria Von Schönfeldt

Int. J. Mol. Sci. 2017, 18(8), 1651; https://doi.org/10.3390/ijms18081651 - 29 Jul 2017

Cited by 79 | Viewed by 11459

Abstract

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). [...] Read more.

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Figure 1

664 KiB

Open AccessReview

Thrombospondins: A Role in Cardiovascular Disease

by Dimitry A. Chistiakov, Alexandra A. Melnichenko, Veronika A. Myasoedova, Andrey V. Grechko and Alexander N. Orekhov

Int. J. Mol. Sci. 2017, 18(7), 1540; https://doi.org/10.3390/ijms18071540 - 17 Jul 2017

Cited by 49 | Viewed by 9836

Abstract

Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, [...] Read more.

Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-β, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-β signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Extracellular Matrix in Development and Disease

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (19 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI