Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Matrix Embedded Instructional Cues Direct Development and Tissue Repair

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Related Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 35358

Share This Special Issue

Special Issue Editors

Prof. Dr. James Melrose

E-Mail Website
Guest Editor

1. Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia
2. Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia
Interests: musculoskeletal disorders; repair biology; GAG pathobiology; stem cells
Special Issues, Collections and Topics in MDPI journals

Dr. Anthony J Hayes

E-Mail Website
Guest Editor

Bioimaging Research Hub, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK
Interests: development; growth & repair of musculoskeletal connective tissues; extracellular matrix; biological imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Besides being a mechanical support, the extracellular and pericellular matrix have long been known to act as scaffolds for cell attachment and they also provide regulatory cues that control the cellular proliferation and differentiation of cells within connective tissues. By deciphering this code which controls cellular behaviour it is becoming clearer how these might be incorporated into tissue repair strategies to improve functional recovery of damaged tissues. These repair cues are diverse entities and have been identified in bioactive peptide modules as well as in specific glycosaminoglycan sequences. Enzymatic processing of the extracellular and pericellular matrix can generate these bioactive fragments in pathological tissues however intrinsic repair is often unsuccessful unless additional support is provided to effect functional recovery. The aim of this issue is to assemble a collection of papers to further this area of repair biology which has undergone significant advances particularly in the development of bioactive functional cell directive biomatrices that promote repair and regeneration of tissues and recovery of tissue function. Multi-functional tissue proteoglycans with cell regulatory properties participate in many aspects of these repair processes applicable to the promotion of this pathway to functional recovery. Hyaluronan also has significant regulatory properties that promote cell directed repair of tissues.

Areas of interest in the issue: Cartilage and tendon repair; the nerve-neuromuscular interface; understanding the roles of proteoglycans in tissue form, function, and repair; Bio-instructive matrices controlling stem cell behavior that promotes tissue repair; advances in mechano-and electroconductive repair biomatrices; the impact of nanotechnology and 3D printing on tissue repair strategies; bioactive matricryptic ECM component fragments and tissue repair; artificial proteoglycans; understanding the cell directive cues provided by glycosaminoglycans in neural repair; the importance of the ECM in the functional properties of the CNS/PNS; advances in muscular dystrophy repair biology; advances in IVD repair; advances in vascular repair of connective tissues; HS biology and tissue repair; HA and its roles in the stem cell niche in brain and spinal cord repair; HA, remodeling and repair of the traumatised brain ECM.

Prof. Dr. James Melrose
Dr. Anthony J Hayes
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ECM
matrix
tissue repair
repair biology
functional recovery

Related Special Issue

Matrix Embedded Instructional Cues Direct Development and Tissue Repair 2.0 in International Journal of Molecular Sciences (5 articles)

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

14 pages, 4896 KiB

Open AccessArticle

A Single Injection of NTG-101 Reduces the Expression of Pain-Related Neurotrophins in a Canine Model of Degenerative Disc Disease

by Ajay Matta, Muhammad Zia Karim, Hoda Gerami, Bettina Zoe Benigno, Ivan Cheng, Arne Mehrkens and William Mark Erwin

Int. J. Mol. Sci. 2022, 23(10), 5717; https://doi.org/10.3390/ijms23105717 - 20 May 2022

Cited by 3 | Viewed by 1622

Abstract

Background: Tissue sources of pain emanating from degenerative discs remains incompletely understood. Canine intervertebral discs (IVDs) were needle puncture injured, 4-weeks later injected with either phosphate-buffered saline (PBS) or NTG-101, harvested after an additional fourteen weeks and then histologically evaluated for the expression of NGFr, BDNF, TrkB and CALCRL proteins. Quantification was performed using the HALO automated cell-counting scoring platform. Immunohistochemical analysis was also performed on human IVD tissue samples obtained from spinal surgery. Immunohistochemical analysis and quantification of neurotrophins and neuropeptides was performed using an in vivo canine model of degenerative disc disease and human degenerative disc tissue sections. Discs injected with NTG-101 showed significantly lower levels of Nerve Growth Factor receptor (NGFr/TrkA, p = 0.0001), BDNF (p = 0.009), TrkB (p = 0.002) and CALCRL (p = 0.008) relative to PBS injections. Human IVD tissue obtained from spinal surgery due to painful DDD show robust expression of NGFr, BDNF, TrkB and CALCRL proteins. A single intradiscal injection of NTG-101 significantly inhibits the expression of NGFr, BDNF, TrkB and CALCRL proteins in degenerative canine IVDs. These results strongly suggest that NTG-101 inhibits the development of neurotrophins that are strongly associated with painful degenerative disc disease and may have profound effects upon the management of patients living with discogenic pain. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 663 KiB

Open AccessReview

The Specific Role of Dermatan Sulfate as an Instructive Glycosaminoglycan in Tissue Development

by Shuji Mizumoto and Shuhei Yamada

Int. J. Mol. Sci. 2022, 23(13), 7485; https://doi.org/10.3390/ijms23137485 - 05 Jul 2022

Cited by 11 | Viewed by 4773

Abstract

The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers–Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Figure 1

15 pages, 373 KiB

Open AccessReview

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

by Yi Sun, Minmin Lyu, Qiuji Lu, Kenneth Cheung and Victor Leung

Int. J. Mol. Sci. 2022, 23(12), 6612; https://doi.org/10.3390/ijms23126612 - 14 Jun 2022

Cited by 9 | Viewed by 2438

Abstract

A growing body of evidence in humans and animal models indicates an association between intervertebral disc degeneration (IDD) and increased fibrotic elements in the nucleus pulposus (NP). These include enhanced matrix turnover along with the abnormal deposition of collagens and other fibrous matrices, the emergence of fibrosis effector cells, such as macrophages and active fibroblasts, and the upregulation of the fibroinflammatory factors TGF-β1 and IL-1/-13. Studies have suggested a role for NP cells in fibroblastic differentiation through the TGF-βR1-Smad2/3 pathway, inflammatory activation and mechanosensing machineries. Moreover, NP fibrosis is linked to abnormal MMP activity, consistent with the role of matrix proteases in regulating tissue fibrosis. MMP-2 and MMP-12 are the two main profibrogenic markers of myofibroblastic NP cells. This review revisits studies in the literature relevant to NP fibrosis in an attempt to stratify its biochemical features and the molecular identity of fibroblastic cells in the context of IDD. Given the role of fibrosis in tissue healing and diseases, the perspective may provide new insights into the pathomechanism of IDD and its management. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

12 pages, 1806 KiB

Open AccessReview

The Extracellular Matrix of Articular Cartilage Controls the Bioavailability of Pericellular Matrix-Bound Growth Factors to Drive Tissue Homeostasis and Repair

by Tonia L. Vincent, Oliver McClurg and Linda Troeberg

Int. J. Mol. Sci. 2022, 23(11), 6003; https://doi.org/10.3390/ijms23116003 - 26 May 2022

Cited by 14 | Viewed by 3303

Abstract

The extracellular matrix (ECM) has long been regarded as a packing material; supporting cells within the tissue and providing tensile strength and protection from mechanical stress. There is little surprise when one considers the dynamic nature of many of the individual proteins that contribute to the ECM, that we are beginning to appreciate a more nuanced role for the ECM in tissue homeostasis and disease. Articular cartilage is adapted to be able to perceive and respond to mechanical load. Indeed, physiological loads are essential to maintain cartilage thickness in a healthy joint and excessive mechanical stress is associated with the breakdown of the matrix that is seen in osteoarthritis (OA). Although the trigger by which increased mechanical stress drives catabolic pathways remains unknown, one mechanism by which cartilage responds to increased compressive load is by the release of growth factors that are sequestered in the pericellular matrix. These are heparan sulfate-bound growth factors that appear to be largely chondroprotective and displaced by an aggrecan-dependent sodium flux. Emerging evidence suggests that the released growth factors act in a coordinated fashion to drive cartilage repair. Thus, we are beginning to appreciate that the ECM is the key mechano-sensor and mechano-effector in cartilage, responsible for directing subsequent cellular events of relevance to joint health and disease. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Figure 1

15 pages, 5574 KiB

Open AccessReview

Fractone Stem Cell Niche Components Provide Intuitive Clues in the Design of New Therapeutic Procedures/Biomatrices for Neural Repair

by James Melrose

Int. J. Mol. Sci. 2022, 23(9), 5148; https://doi.org/10.3390/ijms23095148 - 05 May 2022

