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1
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Cai D, Liu T, Weng W, Zhu X. Research Progress on Extracellular Matrix-Based Composite Materials in Antibacterial Field. Biomater Res 2025; 29:0128. [PMID: 39822928 PMCID: PMC11735711 DOI: 10.34133/bmr.0128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/07/2024] [Accepted: 12/14/2024] [Indexed: 01/19/2025] Open
Abstract
Due to their exceptional cell compatibility, biodegradability, and capacity to trigger tissue regeneration, extracellular matrix (ECM) materials have drawn considerable attention in tissue healing and regenerative medicine. Interestingly, these materials undergo continuous degradation and release antimicrobial peptides (AMPs) while simultaneously promoting tissue regeneration, thereby exerting a potent antibacterial effect. On this basis, a variety of basic properties of ECM materials, such as porous adsorption, hydrophilic adsorption, group crosslinking, and electrostatic crosslinking, can be used to facilitate the integration of ECM materials and antibacterial agents through physical and chemical approaches in order to enhance the antibacterial efficacy. This article reviews the recent advancements in the study of ECM antibacterial materials, including the antibacterial function and antibacterial mechanism of free-standing ECM materials and ECM-based composite materials. In addition, the urgent challenges and future research prospects of ECM materials in the anti-infection industry are discussed.
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Affiliation(s)
- Dan Cai
- Department of Orthopedics, The First People’s Hospital of Huzhou,
First Affiliated Hospital of Huzhou University, Zhejiang 313000, China
| | - Tuoqin Liu
- Intensive Care Unit, People’s Hospital of Wuxing District, Wuxing District Maternal and Child Health Hospital, Huzhou, Zhejiang 313000, China
| | - Wei Weng
- Department of Orthopedics, The First People’s Hospital of Huzhou,
First Affiliated Hospital of Huzhou University, Zhejiang 313000, China
| | - Xinhong Zhu
- Department of Orthopedics, The First People’s Hospital of Huzhou,
First Affiliated Hospital of Huzhou University, Zhejiang 313000, China
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2
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Kobayashi M, Negishi J, Ishida N, Hashimoto Y, Sasaki Y, Akiyoshi K, Kimura T, Kishida A. Effects of the matrix-bounded nanovesicles of high-hydrostatic pressure decellularized tissues on neural regeneration. SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS 2024; 25:2404380. [PMID: 39308888 PMCID: PMC11413956 DOI: 10.1080/14686996.2024.2404380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/25/2024]
Abstract
Decellularized tissues have been used as implantable materials for tissue regeneration because of their high biofunctionality. We have reported that high hydrostatic pressured (HHP) decellularized tissue developed in our laboratory exhibits good in vivo performance, but the details of the mechanism are still not known. Based on previous reports of bioactive factors called matrix bound nanovesicles (MBVs) within decellularized tissues, this study aims to investigate whether MBVs are also present in decellularized tissues prepared by HHP decellularization, which is different from the previously reported methods. In this study, we tried to extract bioactive factors from HHP decellularized brain and placenta, and evaluated their effects on nerves in vitro and in vivo, where its effects have been previously reported. The results confirmed that those factors can be extracted even if the decellularization method and tissue of origin differ, and that they have effects on a series of processes toward nerve regeneration, such as neurite outgrowth and nerve fiber repair.
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Affiliation(s)
- Mako Kobayashi
- Department of Materials Processing, Graduate School of Engineering, Tohoku University, Sendai, Miyagi, Japan
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
| | - Jun Negishi
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
- Department of Applied Biology, Faculty of Textile Science and Technology, Shinshu University, Ueda City, Nagano, Japan
| | - Naoki Ishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
| | - Yoshihide Hashimoto
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
| | - Yoshihiro Sasaki
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Tsuyoshi Kimura
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
- Department of Biomedical Engineering, Toyo University, Asaka-city, Saitama, Japan
| | - Akio Kishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo, Japan
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3
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Melrose J, Guilak F. Diverse and multifunctional roles for perlecan ( HSPG2) in repair of the intervertebral disc. JOR Spine 2024; 7:e1362. [PMID: 39081381 PMCID: PMC11286675 DOI: 10.1002/jsp2.1362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 06/11/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Perlecan is a widely distributed, modular, and multifunctional heparan sulfate proteoglycan, which facilitates cellular communication with the extracellular environment to promote tissue development, tissue homeostasis, and optimization of biomechanical tissue functions. Perlecan-mediated osmotic mechanotransduction serves to regulate the metabolic activity of cells in tissues subjected to tension, compression, or shear. Perlecan interacts with a vast array of extracellular matrix (ECM) proteins through which it stabilizes tissues and regulates the proliferation or differentiation of resident cell populations. Here we examine the roles of the HS-proteoglycan perlecan in the normal and destabilized intervertebral disc. The intervertebral disc cell has evolved to survive in a hostile weight bearing, acidic, low oxygen tension, and low nutrition environment, and perlecan provides cytoprotection, shields disc cells from excessive compressive forces, and sequesters a range of growth factors in the disc cell environment where they aid in cellular survival, proliferation, and differentiation. The cells in mechanically destabilized connective tissues attempt to re-establish optimal tissue composition and tissue functional properties by changing the properties of their ECM, in the process of chondroid metaplasia. We explore the possibility that perlecan assists in these cell-mediated tissue remodeling responses by regulating disc cell anabolism. Perlecan's mechano-osmotic transductive property may be of potential therapeutic application.
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Affiliation(s)
- James Melrose
- Raymond Purves Bone and Joint Research Laboratory, Kolling InstituteNorthern Sydney Local Health DistrictSt. LeonardsNew South WalesAustralia
- Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyNew South WalesAustralia
- Sydney Medical School, NorthernThe University of SydneySt. LeonardsNew South WalesAustralia
- Faculty of Medicine and HealthThe University of Sydney, Royal North Shore HospitalSt. LeonardsNew South WalesAustralia
| | - Farshid Guilak
- Department of Orthopaedic SurgeryWashington UniversitySt. LouisMissouriUSA
- Department of OrthopaedicsShriners Hospitals for ChildrenSt. LouisMissouriUSA
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Jariwala N, Ozols M, Eckersley A, Mambwe B, Watson REB, Zeef L, Gilmore A, Debelle L, Bell M, Bradley EJ, Doush Y, Keenan A, Courage C, Leroux R, Peschard O, Mondon P, Ringenbach C, Bernard L, Pitois A, Sherratt MJ. Prediction, screening and characterization of novel bioactive tetrapeptide matrikines for skin rejuvenation. Br J Dermatol 2024; 191:92-106. [PMID: 38375775 DOI: 10.1093/bjd/ljae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 02/08/2024] [Accepted: 02/10/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis. OBJECTIVES To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure. METHODS Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities. RESULTS Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine-proline-lysine-glycine) and LSVD (leucine-serine-valine-aspartate), that acted in vitro to enhance the transcription of matrix -organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow's feet and firmness in a mixed population. CONCLUSIONS This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.
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Affiliation(s)
- Nathan Jariwala
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science
| | - Matiss Ozols
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science
- Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, UK
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK
| | - Alexander Eckersley
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science
- Division of Musculoskeletal and Dermatological Sciences
| | | | - Rachel E B Watson
- Division of Musculoskeletal and Dermatological Sciences
- A*STAR Skin Research Laboratory (A*SRL), Agency for Science, Technology and Research (A*STAR) and National Skin Centre, Skin Research Institute of Singapore, Republic of Singapore
| | | | - Andrew Gilmore
- Wellcome Centre for Cell Matrix Research, Division of Cancer Sciences; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Laurent Debelle
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science
- UMR CNRS 7369 MEDyC, Université de Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, SFR CAP Santé, Moulin de la Housse, Reims, France
| | - Mike Bell
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | | | - Yegor Doush
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | - Amy Keenan
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | - Carole Courage
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | | | | | | | | | | | | | - Michael J Sherratt
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Science
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5
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Fujita M, Sasada M, Iyoda T, Fukai F. Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases. Int J Mol Sci 2024; 25:6591. [PMID: 38928297 PMCID: PMC11204155 DOI: 10.3390/ijms25126591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Senescence is a physiological and pathological cellular program triggered by various types of cellular stress. Senescent cells exhibit multiple characteristic changes. Among them, the characteristic flattened and enlarged morphology exhibited in senescent cells is observed regardless of the stimuli causing the senescence. Several studies have provided important insights into pro-adhesive properties of cellular senescence, suggesting that cell adhesion to the extracellular matrix (ECM), which is involved in characteristic morphological changes, may play pivotal roles in cellular senescence. Matricellular proteins, a group of structurally unrelated ECM molecules that are secreted into the extracellular environment, have the unique ability to control cell adhesion to the ECM by binding to cell adhesion receptors, including integrins. Recent reports have certified that matricellular proteins are closely involved in cellular senescence. Through this biological function, matricellular proteins are thought to play important roles in the pathogenesis of age-related diseases, including fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, and cancer. This review outlines recent studies on the role of matricellular proteins in inducing cellular senescence. We highlight the role of integrin-mediated signaling in inducing cellular senescence and provide new therapeutic options for age-related diseases targeting matricellular proteins and integrins.
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Affiliation(s)
- Motomichi Fujita
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan
| | - Manabu Sasada
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan
| | - Takuya Iyoda
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-Doori, Sanyo-Onoda 756-0884, Yamaguchi, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan
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6
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Revert-Ros F, Ventura I, Prieto-Ruiz JA, Hernández-Andreu JM, Revert F. The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen. Int J Mol Sci 2024; 25:6523. [PMID: 38928229 PMCID: PMC11203716 DOI: 10.3390/ijms25126523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/01/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.
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Affiliation(s)
| | | | | | | | - Fernando Revert
- Mitochondrial and Molecular Medicine Research Group, Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain; (F.R.-R.); (I.V.); (J.A.P.-R.); (J.M.H.-A.)
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7
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Filgueiras LA, de Andrade FDCP, Iwao Horita S, Shirsat SD, Achal V, Rai M, Henriques-Pons A, Mendes AN. Analysis of SIKVAV's receptor affinity, pharmacokinetics, and pharmacological characteristics: a matrikine with potent biological function. J Biomol Struct Dyn 2024:1-23. [PMID: 38345036 DOI: 10.1080/07391102.2024.2313709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 01/27/2024] [Indexed: 03/08/2025]
Abstract
Matrikines are biologically active peptides generated from fragments fragmentation of extracellular matrix components (ECM) that are functionally distinct from the original full-length molecule. The active matricryptic sites can be unmasked by ECM components enzymatic degradation or multimerization, heterotypic binding, adsorption to other molecules, cell-mediated mechanical forces, exposure to reactive oxygen species, ECM denaturation, and others. Laminin α1-derived peptide (SIKVAV) is a bioactive peptide derived from laminin-111 that participates in tumor development, cell proliferation, angiogenesis in various cell types. SIKVAV has also a potential pharmaceutical activity that may be used for tissue regeneration and bioengineering in Alzheimer's disease and muscular dystrophies. In this work, we made computational analyzes of SIKVAV regarding the ADMET panel, that stands for Administration, Distribution, Metabolism, Excretion, and Toxicity. Docking analyzes using the α3β1 and α6β1 integrin receptors were performed to fill in the gaps in the SIKVAV's signaling pathway and coupling tests showed that SIKVAV can interact with both receptors. Moreover, there is no indication of cytotoxicity, mutagenic or carcinogenic activity, skin or oral sensitivity. Our analysis suggests that SIKVAV has a high probability of interacting with peroxisome proliferator-activated receptor-gamma (NR-PPAR-γ), which has anti-inflammatory activity. The results of bioinformatics can help understand the participation of SIKVAV in homeostasis and influence the understanding of how this peptide can act as a biological asset in the control of dystrophies, neurodegenerative diseases, and tissue engineering.
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Affiliation(s)
- Livia Alves Filgueiras
- Laboratory of Innovation in Science and Technology - LACITEC, Department of Biophysics and Physiology, Federal University of Piauí, Teresina, Brazil
| | | | - Samuel Iwao Horita
- Laboratory of Innovation in Therapies, Education, and Bioproducts - LITEB, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Shubhangi D Shirsat
- Laboratory of Innovation in Therapies, Education, and Bioproducts - LITEB, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Varenyam Achal
- Environmental Engineering Program, Guangdong Technion - Israel Institute of Technology, Shantou, China
- Technion - Israel Institute of Technology, Haifa, Israel
| | - Mahendra Rai
- Department of Biotechnology, SGB Amravati University, Amravati, India
| | - Andrea Henriques-Pons
- Laboratory of Innovation in Therapies, Education, and Bioproducts - LITEB, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Anderson Nogueira Mendes
- Laboratory of Innovation in Science and Technology - LACITEC, Department of Biophysics and Physiology, Federal University of Piauí, Teresina, Brazil
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8
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Kafili G, Kabir H, Jalali Kandeloos A, Golafshan E, Ghasemi S, Mashayekhan S, Taebnia N. Recent advances in soluble decellularized extracellular matrix for heart tissue engineering and organ modeling. J Biomater Appl 2023; 38:577-604. [PMID: 38006224 PMCID: PMC10676626 DOI: 10.1177/08853282231207216] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2023]
Abstract
Despite the advent of tissue engineering (TE) for the remodeling, restoring, and replacing damaged cardiovascular tissues, the progress is hindered by the optimal mechanical and chemical properties required to induce cardiac tissue-specific cellular behaviors including migration, adhesion, proliferation, and differentiation. Cardiac extracellular matrix (ECM) consists of numerous structural and functional molecules and tissue-specific cells, therefore it plays an important role in stimulating cell proliferation and differentiation, guiding cell migration, and activating regulatory signaling pathways. With the improvement and modification of cell removal methods, decellularized ECM (dECM) preserves biochemical complexity, and bio-inductive properties of the native matrix and improves the process of generating functional tissue. In this review, we first provide an overview of the latest advancements in the utilization of dECM in in vitro model systems for disease and tissue modeling, as well as drug screening. Then, we explore the role of dECM-based biomaterials in cardiovascular regenerative medicine (RM), including both invasive and non-invasive methods. In the next step, we elucidate the engineering and material considerations in the preparation of dECM-based biomaterials, namely various decellularization techniques, dECM sources, modulation, characterizations, and fabrication approaches. Finally, we discuss the limitations and future directions in fabrication of dECM-based biomaterials for cardiovascular modeling, RM, and clinical translation.
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Affiliation(s)
- Golara Kafili
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
| | - Hannaneh Kabir
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, CA, USA
| | | | - Elham Golafshan
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
| | - Sara Ghasemi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Shohreh Mashayekhan
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Nayere Taebnia
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
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9
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Miao MZ, Su QP, Cui Y, Bahnson EM, Li G, Wang M, Yang Y, Collins JA, Wu D, Gu Q, Chubinskaya S, Diekman BO, Yamada KM, Loeser RF. Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis. Sci Signal 2023; 16:eadf8299. [PMID: 37906629 PMCID: PMC10666734 DOI: 10.1126/scisignal.adf8299] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 10/10/2023] [Indexed: 11/02/2023]
Abstract
Mechanical cues sensed by integrins induce cells to produce proteases to remodel the extracellular matrix. Excessive protease production occurs in many degenerative diseases, including osteoarthritis, in which articular cartilage degradation is associated with the genesis of matrix protein fragments that can activate integrins. We investigated the mechanisms by which integrin signals may promote protease production in response to matrix changes in osteoarthritis. Using a fragment of the matrix protein fibronectin (FN) to activate the α5β1 integrin in primary human chondrocytes, we found that endocytosis of the integrin and FN fragment complex drove the production of the matrix metalloproteinase MMP-13. Activation of α5β1 by the FN fragment, but not by intact FN, was accompanied by reactive oxygen species (ROS) production initially at the cell surface, then in early endosomes. These ROS-producing endosomes (called redoxosomes) contained the integrin-FN fragment complex, the ROS-producing enzyme NADPH oxidase 2 (NOX2), and SRC, a redox-regulated kinase that promotes MMP-13 production. In contrast, intact FN was endocytosed and trafficked to recycling endosomes without inducing ROS production. Articular cartilage from patients with osteoarthritis showed increased amounts of SRC and the NOX2 complex component p67phox. Furthermore, we observed enhanced localization of SRC and p67phox at early endosomes, suggesting that redoxosomes could transmit and sustain integrin signaling in response to matrix damage. This signaling mechanism not only amplifies the production of matrix-degrading proteases but also establishes a self-perpetuating cycle that contributes to the ongoing degradation of cartilage matrix in osteoarthritis.
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Affiliation(s)
- Michael Z. Miao
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Division of Oral & Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Curriculum in Oral and Craniofacial Biomedicine, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Qian Peter Su
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Yang Cui
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Edward M. Bahnson
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Gang Li
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA
- eScience Institute, University of Washington, Seattle, WA, 98195, USA
| | - Menglin Wang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yuchen Yang
- State Key Laboratory of Biocontrol, School of Ecology, Sun Yat-sen University, Guangzhou, 510275, China
| | - John A. Collins
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Di Wu
- Division of Oral & Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, NC, 27599, USA
| | - Qisheng Gu
- Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China
- Department of Immunology, Université Paris Cité, Paris, 75006, France
| | - Susan Chubinskaya
- Department of Pediatrics, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Brian O. Diekman
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27695, USA
| | - Kenneth M. Yamada
- Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Richard F. Loeser
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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10
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Lin PK, Davis GE. Extracellular Matrix Remodeling in Vascular Disease: Defining Its Regulators and Pathological Influence. Arterioscler Thromb Vasc Biol 2023; 43:1599-1616. [PMID: 37409533 PMCID: PMC10527588 DOI: 10.1161/atvbaha.123.318237] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/23/2023] [Indexed: 07/07/2023]
Abstract
Because of structural and cellular differences (ie, degrees of matrix abundance and cross-linking, mural cell density, and adventitia), large and medium-sized vessels, in comparison to capillaries, react in a unique manner to stimuli that induce vascular disease. A stereotypical vascular injury response is ECM (extracellular matrix) remodeling that occurs particularly in larger vessels in response to injurious stimuli, such as elevated angiotensin II, hyperlipidemia, hyperglycemia, genetic deficiencies, inflammatory cell infiltration, or exposure to proinflammatory mediators. Even with substantial and prolonged vascular damage, large- and medium-sized arteries, persist, but become modified by (1) changes in vascular wall cellularity; (2) modifications in the differentiation status of endothelial cells, vascular smooth muscle cells, or adventitial stem cells (each can become activated); (3) infiltration of the vascular wall by various leukocyte types; (4) increased exposure to critical growth factors and proinflammatory mediators; and (5) marked changes in the vascular ECM, that remodels from a homeostatic, prodifferentiation ECM environment to matrices that instead promote tissue reparative responses. This latter ECM presents previously hidden matricryptic sites that bind integrins to signal vascular cells and infiltrating leukocytes (in coordination with other mediators) to proliferate, invade, secrete ECM-degrading proteinases, and deposit injury-induced matrices (predisposing to vessel wall fibrosis). In contrast, in response to similar stimuli, capillaries can undergo regression responses (rarefaction). In summary, we have described the molecular events controlling ECM remodeling in major vascular diseases as well as the differential responses of arteries versus capillaries to key mediators inducing vascular injury.
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Affiliation(s)
- Prisca K. Lin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL 33612
| | - George E. Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL 33612
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11
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Chen K, Xu M, Lu F, He Y. Development of Matrix Metalloproteinases-Mediated Extracellular Matrix Remodeling in Regenerative Medicine: A Mini Review. Tissue Eng Regen Med 2023; 20:661-670. [PMID: 37160567 PMCID: PMC10352474 DOI: 10.1007/s13770-023-00536-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 02/25/2023] [Accepted: 03/03/2023] [Indexed: 05/11/2023] Open
Abstract
Extracellular matrix (ECM) components confer biomechanical properties, maintain cell phenotype and mediate tissue homeostasis. ECM remodeling is complex and plays a key role in both physiological and pathological processes. Matrix metalloproteinases (MMPs) are a group of enzymes responsible for ECM degradation and have been accepted as a key regulator in ECM remodeling. In this mini-review, we summarize MMPs categories, functions and the targeted substrates. We then discuss current understanding of the role of MMPs-mediated events, including inflammation reaction, angiogenesis, cellular activities, etc., in ECM remodeling in the context of regenerative medicine.
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Affiliation(s)
- Kaiqi Chen
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Mimi Xu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Yunfan He
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China.
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12
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Salardani M, Barcick U, Zelanis A. Proteolytic signaling in cancer. Expert Rev Proteomics 2023; 20:345-355. [PMID: 37873978 DOI: 10.1080/14789450.2023.2275671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023]
Abstract
INTRODUCTION Cancer is a disease of (altered) biological pathways, often driven by somatic mutations and with several implications. Therefore, the identification of potential markers of disease is challenging. Given the large amount of biological data generated with omics approaches, oncology has experienced significant contributions. Proteomics mapping of protein fragments, derived from proteolytic processing events during oncogenesis, may shed light on (i) the role of active proteases and (ii) the functional implications of processed substrates in biological signaling circuits. Both outcomes have the potential for predicting diagnosis/prognosis in diseases like cancer. Therefore, understanding proteolytic processing events and their downstream implications may contribute to advances in the understanding of tumor biology and targeted therapies in precision medicine. AREAS COVERED Proteolytic events associated with some hallmarks of cancer (cell migration and proliferation, angiogenesis, metastasis, as well as extracellular matrix degradation) will be discussed. Moreover, biomarker discovery and the use of proteomics approaches to uncover proteolytic signaling events will also be covered. EXPERT OPINION Proteolytic processing is an irreversible protein post-translational modification and the deconvolution of biological data resulting from the study of proteolytic signaling events may be used in both patient diagnosis/prognosis and targeted therapies in cancer.
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Affiliation(s)
- Murilo Salardani
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
| | - Uilla Barcick
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
| | - André Zelanis
- Functional Proteomics Laboratory, Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil
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13
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Grilo GA, Cakir SN, Shaver PR, Iyer RP, Whitehead K, McClung JM, Vahdati A, de Castro Brás LE. Collagen matricryptin promotes cardiac function by mediating scar formation. Life Sci 2023; 321:121598. [PMID: 36963720 PMCID: PMC10120348 DOI: 10.1016/j.lfs.2023.121598] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/07/2023] [Accepted: 03/15/2023] [Indexed: 03/26/2023]
Abstract
AIMS A peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. MATERIALS AND METHODS Using a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. KEY FINDINGS Matricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. SIGNIFICANCE Our data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar.
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Affiliation(s)
- Gabriel A Grilo
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Sirin N Cakir
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Patti R Shaver
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Rugmani P Iyer
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Kaitlin Whitehead
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Joseph M McClung
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America; Department of Cardiovascular Sciences, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America; East Carolina Diabetes and Obesity Institute, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America
| | - Ali Vahdati
- Department of Engineering, East Carolina University, Greenville, NC 27858, United States of America
| | - Lisandra E de Castro Brás
- Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America; Department of Cardiovascular Sciences, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America.
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14
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Davis GE, Kemp SS. Extracellular Matrix Regulation of Vascular Morphogenesis, Maturation, and Stabilization. Cold Spring Harb Perspect Med 2023; 13:a041156. [PMID: 35817544 PMCID: PMC10578078 DOI: 10.1101/cshperspect.a041156] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The extracellular matrix represents a critical regulator of tissue vascularization during embryonic development and postnatal life. In this perspective, we present key information and concepts that focus on how the extracellular matrix controls capillary assembly, maturation, and stabilization, and, in addition, contributes to tissue stability and health. In particular, we present and discuss mechanistic details underlying (1) the role of the extracellular matrix in controlling different steps of vascular morphogenesis, (2) the ability of endothelial cells (ECs) and pericytes to coassemble into elongated and narrow capillary EC-lined tubes with associated pericytes and basement membrane matrices, and (3) the identification of specific growth factor combinations ("factors") and peptides as well as coordinated "factor" and extracellular matrix receptor signaling pathways that are required to form stabilized capillary networks.
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Affiliation(s)
- George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, Florida 33612, USA
| | - Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, Florida 33612, USA
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15
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Davis MJ, Earley S, Li YS, Chien S. Vascular mechanotransduction. Physiol Rev 2023; 103:1247-1421. [PMID: 36603156 PMCID: PMC9942936 DOI: 10.1152/physrev.00053.2021] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 01/07/2023] Open
Abstract
This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Scott Earley
- Department of Pharmacology, University of Nevada, Reno, Nevada
| | - Yi-Shuan Li
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
| | - Shu Chien
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
- Department of Medicine, University of California, San Diego, California
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16
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Sueters J, Groenman FA, Bouman MB, Roovers JPW, de Vries R, Smit TH, Huirne JAF. Tissue Engineering Neovagina for Vaginoplasty in Mayer-Rokitansky-Küster-Hauser Syndrome and Gender Dysphoria Patients: A Systematic Review. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:28-46. [PMID: 35819292 DOI: 10.1089/ten.teb.2022.0067] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background: Vaginoplasty is a surgical solution to multiple disorders, including Mayer-Rokitansky-Küster-Hauser syndrome and male-to-female gender dysphoria. Using nonvaginal tissues for these reconstructions is associated with many complications, and autologous vaginal tissue may not be sufficient. The potential of tissue engineering for vaginoplasty was studied through a systematic bibliography search. Cell types, biomaterials, and signaling factors were analyzed by investigating advantages, disadvantages, complications, and research quantity. Search Methods: A systematic search was performed in Medline, EMBASE, Web of Science, and Scopus until March 8, 2022. Term combinations for tissue engineering, guided tissue regeneration, regenerative medicine, and tissue scaffold were applied, together with vaginoplasty and neovagina. The snowball method was performed on references and a Google Scholar search on the first 200 hits. Original research articles on human and/or animal subjects that met the inclusion (reconstruction of vaginal tissue and tissue engineering method) and no exclusion criteria (not available as full text; written in foreign language; nonoriginal study article; genital surgery other than neovaginal reconstruction; and vaginal reconstruction with autologous or allogenic tissue without tissue engineering or scaffold) were assessed. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, the Newcastle-Ottawa Scale, and the Gold Standard Publication Checklist were used to evaluate article quality and bias. Outcomes: A total of 31 out of 1569 articles were included. Data extraction was based on cell origin and type, biomaterial nature and composition, host species, number of hosts and controls, neovaginal size, replacement fraction, and signaling factors. An overview of used tissue engineering methods for neovaginal formation was created, showing high variance of cell types, biomaterials, and signaling factors and the same topics were rarely covered multiple times. Autologous vaginal cells and extracellular matrix-based biomaterials showed preferential properties, and stem cells carry potential. However, quality confirmation of orthotopic cell-seeded acellular vaginal matrix by clinical trials is needed as well as exploration of signaling factors for vaginoplasty. Impact statement General article quality was weak to sufficient due to unreported cofounders and incomplete animal study descriptions. Article quality and heterogenicity made identification of optimal cell types, biomaterials, or signaling factors unreliable. However, trends showed that autologous cells prevent complications and compatibility issues such as healthy cell destruction, whereas stem cells prevent cross talk (interference of signaling pathways by signals from other cell types) and rejection (but need confirmation testing beyond animal trials). Natural (orthotopic) extracellular matrix biomaterials have great preferential properties that encourage future research, and signaling factors for vascularization are important for tissue engineering of full-sized neovagina.
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Affiliation(s)
- Jayson Sueters
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Freek A Groenman
- Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Centre of Expertise on Gender Dysphoria, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Mark-Bram Bouman
- Centre of Expertise on Gender Dysphoria, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Jan Paul W Roovers
- Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Ralph de Vries
- Medical Library, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Theo H Smit
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Department of Medical Biology, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| | - Judith A F Huirne
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Research Institute Reproduction and Development, Amsterdam UMC location AMC, Amsterdam, The Netherlands
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17
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Chavda ND, Sari B, Asiri FM, Hamill KJ. Laminin N-terminus (LaNt) proteins, laminins and basement membrane regulation. Biochem Soc Trans 2022; 50:1541-1553. [PMID: 36355367 PMCID: PMC9788559 DOI: 10.1042/bst20210240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 10/03/2023]
Abstract
Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a repository for nutrients and growth factors, and as biophysical signalling hubs. At the core of all BMs is the laminin (LM) family of proteins. These large heterotrimeric glycoproteins are essential for tissue integrity, and differences between LM family members represent a key nexus in dictating context and tissue-specific functions. These variations reflect genetic diversity within the family, which allows for multiple structurally and functionally distinct heterotrimers to be produced, each with different architectures and affinities for other matrix proteins and cell surface receptors. The ratios of these LM isoforms also influence the biophysical properties of a BM owing to differences in their relative ability to form polymers or networks. Intriguingly, the LM superfamily is further diversified through the related netrin family of proteins and through alternative splicing leading to the generation of non-LM short proteins known as the laminin N-terminus (LaNt) domain proteins. Both the netrins and LaNt proteins contain structural domains involved in LM-to-LM interaction and network assembly. Emerging findings indicate that one netrin and at least one LaNt protein can potently influence the structure and function of BMs, disrupting the networks, changing physical properties, and thereby influencing tissue function. These findings are altering the way that we think about LM polymerisation and, in the case of the LaNt proteins, suggest a hitherto unappreciated form of LM self-regulation.
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Affiliation(s)
- Natasha D. Chavda
- Institute of Life Course and Medical Sciences, University of Liverpool, 6 West Derby Street, Liverpool L78TX, U.K
| | - Bilge Sari
- Institute of Life Course and Medical Sciences, University of Liverpool, 6 West Derby Street, Liverpool L78TX, U.K
| | - Fawziah M. Asiri
- Institute of Life Course and Medical Sciences, University of Liverpool, 6 West Derby Street, Liverpool L78TX, U.K
| | - Kevin J. Hamill
- Institute of Life Course and Medical Sciences, University of Liverpool, 6 West Derby Street, Liverpool L78TX, U.K
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18
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McInnes AD, Moser MAJ, Chen X. Preparation and Use of Decellularized Extracellular Matrix for Tissue Engineering. J Funct Biomater 2022; 13:jfb13040240. [PMID: 36412881 PMCID: PMC9680265 DOI: 10.3390/jfb13040240] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/22/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022] Open
Abstract
The multidisciplinary fields of tissue engineering and regenerative medicine have the potential to revolutionize the practise of medicine through the abilities to repair, regenerate, or replace tissues and organs with functional engineered constructs. To this end, tissue engineering combines scaffolding materials with cells and biologically active molecules into constructs with the appropriate structures and properties for tissue/organ regeneration, where scaffolding materials and biomolecules are the keys to mimic the native extracellular matrix (ECM). For this, one emerging way is to decellularize the native ECM into the materials suitable for, directly or in combination with other materials, creating functional constructs. Over the past decade, decellularized ECM (or dECM) has greatly facilitated the advance of tissue engineering and regenerative medicine, while being challenged in many ways. This article reviews the recent development of dECM for tissue engineering and regenerative medicine, with a focus on the preparation of dECM along with its influence on cell culture, the modification of dECM for use as a scaffolding material, and the novel techniques and emerging trends in processing dECM into functional constructs. We highlight the success of dECM and constructs in the in vitro, in vivo, and clinical applications and further identify the key issues and challenges involved, along with a discussion of future research directions.
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Affiliation(s)
- Adam D. McInnes
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
- Correspondence: ; Tel.: +1-306-966-5435
| | - Michael A. J. Moser
- Department of Surgery, Health Sciences Building, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
| | - Xiongbiao Chen
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
- Department of Mechanical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
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19
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Kafili G, Tamjid E, Niknejad H, Simchi A. Development of injectable hydrogels based on human amniotic membrane and polyethyleneglycol-modified nanosilicates for tissue engineering applications. Eur Polym J 2022. [DOI: 10.1016/j.eurpolymj.2022.111566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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20
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Fraser D, Benoit D. Dual peptide-functionalized hydrogels differentially control periodontal cell function and promote tissue regeneration. BIOMATERIALS ADVANCES 2022; 141:213093. [PMID: 36067642 PMCID: PMC10197021 DOI: 10.1016/j.bioadv.2022.213093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/20/2022] [Indexed: 11/19/2022]
Abstract
Restoring the tooth-supporting tissues lost during periodontitis is a significant clinical challenge, despite advances in both biomaterial and cell-based approaches. This study investigated poly(ethylene glycol) (PEG) hydrogels functionalized with integrin-binding peptides RGD and GFOGER for controlling periodontal ligament cell (PDLC) activity and promoting periodontal tissue regeneration. Dual presentation of RGD and GFOGER within PEG hydrogels potentiated two key PDLC functions, alkaline phosphatase (ALP) activity and matrix mineralization, over either peptide alone and could be tuned to differentially promote each function. Hydrogel matrix mineralization, fostered by high concentrations of GFOGER together with RGD, identified a PDLC phenotype with accelerated matrix adhesion formation and expression of cementoblast and osteoblast genes. In contrast, maximizing ALP activity through high RGD and low GFOGER levels resulted in minimal hydrogel mineralization, in part, through altered PDLC pyrophosphate regulation. Transplantation of PDLCs in hydrogels optimized for either outcome promoted cementum formation in rat periodontal defects; however, only hydrogels optimized for in vitro mineralization improved new bone formation. Overall, these results highlight the utility of engineered hydrogel systems for controlling PDLC functions and their promise for promoting periodontal tissue regeneration.
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Affiliation(s)
- David Fraser
- Translational Biomedical Sciences, University of Rochester Medical Center, Rochester, NY, United States of America; Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Danielle Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, United States of America; Department of Chemical Engineering, University of Rochester, Rochester, NY, United States of America; Materials Science Program, University Rochester, Rochester, NY, United States of America; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United States of America.
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21
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Poulis N, Martin M, Hoerstrup SP, Emmert MY, Fioretta ES. Macrophage-extracellular matrix interactions: Perspectives for tissue engineered heart valve remodeling. Front Cardiovasc Med 2022; 9:952178. [PMID: 36176991 PMCID: PMC9513146 DOI: 10.3389/fcvm.2022.952178] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/15/2022] [Indexed: 11/16/2022] Open
Abstract
In situ heart valve tissue engineering approaches have been proposed as promising strategies to overcome the limitations of current heart valve replacements. Tissue engineered heart valves (TEHVs) generated from in vitro grown tissue engineered matrices (TEMs) aim at mimicking the microenvironmental cues from the extracellular matrix (ECM) to favor integration and remodeling of the implant. A key role of the ECM is to provide mechanical support to and attract host cells into the construct. Additionally, each ECM component plays a critical role in regulating cell adhesion, growth, migration, and differentiation potential. Importantly, the immune response to the implanted TEHV is also modulated biophysically via macrophage-ECM protein interactions. Therefore, the aim of this review is to summarize what is currently known about the interactions and signaling networks occurring between ECM proteins and macrophages, and how these interactions may impact the long-term in situ remodeling outcomes of TEMs. First, we provide an overview of in situ tissue engineering approaches and their clinical relevance, followed by a discussion on the fundamentals of the remodeling cascades. We then focus on the role of circulation-derived and resident tissue macrophages, with particular emphasis on the ramifications that ECM proteins and peptides may have in regulating the host immune response. Finally, the relevance of these findings for heart valve tissue engineering applications is discussed.
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Affiliation(s)
- Nikolaos Poulis
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
| | - Marcy Martin
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
| | - Simon P. Hoerstrup
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
- Wyss Zurich, University and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Maximilian Y. Emmert
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
- Wyss Zurich, University and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- *Correspondence: Maximilian Y. Emmert, ,
| | - Emanuela S. Fioretta
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
- Emanuela S. Fioretta,
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22
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Mohindra R, Mohindra R, Agrawal DK, Thankam FG. Bioactive extracellular matrix fragments in tendon repair. Cell Tissue Res 2022; 390:131-140. [PMID: 36074173 DOI: 10.1007/s00441-022-03684-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 08/30/2022] [Indexed: 11/02/2022]
Abstract
Tendinopathy is a common tendon disorder that causes pain, loss of strength and function, and local inflammation mainly characterized by hypoxia, collagen degradation, and extracellular matrix (ECM) disorganization. Generally, ECM degradation and remodeling is tightly regulated; however, hyperactivation of matrix metalloproteases (MMPs) contributes to excessive collagenolysis under pathologic conditions resulting in tendon ECM degradation. This review article focuses on the production, function, and signaling of matrikines for tendon regeneration following injury with insights into the expression, tissue compliance, and cell proliferation exhibited by various matrikines. Furthermore, the regenerative properties suggest translational significance of matrikines to improve the outcomes post-injury by assisting with tendon healing.
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Affiliation(s)
- Ritika Mohindra
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Rohit Mohindra
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA
| | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA.
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23
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Kobayashi M, Ishida N, Hashimoto Y, Negishi J, Saga H, Sasaki Y, Akiyoshi K, Kimura T, Kishida A. Extraction and Biological Evaluation of Matrix-Bound Nanovesicles (MBVs) from High-Hydrostatic Pressure-Decellularized Tissues. Int J Mol Sci 2022; 23:ijms23168868. [PMID: 36012126 PMCID: PMC9407827 DOI: 10.3390/ijms23168868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/25/2022] [Accepted: 08/07/2022] [Indexed: 12/22/2022] Open
Abstract
Decellularized tissues are widely used as promising materials in tissue engineering and regenerative medicine. Research on the microstructure and components of the extracellular matrix (ECM) was conducted to improve the current understanding of decellularized tissue functionality. The presence of matrix-bound nanovesicles (MBVs) embedded within the ECM was recently reported. Results of a previous experimental investigation revealed that decellularized tissues prepared using high hydrostatic pressure (HHP) exhibited good in vivo performance. In the current study, according to the hypothesis that MBVs are one of the functional components in HHP-decellularized tissue, we investigated the extraction of MBVs and the associated effects on vascular endothelial cells. Using nanoparticle tracking assay (NTA), transmission electron microscopy (TEM), and RNA analysis, nanosized (100–300 nm) and membranous particles containing small RNA were detected in MBVs derived from HHP-decellularized small intestinal submucosa (SIS), urinary bladder matrix (UBM), and liver. To evaluate the effect on the growth of vascular endothelial cells, which are important in the tissue regeneration process, isolated SIS-derived MBVs were exposed to vascular endothelial cells to induce cell proliferation. These results indicate that MBVs can be extracted from HHP-decellularized tissues and may play a significant role in tissue remodeling.
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Affiliation(s)
- Mako Kobayashi
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku 101-0062, Japan
| | - Naoki Ishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku 101-0062, Japan
| | - Yoshihide Hashimoto
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku 101-0062, Japan
| | - Jun Negishi
- Department of Applied Biology, Faculty of Textile Science and Technology, Shinshu University, 3-15-1 Tokida, Ueda 386-8567, Japan
| | - Hideki Saga
- KM Biologics Co., Ltd., 1314-1 Kyokushi Kawabe, Kikuchi-shi 869-1298, Japan
| | - Yoshihiro Sasaki
- Department of Polymer Chemistry, Graduate School of Engineering, A3-317, Kyoto University, Katsura, Nishikyo-ku 615-8510, Japan
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, A3-317, Kyoto University, Katsura, Nishikyo-ku 615-8510, Japan
| | - Tsuyoshi Kimura
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku 101-0062, Japan
| | - Akio Kishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku 101-0062, Japan
- Correspondence: ; Tel.: +81-35-2808028
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Spronck B, Ramachandra AB, Moriyama L, Toczek J, Han J, Sadeghi MM, Humphrey JD. Deletion of matrix metalloproteinase-12 compromises mechanical homeostasis and leads to an aged aortic phenotype in young mice. J Biomech 2022; 141:111179. [PMID: 35759974 PMCID: PMC9585962 DOI: 10.1016/j.jbiomech.2022.111179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 11/28/2022]
Abstract
Mechanical homeostasis emerges following normal development of the arterial wall and requires thereafter a slow balanced degradation and deposition of extracellular matrix constituents within an unchanging mechanical state. Recent findings suggest that homeostasis is compromised in arterial aging, which contributes to the structural stiffening that is characteristic of aged central arteries. Matrix metalloproteinases (MMPs) have strong proteolytic activity and play fundamental roles in matrix turnover. Here, we use Mmp12-/- mice to examine effects of a potent metalloelastase, MMP-12, on the biomechanical phenotype of the thoracic and abdominal aorta in young and naturally aged mice. A key finding is that germline deletion of the gene (Mmp12) that encodes MMP-12 alters biomechanical properties from normal more in young adult than in older adult mice. Consequently, percent changes in biomechanical properties during aortic aging are greater in wild-type than in MMP-12 deficient mice, though with similar overall decreases in elastic energy storage and distensibility and increases in calculated pulse wave velocity. Reduced elastic energy storage compromises the ability of the aorta to augment antegrade and retrograde blood flow while an increased pulse wave velocity can adversely affect end organs, both conditions being characteristic of aortic aging in humans. In summary, MMP-12 is fundamental for establishing homeostatic values of biomechanical metrics in the aorta and its absence leads to a pre-aged aortic phenotype in young mice.
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Affiliation(s)
- Bart Spronck
- Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT, USA; Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
| | - Abhay B Ramachandra
- Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT, USA
| | - Lauren Moriyama
- Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT, USA
| | - Jakub Toczek
- Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Jinah Han
- Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Mehran M Sadeghi
- Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA
| | - Jay D Humphrey
- Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA
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25
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Matrikines as mediators of tissue remodelling. Adv Drug Deliv Rev 2022; 185:114240. [PMID: 35378216 DOI: 10.1016/j.addr.2022.114240] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/21/2022] [Accepted: 03/26/2022] [Indexed: 11/21/2022]
Abstract
Extracellular matrix (ECM) proteins confer biomechanical properties, maintain cell phenotype and mediate tissue repair (via release of sequestered cytokines and proteases). In contrast to intracellular proteomes, where proteins are monitored and replaced over short time periods, many ECM proteins function for years (decades in humans) without replacement. The longevity of abundant ECM proteins, such as collagen I and elastin, leaves them vulnerable to damage accumulation and their host organs prone to chronic, age-related diseases. However, ECM protein fragmentation can potentially produce peptide cytokines (matrikines) which may exacerbate and/or ameliorate age- and disease-related ECM remodelling. In this review, we discuss ECM composition, function and degradation and highlight examples of endogenous matrikines. We then critically and comprehensively analyse published studies of matrix-derived peptides used as topical skin treatments, before considering the potential for improvements in the discovery and delivery of novel matrix-derived peptides to skin and internal organs. From this, we conclude that while the translational impact of matrix-derived peptide therapeutics is evident, the mechanisms of action of these peptides are poorly defined. Further, well-designed, multimodal studies are required.
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26
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HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma. Biomolecules 2022; 12:biom12010101. [PMID: 35053249 PMCID: PMC8773879 DOI: 10.3390/biom12010101] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/03/2022] [Accepted: 01/06/2022] [Indexed: 12/15/2022] Open
Abstract
Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5–7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels along with severe tissue damage and high mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.
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27
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Popova NV, Jücker M. The Functional Role of Extracellular Matrix Proteins in Cancer. Cancers (Basel) 2022; 14:238. [PMID: 35008401 PMCID: PMC8750014 DOI: 10.3390/cancers14010238] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 02/04/2023] Open
Abstract
The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.
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Affiliation(s)
- Nadezhda V. Popova
- Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997 Moscow, Russia;
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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28
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Kemp SS, Lin PK, Sun Z, Castaño MA, Yrigoin K, Penn MR, Davis GE. Molecular basis for pericyte-induced capillary tube network assembly and maturation. Front Cell Dev Biol 2022; 10:943533. [PMID: 36072343 PMCID: PMC9441561 DOI: 10.3389/fcell.2022.943533] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Here we address the functional importance and role of pericytes in capillary tube network assembly, an essential process that is required for vascularized tissue development, maintenance, and health. Healthy capillaries may be directly capable of suppressing human disease. Considerable advances have occurred in our understanding of the molecular and signaling requirements controlling EC lumen and tube formation in 3D extracellular matrices. A combination of SCF, IL-3, SDF-1α, FGF-2 and insulin ("Factors") in conjunction with integrin- and MT1-MMP-induced signaling are required for EC sprouting behavior and tube formation under serum-free defined conditions. Pericyte recruitment to the abluminal EC tube surface results in elongated and narrow tube diameters and deposition of the vascular basement membrane. In contrast, EC tubes in the absence of pericytes continue to widen and shorten over time and fail to deposit basement membranes. Pericyte invasion, recruitment and proliferation in 3D matrices requires the presence of ECs. A detailed analysis identified that EC-derived PDGF-BB, PDGF-DD, ET-1, HB-EGF, and TGFβ1 are necessary for pericyte recruitment, proliferation, and basement membrane deposition. Blockade of these individual factors causes significant pericyte inhibition, but combined blockade profoundly interferes with these events, resulting in markedly widened EC tubes without basement membranes, like when pericytes are absent.
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Affiliation(s)
- Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Prisca K Lin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Zheying Sun
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Maria A Castaño
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Ksenia Yrigoin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - Marlena R Penn
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
| | - George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, FL, United States
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29
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Elhattab K, Hefzy MS, Hanf Z, Crosby B, Enders A, Smiczek T, Haghshenas M, Jahadakbar A, Elahinia M. Biomechanics of Additively Manufactured Metallic Scaffolds-A Review. MATERIALS (BASEL, SWITZERLAND) 2021; 14:6833. [PMID: 34832234 PMCID: PMC8625735 DOI: 10.3390/ma14226833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022]
Abstract
This review paper is related to the biomechanics of additively manufactured (AM) metallic scaffolds, in particular titanium alloy Ti6Al4V scaffolds. This is because Ti6Al4V has been identified as an ideal candidate for AM metallic scaffolds. The factors that affect the scaffold technology are the design, the material used to build the scaffold, and the fabrication process. This review paper includes thus a discussion on the design of Ti6A4V scaffolds in relation to how their behavior is affected by their cell shapes and porosities. This is followed by a discussion on the post treatment and mechanical characterization including in-vitro and in-vivo biomechanical studies. A review and discussion are also presented on the ongoing efforts to develop predictive tools to derive the relationships between structure, processing, properties and performance of powder-bed additive manufacturing of metals. This is a challenge when developing process computational models because the problem involves multi-physics and is of multi-scale in nature. Advantages, limitations, and future trends in AM scaffolds are finally discussed. AM is considered at the forefront of Industry 4.0, the fourth industrial revolution. The market of scaffold technology will continue to boom because of the high demand for human tissue repair.
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Affiliation(s)
| | - Mohamed Samir Hefzy
- Department of Mechanical, Industrial & Manufacturing Engineering, College of Engineering, The University of Toledo, Toledo, OH 43606, USA; (K.E.); (Z.H.); (B.C.); (A.E.); (T.S.); (M.H.); (A.J.); (M.E.)
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30
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Lopera Higuita M, Lopera Giraldo JF, Sarrafian TL, Griffiths LG. Tissue engineered bovine saphenous vein extracellular matrix scaffolds produced via antigen removal achieve high in vivo patency rates. Acta Biomater 2021; 134:144-159. [PMID: 34192567 DOI: 10.1016/j.actbio.2021.06.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022]
Abstract
Diseases of small diameter blood vessels encompass the largest portion of cardiovascular diseases, with over 4.2 million people undergoing autologous vascular grafting every year. However, approximately one third of patients are ineligible for autologous vascular grafting due to lack of suitable donor vasculature. Acellular extracellular matrix (ECM) scaffolds derived from xenogeneic vascular tissue have potential to serve as ideal biomaterials for production of off-the-shelf vascular grafts capable of eliminating the need for autologous vessel harvest. A modified antigen removal (AR) tissue process, employing aminosulfabetaine-16 (ASB-16) was used to create off-the-shelf small diameter (< 3 mm) vascular graft from bovine saphenous vein ECM scaffolds with significantly reduced antigenic content, while retaining native vascular ECM protein structure and function. Elimination of native tissue antigen content conferred graft-specific adaptive immune avoidance, while retention of native ECM protein macromolecular structure resulted in pro-regenerative cellular infiltration, ECM turnover and innate immune self-recognition in a rabbit subpannicular model. Finally, retention of the delicate vascular basement membrane protein integrity conferred endothelial cell repopulation and 100% patency rate in a rabbit jugular interposition model, comparable only to Autograft implants. Alternatively, the lack of these important basement membrane proteins in otherwise identical scaffolds yielded a patency rate of only 20%. We conclude that acellular antigen removed bovine saphenous vein ECM scaffolds have potential to serve as ideal off-the-shelf small diameter vascular scaffolds with high in vivo patency rates due to their low antigen content, retained native tissue basement membrane integrity and preserved native ECM structure, composition and functional properties. STATEMENT OF SIGNIFICANCE: The use of autologous vessels for the treatment of small diameter vascular diseases is common practice. However, the use of autologous tissue poses significant complications due to tissue harvest and limited availability. Developing an alternative vessel for use for the treatment of small diameter vessel diseases can potentially increase the success rate of autologous vascular grafting by eliminating complications related to the use of autologous vessel and increased availability. This manuscript demonstrates the potential of non-antigenic extracellular matrix (ECM) scaffolds derived from xenogeneic vascular tissue as off-the-shelf vascular grafts for the treatment of small diameter vascular diseases.
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Affiliation(s)
| | - Juan F Lopera Giraldo
- Department of Plastic Surgery, Clínica Las Américas, Antioquia, Dg. 75B ##2A-80/140, Medellín, Colombia
| | - Tiffany L Sarrafian
- Department of Thoracic Surgery, Mayo Clinic, 200 1st St SW, Rochester MN, USA
| | - Leigh G Griffiths
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
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31
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Fujita M, Suzuki H, Fukai F. Involvement of integrin-activating peptides derived from tenascin-C in colon cancer progression. World J Gastrointest Oncol 2021; 13:980-994. [PMID: 34616507 PMCID: PMC8465449 DOI: 10.4251/wjgo.v13.i9.980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/03/2021] [Accepted: 08/11/2021] [Indexed: 02/06/2023] Open
Abstract
Tenascin-C (TNC) is an adhesion modulatory protein present in the extracellular matrix that is highly expressed in several malignancies, including colon cancer. Although TNC is considered a negative prognostic factor for cancer patients, the substantial role of the TNC molecule in colorectal carcinogenesis and its malignant progression is poorly understood. We previously found that TNC has a cryptic functional site and that a TNC peptide containing this site, termed TNIIIA2, can potently and persistently activate beta1-integrins. In contrast, the peptide FNIII14, which contains a cryptic bioactive site within the fibronectin molecule, can inactivate beta1-integrins. This review presents the role of TNC in the development of colitis-associated colorectal cancer and in the malignant progression of colon cancer, particularly the major involvement of its cryptic functional site TNIIIA2. We propose new possible prophylactic and therapeutic strategies based on inhibition of the TNIIIA2-induced beta1-integrin activation by peptide FNIII14.
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Affiliation(s)
- Motomichi Fujita
- Department of Molecular Patho-Physiology, Tokyo University of Science, Noda 278-8510, Chiba, Japan
| | - Hideo Suzuki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Tokyo University of Science, Noda 278-8510, Chiba, Japan
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32
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Fujita M, Sasada M, Eguchi M, Iyoda T, Okuyama S, Osawa T, Tsuzuranuki K, Sakamoto M, Hagihara Y, Matsumura M, Osada S, Kodama H, Higami Y, Fukai F. Induction of cellular senescence in fibroblasts through β1-integrin activation by tenascin-C-derived peptide and its protumor effect. Am J Cancer Res 2021; 11:4364-4379. [PMID: 34659892 PMCID: PMC8493383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/13/2021] [Indexed: 06/13/2023] Open
Abstract
Tenascin-C is upregulated during inflammation and tumorigenesis, and its expression level is correlated with a poor prognosis in several malignancies. Nevertheless, the substantial role of tenascin-C in cancer progression is poorly understood. Previously, we found that a peptide derived from tenascin-C, termed TNIIIA2, acts directly on tumor cells to activate β1-integrin and induce malignant progression. Here, we show that β1-integrin activation by TNIIIA2 in human fibroblasts indirectly contributes to cancer progression through the induction of cellular senescence. Prolonged treatment of fibroblasts with TNIIIA2 induced cellular senescence, as characterized by the suppression of cell growth and the induction of senescence-associated-β-galactosidase and p16INK4a expression. The production of reactive oxygen species and subsequent DNA damage were responsible for the TNIIIA2-induced senescence of fibroblasts. Interestingly, peptide FNIII14, which inactivates β1-integrin, inhibited fibroblast senescence induced not only by TNIIIA2 but also by H2O2, suggesting that β1-integrin activation plays a critical role in the induction of senescence in fibroblasts. Moreover, TNIIIA2-induced senescent fibroblasts secreted heparin-binding epidermal growth factor-like growth factor (HB-EGF), which caused preneoplastic epithelial HaCaT cells to acquire malignant properties, including colony-forming and focus-forming abilities. Thus, our study demonstrates that tenascin-C-derived peptide TNIIIA2 induces cellular senescence in fibroblasts through β1-integrin activation, causing cancer progression via the secretion of humoral factors such as HB-EGF.
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Affiliation(s)
- Motomichi Fujita
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Manabu Sasada
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
- Clinical Research Center in Hiroshima, Hiroshima University HospitalHiroshima, Japan
| | - Mayu Eguchi
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Takuya Iyoda
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City UniversityYamaguchi, Japan
| | - Shin Okuyama
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Takuro Osawa
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Kenta Tsuzuranuki
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Mamoru Sakamoto
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Yu Hagihara
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Masaki Matsumura
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Satoshi Osada
- Faculty of Science and Engineering, Saga UniversitySaga, Japan
| | - Hiroaki Kodama
- Faculty of Science and Engineering, Saga UniversitySaga, Japan
| | - Yoshikazu Higami
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of ScienceChiba, Japan
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Tonti OR, Larson H, Lipp SN, Luetkemeyer CM, Makam M, Vargas D, Wilcox SM, Calve S. Tissue-specific parameters for the design of ECM-mimetic biomaterials. Acta Biomater 2021; 132:83-102. [PMID: 33878474 PMCID: PMC8434955 DOI: 10.1016/j.actbio.2021.04.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/18/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023]
Abstract
The extracellular matrix (ECM) is a complex network of biomolecules that mechanically and biochemically directs cell behavior and is crucial for maintaining tissue function and health. The heterogeneous organization and composition of the ECM varies within and between tissue types, directing mechanics, aiding in cell-cell communication, and facilitating tissue assembly and reassembly during development, injury and disease. As technologies like 3D printing rapidly advance, researchers are better able to recapitulate in vivo tissue properties in vitro; however, tissue-specific variations in ECM composition and organization are not given enough consideration. This is in part due to a lack of information regarding how the ECM of many tissues varies in both homeostatic and diseased states. To address this gap, we describe the components and organization of the ECM, and provide examples for different tissues at various states of disease. While many aspects of ECM biology remain unknown, our goal is to highlight the complexity of various tissues and inspire engineers to incorporate unique components of the native ECM into in vitro platform design and fabrication. Ultimately, we anticipate that the use of biomaterials that incorporate key tissue-specific ECM will lead to in vitro models that better emulate human pathologies. STATEMENT OF SIGNIFICANCE: Biomaterial development primarily emphasizes the engineering of new materials and therapies at the expense of identifying key parameters of the tissue that is being emulated. This can be partially attributed to the difficulty in defining the 3D composition, organization, and mechanics of the ECM within different tissues and how these material properties vary as a function of homeostasis and disease. In this review, we highlight a range of tissues throughout the body and describe how ECM content, cell diversity, and mechanical properties change in diseased tissues and influence cellular behavior. Accurately mimicking the tissue of interest in vitro by using ECM specific to the appropriate state of homeostasis or pathology in vivo will yield results more translatable to humans.
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Affiliation(s)
- Olivia R Tonti
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Hannah Larson
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sarah N Lipp
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Callan M Luetkemeyer
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Megan Makam
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Diego Vargas
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sean M Wilcox
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States
| | - Sarah Calve
- Paul M. Rady Department of Mechanical Engineering, University of Colorado - Boulder, 1111 Engineering Center, 427 UCB, Boulder, CO 80309, United States.
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Ambade AS, Hassoun PM, Damico RL. Basement Membrane Extracellular Matrix Proteins in Pulmonary Vascular and Right Ventricular Remodeling in Pulmonary Hypertension. Am J Respir Cell Mol Biol 2021; 65:245-258. [PMID: 34129804 PMCID: PMC8485997 DOI: 10.1165/rcmb.2021-0091tr] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 06/14/2021] [Indexed: 12/13/2022] Open
Abstract
The extracellular matrix (ECM), a highly organized network of structural and nonstructural proteins, plays a pivotal role in cellular and tissue homeostasis. Changes in the ECM are critical for normal tissue repair, whereas dysregulation contributes to aberrant tissue remodeling. Pulmonary arterial hypertension is a severe disorder of the pulmonary vasculature characterized by pathologic remodeling of the pulmonary vasculature and right ventricle, increased production and deposition of structural and nonstructural proteins, and altered expression of ECM growth factors and proteases. Furthermore, ECM remodeling plays a significant role in disease progression, as several dynamic changes in its composition, quantity, and organization are documented in both humans and animal models of disease. These ECM changes impact vascular cell biology and affect proliferation of resident cells. Furthermore, ECM components determine the tissue architecture of the pulmonary and myocardial vasculature as well as the myocardium itself and provide mechanical stability crucial for tissue homeostasis. However, little is known about the basement membrane (BM), a specialized, self-assembled conglomerate of ECM proteins, during remodeling. In the vasculature, the BM is in close physical association with the vascular endothelium and smooth muscle cells. While in the myocardium, each cardiomyocyte is enclosed by a BM that serves as the interface between cardiomyocytes and the surrounding interstitial matrix. In this review, we provide a brief overview on the current state of knowledge of the BM and its ECM composition and their impact on pulmonary vascular remodeling and right ventricle dysfunction and failure in pulmonary arterial hypertension.
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Affiliation(s)
- Anjira S Ambade
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Paul M Hassoun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Rachel L Damico
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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Torregrossa M, Kakpenova A, Simon JC, Franz S. Modulation of macrophage functions by ECM-inspired wound dressings - a promising therapeutic approach for chronic wounds. Biol Chem 2021; 402:1289-1307. [PMID: 34390641 DOI: 10.1515/hsz-2021-0145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022]
Abstract
Nonhealing chronic wounds are among the most common skin disorders with increasing incidence worldwide. However, their treatment is still dissatisfying, that is why novel therapeutic concepts targeting the sustained inflammatory process have emerged. Increasing understanding of chronic wound pathologies has put macrophages in the spotlight of such approaches. Herein, we review current concepts and perspectives of therapeutic macrophage control by ECM-inspired wound dressing materials. We provide an overview of the current understanding of macrophage diversity with particular view on their roles in skin and in physiological and disturbed wound healing processes. Based on this we discuss strategies for their modulation in chronic wounds and how such strategies can be tailored in ECM-inspired wound dressing. The latter utilize and mimic general principles of ECM-mediated cell control, such as binding and delivery of signaling molecules and direct signaling to cells specifically adapted for macrophage regulation in wounds. In this review, we present examples of most recent approaches and discuss ideas for their further development.
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Affiliation(s)
- Marta Torregrossa
- Department of Dermatology, Venerology and Allergology, Max Bürger Research Centre, Leipzig University, Johannisallee 30, D-04103 Leipzig, Germany
| | - Ainur Kakpenova
- Department of Dermatology, Venerology and Allergology, Max Bürger Research Centre, Leipzig University, Johannisallee 30, D-04103 Leipzig, Germany
| | - Jan C Simon
- Department of Dermatology, Venerology and Allergology, Max Bürger Research Centre, Leipzig University, Johannisallee 30, D-04103 Leipzig, Germany
| | - Sandra Franz
- Department of Dermatology, Venerology and Allergology, Max Bürger Research Centre, Leipzig University, Johannisallee 30, D-04103 Leipzig, Germany
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Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z, Miao H, Ren T, Yang Y, Li G, Song X, Hu Y, Wang X, Huang Y, Liu Y. LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:797-810. [PMID: 33614230 PMCID: PMC7868718 DOI: 10.1016/j.omtn.2021.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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Affiliation(s)
- Ruiyan Yuan
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bo Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China
| | - Zhaohui Jin
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jiacheng Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Ziyu Shao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huijie Miao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tai Ren
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoqiang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaoling Song
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunping Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu’an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Ying Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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Allen KB, Adams JD, Badylak SF, Garrett HE, Mouawad NJ, Oweida SW, Parikshak M, Sultan PK. Extracellular Matrix Patches for Endarterectomy Repair. Front Cardiovasc Med 2021; 8:631750. [PMID: 33644135 PMCID: PMC7904872 DOI: 10.3389/fcvm.2021.631750] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/25/2021] [Indexed: 12/15/2022] Open
Abstract
Patch repair is the preferred method for arteriotomy closure following femoral or carotid endarterectomy. Choosing among available patch options remains a clinical challenge, as current evidence suggests roughly comparable outcomes between autologous grafts and synthetic and biologic materials. Biologic patches have potential advantages over other materials, including reduced risk for infection, mitigation of an excessive foreign body response, and the potential to remodel into healthy, vascularized tissue. Here we review the use of decellularized extracellular matrix (ECM) for cardiovascular applications, particularly endarterectomy repair, and the capacity of these materials to remodel into native, site-appropriate tissues. Also presented are data from two post-market observational studies of patients undergoing iliofemoral and carotid endarterectomy patch repair as well as one histologic case report in a challenging iliofemoral endarterectomy repair, all with the use of small intestine submucosa (SIS)-ECM. In alignment with previously reported studies, high patency was maintained, and adverse event rates were comparable to previously reported rates of patch angioplasty. Histologic analysis from one case identified constructive remodeling of the SIS-ECM, consistent with the histologic characteristics of the endarterectomized vessel. These clinical and histologic results align with the biologic potential described in the academic ECM literature. To our knowledge, this is the first histologic demonstration of SIS-ECM remodeling into site-appropriate vascular tissues following endarterectomy. Together, these findings support the safety and efficacy of SIS-ECM for patch repair of femoral and carotid arteriotomy.
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Affiliation(s)
- Keith B Allen
- St. Luke's Hospital of Kansas City, St. Luke's Mid America Heart Institute, Kansas City, MO, United States
| | - Joshua D Adams
- Carilion Clinic Aortic and Endovascular Surgery, Roanoke, VA, United States
| | - Stephen F Badylak
- Department of Bioengineering, Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - H Edward Garrett
- Cardiovascular Surgery Clinic, University of Tennessee, Memphis, Memphis, TN, United States
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Xydias D, Ziakas G, Psilodimitrakopoulos S, Lemonis A, Bagli E, Fotsis T, Gravanis A, Tzeranis DS, Stratakis E. Three-dimensional characterization of collagen remodeling in cell-seeded collagen scaffolds via polarization second harmonic generation. BIOMEDICAL OPTICS EXPRESS 2021; 12:1136-1153. [PMID: 33680563 PMCID: PMC7901316 DOI: 10.1364/boe.411501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/24/2020] [Accepted: 12/01/2020] [Indexed: 05/08/2023]
Abstract
In this study, we use non-linear imaging microscopy to characterize the structural properties of porous collagen-GAG scaffolds (CGS) seeded with human umbilical vein endothelial cells (HUVECs), as well as human mesenchymal stem cells (hMSCs), a co-culture previously reported to form vessel-like structures inside CGS. The evolution of the resulting tissue construct was monitored over 10 days via simultaneous two- and three-photon excited fluorescence microscopy. Time-lapsed 2- and 3-photon excited fluorescence imaging was utilized to monitor the temporal evolution of the vascular-like structures up to 100 µm inside the scaffold up to 10 days post-seeding. 3D polarization-dependent second harmonic generation (PSHG) was utilized to monitor collagen-based scaffold remodeling and determine collagen fibril orientation up to 200 µm inside the scaffold. We demonstrate that polarization-dependent second harmonic generation can provide a novel way to quantify the reorganization of the collagen architecture in CGS simultaneously with key biomechanical interactions between seeded cells and CGS that regulate the formation of vessel-like structures inside 3D tissue constructs. A comparison between samples at different days in vitro revealed that gradually, the scaffolds developed an orthogonal net-like architecture, previously found in real skin.
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Affiliation(s)
- Dionysios Xydias
- Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, Greece
- Department of Materials Science and Technology, School of Sciences and Engineering, University of Crete, Greece
| | - Georgios Ziakas
- Department of Materials Science and Technology, School of Sciences and Engineering, University of Crete, Greece
| | | | - Andreas Lemonis
- Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, Greece
| | - Eleni Bagli
- Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Ioannina, Greece
| | - Theodore Fotsis
- Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Ioannina, Greece
| | - Achille Gravanis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Greece
- Department of Pharmacology, School of Medicine, University of Crete, Greece
| | - Dimitrios S. Tzeranis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Greece
- Department of Mechanical and Manufacturing Engineering, University of Cyprus, Cyprus, Greece
| | - Emmanuel Stratakis
- Institute of Electronic Structure and Laser, Foundation for Research and Technology-Hellas, Greece
- Department of Physics, School of Sciences and Engineering, University of Crete, Greece
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Gharesouran J, Hosseinzadeh H, Ghafouri-Fard S, Jabbari Moghadam Y, Ahmadian Heris J, Jafari-Rouhi AH, Taheri M, Rezazadeh M. New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa. Orphanet J Rare Dis 2021; 16:51. [PMID: 33509220 PMCID: PMC7845118 DOI: 10.1186/s13023-021-01696-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background FBLN5-related cutis laxa (CL) is a rare disorder that involves elastic fiber-enriched tissues and is characterized by lax skin and variable systemic involvement such as pulmonary emphysema, arterial involvement, inguinal hernias, hollow viscus diverticula and pyloric stenosis. This type of CL follows mostly autosomal recessive (AR) and less commonly autosomal dominant patterns of inheritance. Results In this study, we detected a novel homozygous missense variant in exon 6 of FBLN5 gene (c.G544C, p.A182P) by using whole exome sequencing in a consanguineous Iranian family with two affected members. Our twin patients showed some of the clinical manifestation of FBLN5-related CL but they did not present pulmonary complications, gastrointestinal and genitourinary abnormalities. The notable thing about this monozygotic twin sisters is that only one of them showed ventricular septal defect, suggesting that this type of CL has intrafamilial variability. Co-segregation analysis showed the patients’ parents and relatives were heterozygous for detected variation suggesting AR form of the CL. In silico prediction tools showed that this mutation is pathogenic and 3D modeling of the normal and mutant protein revealed relative structural alteration of fibulin-5 suggesting that the A182P can contribute to the CL phenotype via the combined effect of lack of protein function and partly misfolding-associated toxicity. Conclusion We underlined the probable roles and functions of the involved domain of fibulin-5 and proposed some possible mechanisms involved in AR form of FBLN5-related CL. However, further functional studies and subsequent clinical and molecular investigations are needed to confirm our findings.
