Application of marrow mesenchymal stem cell‐derived extracellular matrix in peripheral nerve tissue engineering

To advance molecular and cellular therapy into the clinic for peripheral nerve injury, modification of neural scaffolds with the extracellular matrix (ECM) of peripheral nerves has been established as a promising alternative to direct inclusion of support cells and/or growth factors within a neural scaffold, while cell‐derived ECM proves to be superior to tissue‐derived ECM in the modification of neural scaffolds. Based on the fact that bone marrow mesenchymal stem cells (BMSCs), just like Schwann cells, are adopted as support cells within a neural scaffold, in this study we used BMSCs as parent cells to generate ECM for application in peripheral nerve tissue engineering. A chitosan nerve guidance conduit (NGC) and silk fibroin filamentous fillers were respectively prepared for co‐culture with purified BMSCs, followed by decellularization to stimulate ECM deposition. The ECM‐modified NGC and lumen fillers were then assembled into a chitosan–silk fibroin‐based, BMSC‐derived, ECM‐modified neural scaffold, which was implanted into rats to bridge a 10 mm‐long sciatic nerve gap. Histological and functional assessments after implantation showed that regenerative outcomes achieved by our engineered neural scaffold were better than those achieved by a plain chitosan–silk fibroin scaffold, and suggested the benefits of BMSC‐derived ECM for peripheral nerve repair. Copyright © 2016 John Wiley & Sons, Ltd.     

Functionalized PVA–silk blended nanofibrous mats promote diabetic wound healing via regulation of extracellular matrix and tissue remodelling

Chronic cutaneous ulcers, a complex pathophysiological diabetic condition, represent a critical clinical challenge in the current diabetes mellitus pandemic. Consequently, there is a compelling need for bioactive dressings that can trigger healing processes for complete wound repair. Silk fibroin (SF), a natural protein polymer from mulberry and non‐mulberry silkworms, has properties that support accelerated wound healing rate. SF from non‐mulberry variety possesses additional cell‐binding motifs (arginine, glycine, and aspartate), offering cell–material interactions. This study is aimed to investigate wound healing efficacy of dressings made up of various SF varieties blended with poly(vinyl alcohol) biopolymer in alloxan‐induced diabetic rabbit model. The nanofibrous mats have been developed using electrospinning and functionalized with growth factors and LL‐37 antimicrobial peptide for sustained delivery. Following post 14‐day treatment, non‐mulberry SF (NMSF)‐based dressings healed the wounds faster, in comparison with their mulberry Bombyx mori SF, poly(vinyl alcohol), and control counterparts (p < .01). NMSF‐based dressings also supported faster granulation tissue development, angiogenesis, and reepithelialization of wounds. Gene expression study of matrix metalloproteinases and collagen proteins affirmed higher extent of tissue remodelling during the repair process. Furthermore, there was organized extracellular matrix deposition (collagen type I, collagen type III, elastin, and reticulin) and higher wound breaking strength in NMSF compared with other groups after 4 weeks. These results validated the potential of NMSF‐based bioactive dressings to regulate extracellular matrix deposition leading to faster and complete repair of chronic diabetic cutaneous wounds.     

Spatiotemporal mapping of matrix remodelling and evidence of in situ elastogenesis in experimental abdominal aortic aneurysms

Spatiotemporal changes in the extracellular matrix (ECM) were studied within abdominal aortic aneurysms (AAAs) generated in rats via elastase infusion. At 7, 14 and 21 days post‐induction, AAA tissues were divided into proximal, mid‐ and distal regions, based on their location relative to the renal arteries and the region of maximal aortic diameter. Wall thicknesses differed significantly between the AAA spatial regions, initially increasing due to positive matrix remodelling and then decreasing due to wall thinning and compaction of matrix as the disease progressed. Histological images analysed using custom segmentation tools indicated significant differences in ECM composition and structure vs healthy tissue, and in the extent and nature of matrix remodelling between the AAA spatial regions. Histology and immunofluorescence (IF) labelling provided evidence of neointimal AAA remodelling, characterized by presence of elastin‐containing fibres. This remodelling was effected by smooth muscle α‐actin‐positive neointimal cells, which transmission electron microscopy (TEM) showed to differ morphologically from medial SMCs. TEM of the neointima further showed the presence of elongated deposits of amorphous elastin and the presence of nascent, but not mature, elastic fibres. These structures appeared to be deficient in at least one microfibrillar component, fibrillin‐1, which is critical to mature elastic fibre assembly. The substantial production of elastin and elastic fibre‐like structures that we observed in the AAA neointima, which was not observed elsewhere within AAA tissues, provides a unique opportunity to capitalize on this autoregenerative phenomenon and direct it from the standpoint of matrix organization towards restoring healthy aortic matrix structure, mechanics and function. Copyright © 2014 John Wiley & Sons, Ltd.     

Proteomics and N‐glycoproteomics analysis of an extracellular matrix‐based scaffold‐human treated dentin matrix

Extracellular matrix (ECM)‐based biomaterials developed from mammalian tissues have been successfully used in preclinical and clinical tissue engineering applications. We have previously reported about the applicability of dentin‐based scaffold, treated dentin matrix (TDM), for tooth root regeneration. However, TDM protein composition has not been characterized. Here, we used a shotgun proteomic strategy to profile human TDM proteome. N‐glycoproteins were enriched by lectin affinity chromatography and identified by mass spectrometry. The total human TDM proteome was compared with the previously published human dentin proteome, and bioinformatics analysis were performed accordingly. In total, 708 proteins were identified by mass spectrometry in human TDM, of which 208 were N‐glycoproteins with 318 identified glycosylation sites. Collagens, proteoglycans, small integrin‐binding ligand N‐linked glycoproteins (SIBLINGs), and growth factors, such as COL1A1, biglycan, dentin sialoprotein, and transforming growth factor beta 1, were identified. Glycoproteins were enriched in “biological processes” Gene Ontology terms such as cellular process, biological regulation, response to stimulus, metabolic process, immune system process, and biological adhesion. Thus, our comprehensive study of the human TDM proteome revealed that dentin proteins are more heterogeneous than previously documented. Our findings provide clues for designing new biomaterials for tooth root regeneration and understanding dentin formation.     

Ascorbic acid promotes extracellular matrix deposition while preserving valve interstitial cell quiescence within 3D hydrogel scaffolds

Current options for aortic valve replacements are non‐viable and thus lack the ability to grow and remodel, which can be problematic for paediatric applications. Toward the development of living valve substitutes that can grow and remodel, porcine aortic valve interstitial cells (VICs) were isolated and encapsulated within proteolytically degradable and cell‐adhesive poly(ethylene glycol) (PEG) hydrogels, in an effort to study their phenotypes and functions. The results showed that encapsulated VICs maintained high viability and proliferated within the hydrogels. The VICs actively remodelled the hydrogels via secretion of matrix metalloproteinase‐2 (MMP‐2) and deposition of new extracellular matrix (ECM) components, including collagens I and III. The soft hydrogels with compressive moduli of ~4.3 kPa quickly reverted VICs from an activated myofibroblastic phenotype to a quiescent, unactivated phenotype, evidenced by the loss of α‐smooth muscle actin expression upon encapsulation. In an effort to promote VIC‐mediated ECM production, ascorbic acid (AA) was supplemented in the medium to investigate its effects on VIC function and phenotype. AA treatment enhanced VIC spreading and proliferation, and inhibited apoptosis. AA treatment also promoted VIC‐mediated ECM remodelling by increasing MMP‐2 activity and depositing collagens I and III. AA treatment did not significantly influence the expression of α‐smooth muscle actin (myofibroblast activation marker) and alkaline phosphatase (osteogenic differentiation marker). No calcification or nodule formation was observed within the cell‐laden hydrogels, with or without AA treatment. These results suggest the potential of this system and the beneficial effect of AA in heart valve tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd.     

糖尿病患者的C反应蛋白与细胞外基质变化

目的观察 2型糖尿病( T2DM)患者 C反应蛋白( CRP)与细胞外基质( ECM)的变化,并探讨其对 DM慢性并发症的影响.方法测定 64例 2型 DM者和 30例健康对照组的 CRP、透明质酸( HA)、Ⅳ型胶原( CⅣ)、Ⅲ型前胶原( PCⅢ)水平,并根据有无慢性并发症存在,把 2型 DM者分成 A、B两组,对各组间进行比较分析.结果① DM组的 CRP、HA、CⅣ水平均较正常对照组有显著意义的升高( P<0.05).而有慢性并发症的 A组较无并发症的 B组 CRP、CⅣ水平有显著意义的升高( P<0.05);②在合并有慢性并发症的 A组中, CRP与 CⅣ水平有正相关( r=0.3714, P<0.05),而在未分组的 DM组中,二者无相关性.结论 CRP与糖尿病慢性并发症有关,而 ECM特别是功能相关蛋白如 CⅣ增加,可能是 CRP与慢性并发症之间的介导因素.     

Transplantation of three‐dimensional artificial human vascular tissues fabricated using an extracellular matrix nanofilm‐based cell‐accumulation technique

We have established a novel three‐dimensional (3D) tissue‐constructing technique, referred to as the ‘cell‐accumulation method’, which is based on the self‐assembly of cultured human cells. In this technique, cells are coated with fibronectin and gelatin to construct extracellular matrix (ECM) nanofilms and cultured to form multi‐layers in vitro. By using this method, we have successfully fabricated artificial tissues with vascular networks constructed by co‐cultivation of human umbilical vein‐derived vascular endothelial cells between multi‐layers of normal human dermal fibroblasts. In this study, to assess these engineered vascular tissues as therapeutic implants, we transplanted the 3D human tissues with microvascular networks, fabricated based on the cell‐accumulation method, onto the back skin of nude mice. After the transplantation, we found vascular networks with perfusion of blood in the transplanted graft. At the boundary between host and implanted tissue, connectivity between murine and human vessels was found. Transmission electron microscopy of the implanted artificial vascular tubules demonstrated the ultrastructural features of blood capillaries. Moreover, maturation of the vascular tissues after transplantation was shown by the presence of pericyte‐like cells and abundant collagen fibrils in the ECM surrounding the vasculature. These results demonstrated that artificial human vascular tissues constructed by our method were engrafted and matured in animal skin. In addition, the implanted artificial human vascular networks were connected with the host circulatory system by anastomosis. This method is an attractive technique for engineering prevascularized artificial tissues for transplantation. Copyright © 2015 John Wiley & Sons, Ltd.     

The host response to allogeneic and xenogeneic biological scaffold materials

The clinical use of biological scaffold materials has become commonplace. Such scaffolds are composed of extracellular matrix (ECM), or components of ECM, derived from allogeneic or xenogeneic tissues. Such scaffold materials vary widely in their source tissue, processing methods and sterilization methods. The success or failure of an ECM scaffold for a given application is dependent on the host response following implantation; a response that is largely mediated by the innate immune system and which is influenced by a numerous factors, including the processing methods used in the preparation of biological scaffolds. The present paper reviews various aspects of the host response to biological scaffolds and factors that affect this response. In addition, some of the logistical, regulatory and reconstructive implications associated with the use of biological scaffolds are discussed. Copyright © 2014 John Wiley & Sons, Ltd.     

The mechanobiology of tendon fibroblasts under static and uniaxial cyclic load in a 3D tissue engineered model mimicking native extracellular matrix

Tendon mechanobiology plays a vital role in tendon repair and regeneration; however, this mechanism is currently poorly understood. We tested the role of different mechanical loads on extracellular matrix (ECM) remodelling gene expression and the morphology of tendon fibroblasts in collagen hydrogels, designed to mimic native tissue. Hydrogels were subjected to precise static or uniaxial loading patterns of known magnitudes and sampled to analyse gene expression of known mechano‐responsive ECM‐associated genes (Collagen I, Collagen III, Tenomodulin, and TGF‐β). Tendon fibroblast cytomechanics was studied under load by using a tension culture force monitor, with immunofluorescence and immunohistological staining used to examine cell morphology. Tendon fibroblasts subjected to cyclic load showed that endogenous matrix tension was maintained, with significant concomitant upregulation of ECM remodelling genes, Collagen I, Collagen III, Tenomodulin, and TGF‐β when compared with static load and control samples. These data indicate that tendon fibroblasts acutely adapt to the mechanical forces placed upon them, transmitting forces across the ECM without losing mechanical dynamism. This model demonstrates cell‐material (ECM) interaction and remodelling in preclinical a platform, which can be used as a screening tool to understand tendon regeneration.     

Tissue engineering with the aid of inkjet printers

Tissue engineering holds the promise to create revolutionary new therapies for tissue and organ regeneration. This emerging field is extremely broad and eclectic in its various approaches. However, all strategies being developed are based on the therapeutic delivery of one or more of the following types of tissue building-blocks: cells; extracellular matrices or scaffolds; and hormones or other signaling molecules. So far, most work has used essentially homogenous combinations of these components, with subsequent self-organization to impart some level of tissue functionality occurring during in vitro culture or after transplantation. Emerging ‘bioprinting’ methodologies are being investigated to create tissue engineered constructs initially with more defined spatial organization, motivated by the hypothesis that biomimetic patterns can achieve improved therapeutic outcomes. Bioprinting based on inkjet and related printing technologies can be used to fabricate persistent biomimetic patterns that can be used both to study the underlying biology of tissue regeneration and potentially be translated into effective clinical therapies. However, recapitulating nature at even the most primitive levels such that printed cells, extracellular matrices and hormones become integrated into hierarchical, spatially organized three-dimensional tissue structures with appropriate functionality remains a significant challenge.     

Beneficial role of l‐arginine in cardiac matrix remodelling in insulin resistant rats

Background The study was performed to determine whether sucrose‐induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1·25 g die^?1 of L‐arginine (ARG) to a sucrose diet could prevent both the sucrose‐induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes. Materials and methods Experiments were performed on 38 male Sprague‐Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L‐arginine (1·25 g die^?1) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine‐monophosphate (c‐GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed. Results At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c‐GMP levels and the integrated c‐GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP‐9 protein expression increased 10·5‐fold, MMP‐2 protein expression increased 2·4‐fold and the expression of tissue inhibitors of metalloproteinase (TIMP‐1) increased 1·7‐fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP‐9, MMP‐2, and TIMP‐1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats. Conclusions SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP‐1 balance.     

The effects of fibrin and fibrin‐agarose on the extracellular matrix profile of bioengineered oral mucosa

Several studies have developed efficient oral mucosa constructs using different types of scaffold. However, the changes in the morphology and gene and protein expression profile that could occur in these artificial constructs remain unknown. This study compared the histology and expression of several extracellular matrix molecules in human artificial oral mucosa developed using two different types of scaffolds: fibrin and fibrin‐agarose. To that end, bioengineered oral mucosa stromas were constructed from biopsy samples of human oral mucosa and the substitute generated was analyzed at different periods of time in culture. Histological analysis was carried out by light and transmission electron microscopy and the expression of collagen types I, III, and VI, the proteoglycans decorin and biglycan, and the different chains of laminin, were assessed by immunoperoxidase technique. This study found that fibrin scaffolds accelerated fibroblast growth and remodeling of the scaffold, thus enhancing collagen fibrillogenesis. In the fibrin‐agarose scaffold, the morphology and organization of the fibroblasts did not change during the culture period. All extracellular matrix proteins analyzed were expressed in both scaffolds. However, in fibrin scaffolds, these proteins were widely distributed and replaced the scaffold during the follow‐up period. These results show that the substitutes generated showed histological and molecular similarities with native human oral mucosa stroma. In addition, it was observed that the nature of the biomaterial influenced the behaviour of the oral stromal fibroblasts, thereby modulating their growth, protein synthesis, and collagen fibrillogenesis. Copyright © 2011 John Wiley & Sons, Ltd.     

Quantitative multispectral imaging of Herovici's polychrome for the assessment of collagen content and tissue remodelling

Bioprosthetic devices, constructed from a variety of materials, are routinely implanted in a variety of anatomical locations. Essential to their success is the formation of a non‐destructive interface with the host tissue and appropriate tissue remodelling. Traditionally, the main method of assessing the host–material interface has been qualitative histological evaluation, using pattern recognition and comparative assessment to identify changes in the normal tissue architecture that are characteristic of scar tissue. In the present study, the recently developed technique of multispectral imaging was used to revisit a little‐described histological stain, Herovici's polychrome, which is capable of distinguishing between types I and III collagen. Combined, these techniques allowed quantification of collagen content and distribution of collagen types within a tissue sample. Samples of rat tail and human scar tissue were used to optimize the staining, while comparison with immunolabelled samples was used to develop a reproducible quantification system, based on the specific colour profiles for types I and III collagen. Finally the remodelling of rat abdominal wall defects repaired with crosslinked or non‐crosslinked extracellular matrix scaffolds derived from porcine urinary bladder was assessed with this technique. Compared to standard histological assessment, the combination of multispectral imaging and Herovici's polychrome staining presents a quick, simple, reliable technique that can provide accurate quantification of tissue remodelling and specifically identify the expression and distribution of types I and III collagen. Copyright © 2011 John Wiley & Sons, Ltd.     

Decellularized pancreas as a native extracellular matrix scaffold for pancreatic islet seeding and culture

Diabetes mellitus involves the loss of function and/or absolute numbers of insulin‐producing β cells in pancreatic islets. Islet transplantation is currently being investigated as a potential cure, and advances in tissue engineering methods can be used to improve pancreatic islets survival and functionality. Transplanted islets experience anoikis, hypoxia, and inflammation‐mediated immune response, leading to early damage and subsequent failure of the graft. Recent development in tissue engineering enables the use of decellularized organs as scaffolds for cell therapies. Decellularized pancreas could be a suitable scaffold as it can retain the native extracellular matrix and vasculature. In this study, mouse pancreata were decellularized by perfusion using 0.5% sodium dodecyl sulfate. Different characterizations revealed that the resulting matrix was free of cells and retained part of the pancreas extracellular matrix including the vasculature and its internal elastic basal lamina, the ducts with their basal membrane, and the glycosaminoglycan and collagen structures. Islets were infused into the ductal system of decellularized pancreata, and glucose‐stimulated insulin secretion results confirmed their functionality after 48 hr. Also, recellularizing the decellularized pancreas with green fluorescent protein‐tagged INS‐1 cells and culturing the system over 120 days confirmed the biocompatibility and non‐toxic nature of the scaffold. Green fluorescent protein‐tagged INS‐1 cells formed pseudoislets that were, over time, budding out of the decellularized pancreata. Decellularized pancreatic scaffolds seeded with endocrine pancreatic tissue could be a potential bioengineered organ for transplantation.     

Human endothelial colony‐forming cells expanded with an improved protocol are a useful endothelial cell source for scaffold‐based tissue engineering

One of the major challenges in tissue engineering is to supply larger three‐dimensional (3D) bioengineered tissue transplants with sufficient amounts of nutrients and oxygen and to allow metabolite removal. Consequently, artificial vascularization strategies of such transplants are desired. One strategy focuses on endothelial cells capable of initiating new vessel formation, which are settled on scaffolds commonly used in tissue engineering. A bottleneck in this strategy is to obtain sufficient amounts of endothelial cells, as they can be harvested only in small quantities directly from human tissues. Thus, protocols are required to expand appropriate cells in sufficient amounts without interfering with their capability to settle on scaffold materials and to initiate vessel formation. Here, we analysed whether umbilical cord blood (CB)‐derived endothelial colony‐forming cells (ECFCs) fulfil these requirements. In a first set of experiments, we showed that marginally expanded ECFCs settle and survive on different scaffold biomaterials. Next, we improved ECFC culture conditions and developed a protocol for ECFC expansion compatible with 'Good Manufacturing Practice' (GMP) standards. We replaced animal sera with human platelet lysates and used a novel type of tissue‐culture ware. ECFCs cultured under the new conditions revealed significantly lower apoptosis and increased proliferation rates. Simultaneously, their viability was increased. Since extensively expanded ECFCs could still settle on scaffold biomaterials and were able to form tubular structures in Matrigel assays, we conclude that these ex vivo‐expanded ECFCs are a novel, very potent cell source for scaffold‐based tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.     

Prevascularization of natural nanofibrous extracellular matrix for engineering completely biological three‐dimensional prevascularized tissues for diverse applications

Self‐sustainability after implantation is one of the critical obstacles facing large engineered tissues. A preformed functional vascular network provides an effective solution for solving the mass transportation problem. With the support of mural cells, endothelial cells (ECs) can form microvessels within engineered tissues. As an important mural cell, human mesenchymal stem cells (hMSCs) not only stabilize the engineered microvessel network, but also preserve their multi‐potency when grown under optimal culture conditions. A prevascularized hMSC/extracellular matrix (ECM) sheet fabricated by the combination of hMSCs, ECs and a naturally derived nanofibrous ECM scaffold offers great opportunity for engineering mechanically strong and completely biological three‐dimensional prevascularized tissues. The objective of this study was to create a prevascularized hMSC/ECM sheet by co‐culturing ECs and hMSCs on a nanofibrous ECM scaffold. Physiologically low oxygen (2% O₂) was introduced during the 7 day hMSC culture to preserve the stemness of hMSCs and thereby their capability to secrete angiogenic factors. The ECs were then included to form microvessels under normal oxygen (20% O₂) for up to 7 days. The results showed that a branched and mature vascular network was formed in the co‐culture condition. Angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiopoietin‐1 (Ang‐1) were significantly increased by low‐oxygen culture of hMSCs, which further stabilized and supported the maturation of microvessels. A differentiation assay of the prevascularized ECM scaffold demonstrated a retained hMSC multi‐potency in the hypoxia cultured samples. The prevascularized hMSC/ECM sheet holds great promise for engineering three‐dimensional prevascularized tissues for diverse applications.     