Cited by 5 | Viewed by 2544

Abstract

The aim of this study was to illustrate recent developments in neural repair utilizing hyaluronan as a carrier of olfactory bulb stem cells and in new bioscaffolds to promote neural repair. Hyaluronan interacts with brain hyalectan proteoglycans in protective structures around neurons in perineuronal nets, which also have roles in the synaptic plasticity and development of neuronal cognitive properties. Specialist stem cell niches termed fractones located in the sub-ventricular and sub-granular regions of the dentate gyrus of the hippocampus migrate to the olfactory bulb, which acts as a reserve of neuroprogenitor cells in the adult brain. The extracellular matrix associated with the fractone stem cell niche contains hyaluronan, perlecan and laminin α5, which regulate the quiescent recycling of stem cells and also provide a means of escaping to undergo the proliferation and differentiation to a pluripotent migratory progenitor cell type that can participate in repair processes in neural tissues. Significant improvement in the repair of spinal cord injury and brain trauma has been reported using this approach. FGF-2 sequestered by perlecan in the neuroprogenitor niche environment aids in these processes. Therapeutic procedures have been developed using olfactory ensheathing stem cells and hyaluronan as a carrier to promote neural repair processes. Now that recombinant perlecan domain I and domain V are available, strategies may also be expected in the near future using these to further promote neural repair strategies. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Graphical abstract

11 pages, 858 KiB

Open AccessReview

Extracellular Vesicles: Interplay with the Extracellular Matrix and Modulated Cell Responses

by Aleen Al Halawani, Suzanne M. Mithieux, Giselle C. Yeo, Elham Hosseini-Beheshti and Anthony S. Weiss

Int. J. Mol. Sci. 2022, 23(6), 3389; https://doi.org/10.3390/ijms23063389 - 21 Mar 2022

Cited by 32 | Viewed by 4371

Abstract

The discovery that cells secrete extracellular vesicles (EVs), which carry a variety of regulatory proteins, nucleic acids, and lipids, has shed light on the sophisticated manner by which cells can communicate and accordingly function. The bioactivity of EVs is not only defined by their internal content, but also through their surface associated molecules, and the linked downstream signaling effects they elicit in target cells. The extracellular matrix (ECM) contains signaling and structural molecules that are central to tissue maintenance and repair. Recently, a subset of EVs residing within the extracellular matrix has been identified. Although some roles have been proposed for matrix-bound vesicles, their role as signaling molecules within the ECM is yet to be explored. Given the close association of EVs and the ECM, it is not surprising that EVs partly mediate repair and regeneration by modulating matrix deposition and degradation through their cellular targets. This review addresses unique EV features that allow them to interact with and navigate through the ECM, describes how their release and content is influenced by the ECM, and emphasizes the emerging role of stem-cell derived EVs in tissue repair and regeneration through their matrix-modulating properties. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Figure 1

25 pages, 6729 KiB

Open AccessReview

Regulation of FGF-2, FGF-18 and Transcription Factor Activity by Perlecan in the Maturational Development of Transitional Rudiment and Growth Plate Cartilages and in the Maintenance of Permanent Cartilage Homeostasis

by Anthony J. Hayes, John Whitelock and James Melrose

Int. J. Mol. Sci. 2022, 23(4), 1934; https://doi.org/10.3390/ijms23041934 - 09 Feb 2022

Cited by 13 | Viewed by 2787

Abstract

The aim of this study was to highlight the roles of perlecan in the regulation of the development of the rudiment developmental cartilages and growth plate cartilages, and also to show how perlecan maintains permanent articular cartilage homeostasis. Cartilage rudiments are transient developmental templates containing chondroprogenitor cells that undergo proliferation, matrix deposition, and hypertrophic differentiation. Growth plate cartilage also undergoes similar changes leading to endochondral bone formation, whereas permanent cartilage is maintained as an articular structure and does not undergo maturational changes. Pericellular and extracellular perlecan-HS chains interact with growth factors, morphogens, structural matrix glycoproteins, proteases, and inhibitors to promote matrix stabilization and cellular proliferation, ECM remodelling, and tissue expansion. Perlecan has mechanotransductive roles in cartilage that modulate chondrocyte responses in weight-bearing environments. Nuclear perlecan may modulate chromatin structure and transcription factor access to DNA and gene regulation. Snail-1, a mesenchymal marker and transcription factor, signals through FGFR-3 to promote chondrogenesis and maintain Acan and type II collagen levels in articular cartilage, but prevents further tissue expansion. Pre-hypertrophic growth plate chondrocytes also express high Snail-1 levels, leading to cessation of Acan and CoI2A1 synthesis and appearance of type X collagen. Perlecan differentially regulates FGF-2 and FGF-18 to maintain articular cartilage homeostasis, rudiment and growth plate cartilage growth, and maturational changes including mineralization, contributing to skeletal growth. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Graphical abstract

9 pages, 254 KiB

Open AccessReview

Current Status of the Instructional Cues Provided by Notochordal Cells in Novel Disc Repair Strategies

by Ajay Matta and William Mark Erwin

Int. J. Mol. Sci. 2022, 23(1), 427; https://doi.org/10.3390/ijms23010427 - 31 Dec 2021