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Affiliation(s)
- Jalal Gharesouran
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Hosseinzadeh
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yalda Jabbari Moghadam
- Department of Otorhinolaryngology, School of Medicine, Sina Medical Research and Training Hospital, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Pediatrics, School of Medicine, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Rezazadeh
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.
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40
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Sugiyama A, Okada M, Otani K, Yamawaki H. [Development of basic research toward clinical application of cleaved fragment of type IV collagen]. Nihon Yakurigaku Zasshi 2021; 156:282-287. [PMID: 34470932 DOI: 10.1254/fpj.21016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Basement membrane is a dense sheet-like extracellular matrix (ECM), which separates cells from surrounding interstitium. Type IV collagen is a major component of basement membrane and three of six α chains (namely α1-α6 chains) form a triple-helix structure. Recently, endogenous bioactive factors called "matricryptins" or "matrikines", which are produced by degrading and cleaving C-terminal domain of type IV collagen, attract attentions as a novel therapeutic target or a candidate for biomarkers. In all type IV collagens, matricryptins called arresten (α1 chain), canstatin (α2), tumstatin (α3), tetrastatin (α4), pentastatin (α5), and hexastatin (α6), have been identified. The type IV collagen-derived matricryptins have been previously studied as new therapeutic targets for neoplastic diseases since they exert anti-angiogenic and/or anti-tumor effects. On the other hand, we have recently demonstrated the cardioprotective effects of matricryptins in addition to the altered expression levels in cardiac diseases. In this review, we introduce the results of fundamental studies for the type IV collagen-derived matricryptins in various diseases, such as neoplastic diseases and cardiac diseases, and discuss the potential clinical application as novel therapeutic agents and biomarkers.
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Affiliation(s)
- Akira Sugiyama
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Muneyoshi Okada
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Kosuke Otani
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
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Latorre M, Spronck B, Humphrey JD. Complementary roles of mechanotransduction and inflammation in vascular homeostasis. Proc Math Phys Eng Sci 2021; 477:20200622. [PMID: 33642928 PMCID: PMC7897647 DOI: 10.1098/rspa.2020.0622] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022] Open
Abstract
Arteries are exposed to relentless pulsatile haemodynamic loads, but via mechanical homeostasis they tend to maintain near optimal structure, properties and function over long periods in maturity in health. Numerous insults can compromise such homeostatic tendencies, however, resulting in maladaptations or disease. Chronic inflammation can be counted among the detrimental insults experienced by arteries, yet inflammation can also play important homeostatic roles. In this paper, we present a new theoretical model of complementary mechanobiological and immunobiological control of vascular geometry and composition, and thus properties and function. We motivate and illustrate the model using data for aortic remodelling in a common mouse model of induced hypertension. Predictions match the available data well, noting a need for increased data for further parameter refinement. The overall approach and conclusions are general, however, and help to unify two previously disparate literatures, thus leading to deeper insight into the separate and overlapping roles of mechanobiology and immunobiology in vascular health and disease.
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Affiliation(s)
- Marcos Latorre
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Bart Spronck
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA,Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Jay D. Humphrey
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA,Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA,e-mail:
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42
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Franklin A, Gi Min J, Oda H, Kaizawa Y, Leyden J, Wang Z, Chang J, Fox PM. Homing of Adipose-Derived Stem Cells to a Tendon-Derived Hydrogel: A Potential Mechanism for Improved Tendon-Bone Interface and Tendon Healing. J Hand Surg Am 2020; 45:1180.e1-1180.e12. [PMID: 32605739 DOI: 10.1016/j.jhsa.2020.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 01/29/2020] [Accepted: 05/07/2020] [Indexed: 02/02/2023]
Abstract
PURPOSE Tendons are difficult to heal owing to their hypocellularity and hypovascularity. Our laboratory has developed a tendon-derived hydrogel (tHG) that significantly improves tendon healing in an animal model. We hypothesized that a potential mechanism for improved healing with tHG is through the attraction of systemic stem cells. METHODS Homing of systemic adipose-derived stem cells (ADSCs) to tendon injuries was assessed with acute and chronic injury models. Injury sites were treated with saline or tHG, and animals given a tail vein injection (TVI) of labeled ADSCs 1 week after treatment. One week following TVI, rats were harvested for histology. To further evaluate a potential difference in homing to tHG, a subcutaneous injection (SQI) model was used. Rats were treated with an SQI of saline, silicone, ADSCs in media, tHG, tHG + fibroblasts (FBs), or tHG + ADSCs on day 0. One week after SQI, rats underwent TVI with labeled ADSCs. Samples were harvested 2 or 3 weeks after SQI for analysis. Flow cytometry confirmed homing in the SQI model. RESULTS Systemically delivered ADSCs homed to both acute tendon and chronic tendon-bone interface (TBI) injury sites. Despite their presence at the injury site, there was no difference in the number of macrophages, amount of cell proliferation, or angiogenesis 1 week after stem cell delivery. In an SQI model, ADSCs homed to tHG. There was no difference in the number of ADSCs homing to tHG alone versus tHG + ADSCs. However, there was an increase in the number of living cells, general immune cells, and T-cells present at tHG + ADSC versus tHG alone. CONCLUSIONS The ADSCs home to tendon injury sites and tHG. We believe the attraction of additional systemic ADSCs is one mechanism for improved tendon and TBI healing with tHG. CLINICAL RELEVANCE Treatment of tendon and TBI injuries with tHG can augment healing via homing of systemic stem cells.
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Affiliation(s)
- Austin Franklin
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Jung Gi Min
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Hiroki Oda
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Yukitoshi Kaizawa
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Jacinta Leyden
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Zhen Wang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - James Chang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
| | - Paige M Fox
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, CA; Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA.
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Liao J, Xu B, Zhang R, Fan Y, Xie H, Li X. Applications of decellularized materials in tissue engineering: advantages, drawbacks and current improvements, and future perspectives. J Mater Chem B 2020; 8:10023-10049. [PMID: 33053004 DOI: 10.1039/d0tb01534b] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Decellularized materials (DMs) are attracting more and more attention because of their native structures, comparatively high bioactivity, low immunogenicity and good biodegradability, which are difficult to be imitated by synthetic materials. Recently, DMs have been demonstrated to possess great potential to overcome the disadvantages of autografts and have become a kind of promising material for tissue engineering. In this systematic review, we aimed to not only provide a quick access for understanding DMs, but also bring new ideas to utilize them more appropriately in tissue engineering. Firstly, the preparation of DMs was introduced. Then, the updated applications of DMs derived from different tissues and organs in tissue engineering were comprehensively summarized. In particular, their advantages, drawbacks and current improvements were emphasized. Moreover, we analyzed and proposed future perspectives.
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Affiliation(s)
- Jie Liao
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing 100083, China.
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44
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Itagaki K, Sasada M, Miyazaki S, Iyoda T, Imaizumi T, Haga M, Kuga A, Inomata H, Kondo Y, Osada S, Kodama H, Higami Y, Fukai F. Exposure of the cryptic de-adhesive site FNIII14 in fibronectin molecule and its binding to membrane-type eEF1A induce migration and invasion of cancer cells via β1-integrin inactivation. Am J Cancer Res 2020; 10:3990-4004. [PMID: 33294281 PMCID: PMC7716165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/13/2020] [Indexed: 06/12/2023] Open
Abstract
Cell migration is a highly coordinated process that involves not only integrin-mediated adhesion but also de-adhesion. We previously found that a cryptic de-adhesive site within fibronectin molecule, termed FNIII14, weakens cell adhesion to the extracellular matrix by inactivating β1-integrins. Surprisingly, eukaryotic translation elongation factor-1A (eEF1A), an essential factor during protein biosynthesis, was identified as a membrane receptor that mediates the de-adhesive effect of FNIII14. Here, we demonstrate that FNIII14-mediated de-adhesion causes enhanced migration and invasion in two types of highly invasive/metastatic cancer cells, resulting in the initiation of metastasis. Both in vitro migration and invasion of highly invasive human melanoma cell line, Mum2B, were inhibited by a matrix metalloproteinase (MMP)-2/9 inhibitor or a function-blocking antibody against FNIII14 (anti-FNIII14 Ab), suggesting that MMP-mediated exposure of the cryptic de-adhesive site FNIII14 was responsible for Mum2B cell migration and invasion. The MMP-induced FNIII14 exposure was also shown to be functional in the migration and invasion of highly metastatic mouse breast cancer cell line 4T1. Overexpression and knockdown experiments of eEF1A in Mum2B cells revealed that the migration and invasion were dependent on the membrane levels of eEF1A. In vivo experiments using tumor xenograft mouse models derived from Mum2B and 4T1 cell lines showed that the anti-FNIII14 Ab has a significant anti-metastatic effect. Thus, these results provide novel insights into the regulation of cancer cell migration and invasion and suggest promising targets for anti-metastasis strategies.
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Affiliation(s)
- Keisuke Itagaki
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Manabu Sasada
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Satoru Miyazaki
- Department of Medical and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Takuya Iyoda
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Takahiro Imaizumi
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Makoto Haga
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Akira Kuga
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Hiroki Inomata
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Yosuke Kondo
- Department of Medical and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Satoshi Osada
- Department of Biochemistry, Faculty of Science and Engineering, Saga University1 Honjo-machi, Saga 840-8502, Japan
| | - Hiroaki Kodama
- Department of Biochemistry, Faculty of Science and Engineering, Saga University1 Honjo-machi, Saga 840-8502, Japan
| | - Yoshikazu Higami
- Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
| | - Fumio Fukai
- Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan
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Preparation and characterization of amnion hydrogel and its synergistic effect with adipose derived stem cells towards IL1β activated chondrocytes. Sci Rep 2020; 10:18751. [PMID: 33127964 PMCID: PMC7603317 DOI: 10.1038/s41598-020-75921-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 10/13/2020] [Indexed: 12/29/2022] Open
Abstract
Inflammation leads to chondrocyte senescence and cartilage degeneration, resulting in osteoarthritis (OA). Adipose‐derived stem cells (ADSCs) exert paracrine effects protecting chondrocytes from degenerative changes. However, the lack of optimum delivery systems for ADSCs limits its use in the clinic. The use of extracellular matrix based injectable hydrogels has gained increased attention due to their unique properties. In the present study, we developed hydrogels from amnion tissue as a delivery system for ADSCs. We investigated the potential of amnion hydrogel to maintain ADSC functions, the synergistic effect of AM with ADSC in preventing the catabolic responses of inflammation in stimulated chondrocytes. We also investigated the role of Wnt/β-catenin signaling pathway in IL-1β induced inflammation in chondrocytes and the ability of AM-ADSC to inhibit Wnt/β-catenin signaling. Our results showed that AM hydrogels supported cell viability, proliferation, and stemness. ADSCs, AM hydrogels and AM-ADSCs inhibited the catabolic responses of IL-1β and inhibited the Wnt/β-catenin signaling pathway, indicating possible involvement of Wnt/β-catenin signaling pathways in IL-1β induced inflammation. The results also showed that the synergistic effect of AM-ADSCs was more pronounced in preventing catabolic responses in activated chondrocytes. In conclusion, we showed that AM hydrogels can be used as a potential carrier for ADSCs, and can be developed as a potential therapeutic agent for treating OA.
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Bankoti K, Rameshbabu AP, Datta S, Roy M, Goswami P, Roy S, Das AK, Ghosh SK, Dhara S. Carbon nanodot decorated acellular dermal matrix hydrogel augments chronic wound closure. J Mater Chem B 2020; 8:9277-9294. [PMID: 32996553 DOI: 10.1039/d0tb01574a] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Impaired skin regeneration in chronic wounds like in diabetes corresponds to high oxidative stress, poor angiogenesis and insufficient collagen hyperplasia. Therefore, a multifaceted strategy for treatment is required to address critical issues associated with chronic wound healing. Fascinating application of nanomaterials in chronic wounds is still limited; hence, in the present work bioactive solubilized decellularized dermal matrix (sADM) was employed to form a hydrogel with chitosan (CTS) at physiological pH/temperature and modified with reactive oxygen species (ROS) scavenging carbon nanodots (ND). A detailed in vitro investigation found that the ND modified bioactive hydrogel (CsADMND) is suitable for human amniotic membrane derived stem cell (hAMSC) delivery. Also, CsADMND was observed to possess a good ROS scavenging property, hemocompatibility and pro-angiogenic potential as demonstrated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), haemolysis and chick chorioallantoic membrane (CAM) assay, respectively. The hybrid hydrogel promoted migration of cells in vitro in scratch assay owing to its antioxidant potential and the presence of bioactive moieties. Further, its efficacy in healing full thickness (FT) chronic wounds was evaluated in a streptozotocin (STZ) induced diabetic model. The CsADMND hydrogel after association with hAMSCs led to stimulation of early angiogenesis, superior collagen deposition, rapid wound closure, complete reepithelialisation, and formation of distinct organized dermal epidermal junctions (DEJ) post 21 days of healing. These results suggest that the hAMSC laden CsADMND hydrogel may serve as a promising therapeutic strategy for the management of chronic wounds.
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Affiliation(s)
- Kamakshi Bankoti
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Arun Prabhu Rameshbabu
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Sayanti Datta
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Madhurima Roy
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Piyali Goswami
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Sabyasachi Roy
- Department of Gynaecology, Midnapore Medical College, Paschim Medinipur-721101, India
| | - Amit Kumar Das
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Sudip Kumar Ghosh
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Santanu Dhara
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
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Datta S, Rameshbabu AP, Bankoti K, Roy M, Gupta C, Jana S, Das AK, Sen R, Dhara S. Decellularized bone matrix/oleoyl chitosan derived supramolecular injectable hydrogel promotes efficient bone integration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 119:111604. [PMID: 33321648 DOI: 10.1016/j.msec.2020.111604] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/03/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022]
Abstract
Hydrogels derived from decellularized extracellular matrix (ECM) have been widely used as a bioactive matrix for facilitating functional bone tissue regeneration. However, its poor mechanical strength and fast degradation restricts the extensive use for clinical application. Herein, we present a crosslinked decellularized bone ECM (DBM) and fatty acid modified chitosan (oleoyl chitosan, OC) based biohybrid hydrogel (DBM/OC) for delivering human amnion-derived stem cells (HAMSCs) for bone regeneration. DBM/OC hydrogel were benchmarked against collagen-I/OC (Col-I/OC) based hydrogel in terms of their morphological characteristics, rheological analysis, and biological performances. DBM/OC hydrogel with its endogenous growth factors recapitulates the nanofibrillar 3D tissue microenvironment with improved mechanical strength and also exhibited antimicrobial potential along with superior proliferation/differentiation ability. HAMSCs encapsulation potential of DBM/OC hydrogel was established by well spread cytoskeleton morphology post 14 days of cultivation. Further, ex-vivo chick chorioallantoic membrane (CAM) assay revealed excellent neovascularization potential of DBM/OC hydrogel. Subcutaneously implanted DBM/OC hydrogel did not trigger any severe immune response or infection in the host after 21 days. Also, DBM/OC hydrogels and HAMSCs encapsulated DBM/OC hydrogels were implanted at the tibial defect in a rabbit model to assess the bone regeneration ability. Quantitative micro-CT and histomorphological analysis demonstrated that HAMSCs encapsulated DBM/OC hydrogel can support more mature mineralized bone formation at the defect area compared to DBM/OC hydrogel or SHAM. These findings manifested the efficacy of DBM/OC hydrogel as a functional cell-delivery vehicle and osteoinductive template to accelerate bone regeneration.
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Affiliation(s)
- Sayanti Datta
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Arun Prabhu Rameshbabu
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Kamakshi Bankoti
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Madhurima Roy
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Chandrika Gupta
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Subhodeep Jana
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Amit Kumar Das
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Ramkrishna Sen
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
| | - Santanu Dhara
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
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Melrose J. Perlecan, a modular instructive proteoglycan with diverse functional properties. Int J Biochem Cell Biol 2020; 128:105849. [PMID: 32947020 DOI: 10.1016/j.biocel.2020.105849] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/30/2020] [Accepted: 09/13/2020] [Indexed: 12/14/2022]
Abstract
This study reviewed some new aspects of the modular proteoglycan perlecan, a colossal proteoglycan with a 467 kDa core protein and five distinct functional domains. Perlecan is a heparan sulphate proteoglycan that transiently displays native CS sulphation motifs 4-C-3 and 7-D-4 during tissue morphogenesis these are expressed by progenitor cell populations during tissue development. Perlecan is susceptible to fragmentation by proteases during tissue development and in pathological tissues particularly in domains IV and V. The fragmentation pattern of domain IV has been suggested as a means of grading prostate cancer. Domain V of perlecan is of interest due to its interactive properties with integrin α5β1 that promotes pericyte migration enhancing PDGF-BB-induced phosphorylation of PDGFRβ, Src homology region 2 domain-containing phosphatase-2, and focal adhesion kinase supporting the repair of the blood brain barrier following ischaemic stroke. Fragments of domain V can also interact with α2β1 integrin disrupting tube formation by endothelial cells. LG1-LG2, LG3 fragments can antagonise VEGFR2, and α2β1 integrin interactions preventing angiogenesis by endothelial cells. These domain V fragments are of interest as potential anti-tumour agents. Perlecan attached to the luminal surfaces of endothelial cells in blood vessels acts as a flow sensor that signals back to endothelial and smooth muscle cells to regulate vascular tone and blood pressure. Perlecan also acts as a flow sensor in the lacuno-canalicular space regulating osteocytes and bone homeostasis. Along with its biomechanical regulatory properties in cartilaginous tissues this further extends the functional repertoire of this amazingly diverse functional proteoglycan.
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Affiliation(s)
- James Melrose
- Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia; Sydney Medical School, Northern, The University of Sydney, Australia; Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
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Ma SKY, Chan ASF, Rubab A, Chan WCW, Chan D. Extracellular Matrix and Cellular Plasticity in Musculoskeletal Development. Front Cell Dev Biol 2020; 8:781. [PMID: 32984311 PMCID: PMC7477050 DOI: 10.3389/fcell.2020.00781] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Cellular plasticity refers to the ability of cell fates to be reprogrammed given the proper signals, allowing for dedifferentiation or transdifferentiation into different cell fates. In vitro, this can be induced through direct activation of gene expression, however this process does not naturally occur in vivo. Instead, the microenvironment consisting of the extracellular matrix (ECM) and signaling factors, directs the signals presented to cells. Often the ECM is involved in regulating both biochemical and mechanical signals. In stem cell populations, this niche is necessary for maintenance and proper function of the stem cell pool. However, recent studies have demonstrated that differentiated or lineage restricted cells can exit their current state and transform into another state under different situations during development and regeneration. This may be achieved through (1) cells responding to a changing niche; (2) cells migrating and encountering a new niche; and (3) formation of a transitional niche followed by restoration of the homeostatic niche to sequentially guide cells along the regenerative process. This review focuses on examples in musculoskeletal biology, with the concept of ECM regulating cells and stem cells in development and regeneration, extending beyond the conventional concept of small population of progenitor cells, but under the right circumstances even “lineage-restricted” or differentiated cells can be reprogrammed to enter into a different fate.
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Affiliation(s)
- Sophia Ka Yan Ma
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | | | - Aqsa Rubab
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Wilson Cheuk Wing Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.,Department of Orthopedics Surgery and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
| | - Danny Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.,The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
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50
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Kim BS, Das S, Jang J, Cho DW. Decellularized Extracellular Matrix-based Bioinks for Engineering Tissue- and Organ-specific Microenvironments. Chem Rev 2020; 120:10608-10661. [PMID: 32786425 DOI: 10.1021/acs.chemrev.9b00808] [Citation(s) in RCA: 270] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Biomaterials-based biofabrication methods have gained much attention in recent years. Among them, 3D cell printing is a pioneering technology to facilitate the recapitulation of unique features of complex human tissues and organs with high process flexibility and versatility. Bioinks, combinations of printable hydrogel and cells, can be utilized to create 3D cell-printed constructs. The bioactive cues of bioinks directly trigger cells to induce tissue morphogenesis. Among the various printable hydrogels, the tissue- and organ-specific decellularized extracellular matrix (dECM) can exert synergistic effects in supporting various cells at any component by facilitating specific physiological properties. In this review, we aim to discuss a new paradigm of dECM-based bioinks able to recapitulate the inherent microenvironmental niche in 3D cell-printed constructs. This review can serve as a toolbox for biomedical engineers who want to understand the beneficial characteristics of the dECM-based bioinks and a basic set of fundamental criteria for printing functional human tissues and organs.
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Affiliation(s)
- Byoung Soo Kim
- Future IT Innovation Laboratory, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu,, Pohang, Kyungbuk 37673, Republic of Korea.,POSTECH-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Sanskrita Das
- Department of Creative IT Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Jinah Jang
- Future IT Innovation Laboratory, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu,, Pohang, Kyungbuk 37673, Republic of Korea.,Department of Creative IT Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,POSTECH-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,Institute of Convergence Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Dong-Woo Cho
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,POSTECH-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea.,Institute of Convergence Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
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