Matrix‐directed differentiation of human adipose‐derived mesenchymal stem cells to dermal‐like fibroblasts that produce extracellular matrix

Commercially available skin substitutes lack essential non‐immune cells for adequate tissue regeneration of non‐healing wounds. A tissue‐engineered, patient‐specific, dermal substitute could be an attractive option for regenerating chronic wounds, for which adipose‐derived mesenchymal stem cells (ADMSCs) could become an autologous source. However, ADMSCs are multipotent in nature and may differentiate into adipocytes, osteocytes and chondrocytes in vitro, and may develop into undesirable tissues upon transplantation. Therefore, ADMSCs committed to the fibroblast lineage could be a better option for in vitro or in vivo skin tissue engineering. The objective of this study was to standardize in vitro culture conditions for ADMSCs differentiation into dermal‐like fibroblasts which can synthesize extracellular matrix (ECM) proteins. Biomimetic matrix composite, deposited on tissue culture polystyrene (TCPS), and differentiation medium (DM), supplemented with fibroblast‐conditioned medium and growth factors, were used as a fibroblast‐specific niche (FSN) for cell culture. For controls, ADMSCs were cultured on bare TCPS with either DM or basal medium (BM). Culture of ADMSCs on FSN upregulated the expression of differentiation markers such as fibroblast‐specific protein‐1 (FSP‐1) and a panel of ECM molecules specific to the dermis, such as fibrillin‐1, collagen I, collagen IV and elastin. Immunostaining showed the deposition of dermal‐specific ECM, which was significantly higher in FSN compared to control. Fibroblasts derived from ADMSCs can synthesize elastin, which is an added advantage for successful skin tissue engineering as compared to fibroblasts from skin biopsy. To obtain rapid differentiation of ADMSCs to dermal‐like fibroblasts for regenerative medicine, a matrix‐directed differentiation strategy may be employed. Copyright © 2014 John Wiley & Sons, Ltd.     

Thrombospondin-4, tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14: Novel extracellular matrix modulating factors in cardiac remodelling

Abstract

Cardiac remodelling is defined as changes in the size, shape, and function of the heart, which are most commonly caused by hypertension-induced left ventricular hypertrophy and myocardial infarction. Both neurohumoral and inflammatory factors have critical roles in the regulation of cardiac remodelling. A characteristic feature of cardiac remodelling is modification of the extracellular matrix (ECM), often manifested by fibrosis, a process that has vital consequences for the structure and function of the myocardium. In addition to established modulators of the ECM, the matricellular protein thrombospondin-4 (TSP-4) as well as the tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 has been recently shown to modulate cardiac ECM. TSP-4 null mice develop pronounced cardiac hypertrophy and fibrosis with defects in collagen maturation in response to pressure overload. TWEAK and Fn14 belong to the tumour necrosis factor superfamily of proinflammatory cytokines. Recently it was shown that elevated levels of circulating TWEAK via Fn14 critically affect the cardiac ECM, characterized by increasing fibrosis and cardiomyocyte hypertrophy in mice.

Here we review the literature concerning the role of matricellular proteins and inflammation in cardiac ECM remodelling, with a special focus on TSP-4, TWEAK, and its receptor Fn14.     

The potential role of tissue‐engineered urethral substitution: clinical and preclinical studies

Urethral strictures and anomalies remain among the difficult problems in urology, with urethroplasty procedures being the most effective treatment options. The two major types of urethroplasty are anastomotic urethroplasty and widening the urethral lumen using flaps or grafts (i.e. substitution urethroplasty). However, no ideal material for the latter has been found so far. Designing and selecting such a material is a necessary and challenging endeavour, driving the need for further bioengineered urethral tissue research. This article reviews currently available studies on the potentialities of tissue engineering in urethral reconstruction, in particular those describing the use of both acellular and recellularized tissue‐engineered constructs in animal and human models. Possible future developments in this field are also discussed. Copyright © 2015 John Wiley & Sons, Ltd.