Cited by 5 | Viewed by 1611

Abstract

Numerous publications over the past 22 years, beginning with a seminal paper by Aguiar et al., have demonstrated the ability of notochordal cell-secreted factors to confer anabolic effects upon intervertebral disc (IVD) cells. Since this seminal paper, other scientific publications have demonstrated that notochordal cells secrete soluble factors that can induce anti-inflammatory, pro-anabolic and anti-cell death effects upon IVD nucleus pulposus (NP) cells in vitro and in vivo, direct human bone marrow-derived mesenchymal stem cells toward an IVD NP-like phenotype and repel neurite ingrowth. More recently these factors have been characterized, identified, and used therapeutically to induce repair upon injured IVDs in small and large pre-clinical animal models. Further, notochordal cell-rich IVD NPs maintain a stable, healthy extracellular matrix whereas notochordal cell-deficient IVDs result in a biomechanically and extracellular matrix defective phenotype. Collectively this accumulating body of evidence indicates that the notochordal cell, the cellular originator of the intervertebral disc holds vital instructional cues to establish, maintain and possibly regenerate the intervertebral disc. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

30 pages, 4664 KiB

Open AccessReview

Mechanical Cues: Bidirectional Reciprocity in the Extracellular Matrix Drives Mechano-Signalling in Articular Cartilage

by Sophie Jane Gilbert, Cleo Selina Bonnet and Emma Jane Blain

Int. J. Mol. Sci. 2021, 22(24), 13595; https://doi.org/10.3390/ijms222413595 - 18 Dec 2021

Cited by 37 | Viewed by 5720

Abstract

The composition and organisation of the extracellular matrix (ECM), particularly the pericellular matrix (PCM), in articular cartilage is critical to its biomechanical functionality; the presence of proteoglycans such as aggrecan, entrapped within a type II collagen fibrillar network, confers mechanical resilience underweight-bearing. Furthermore, components of the PCM including type VI collagen, perlecan, small leucine-rich proteoglycans—decorin and biglycan—and fibronectin facilitate the transduction of both biomechanical and biochemical signals to the residing chondrocytes, thereby regulating the process of mechanotransduction in cartilage. In this review, we summarise the literature reporting on the bidirectional reciprocity of the ECM in chondrocyte mechano-signalling and articular cartilage homeostasis. Specifically, we discuss studies that have characterised the response of articular cartilage to mechanical perturbations in the local tissue environment and how the magnitude or type of loading applied elicits cellular behaviours to effect change. In vivo, including transgenic approaches, and in vitro studies have illustrated how physiological loading maintains a homeostatic balance of anabolic and catabolic activities, involving the direct engagement of many PCM molecules in orchestrating this slow but consistent turnover of the cartilage matrix. Furthermore, we document studies characterising how abnormal, non-physiological loading including excessive loading or joint trauma negatively impacts matrix molecule biosynthesis and/or organisation, affecting PCM mechanical properties and reducing the tissue’s ability to withstand load. We present compelling evidence showing that reciprocal engagement of the cells with this altered ECM environment can thus impact tissue homeostasis and, if sustained, can result in cartilage degradation and onset of osteoarthritis pathology. Enhanced dysregulation of PCM/ECM turnover is partially driven by mechanically mediated proteolytic degradation of cartilage ECM components. This generates bioactive breakdown fragments such as fibronectin, biglycan and lumican fragments, which can subsequently activate or inhibit additional signalling pathways including those involved in inflammation. Finally, we discuss how bidirectionality within the ECM is critically important in enabling the chondrocytes to synthesise and release PCM/ECM molecules, growth factors, pro-inflammatory cytokines and proteolytic enzymes, under a specified load, to influence PCM/ECM composition and mechanical properties in cartilage health and disease. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Figure 1

35 pages, 9542 KiB

Open AccessReview

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

by James Melrose, Anthony J. Hayes and Gregory Bix

Int. J. Mol. Sci. 2021, 22(11), 5583; https://doi.org/10.3390/ijms22115583 - 25 May 2021

Cited by 23 | Viewed by 4671

Abstract

Background. The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. Aims. To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. Conclusions. This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration. Full article

(This article belongs to the Special Issue Matrix Embedded Instructional Cues Direct Development and Tissue Repair)

► Show Figures

Journal Menu

Journal Browser

Matrix Embedded Instructional Cues Direct Development and Tissue Repair

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Related Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI