Tenascin-C promotes acute kidney injury to chronic kidney disease progression by impairing tubular integrity via αvβ6 integrin signaling.
Zhu Haili,Liao Jinlin,Zhou Xianke,Hong Xue,Song Dongyan,Hou Fan Fan,Liu Youhua,Fu Haiyan
Kidney international
Tenascin-C is an extracellular matrix glycoprotein that plays a critical role in kidney fibrosis by orchestrating a fibrogenic niche. Here, we demonstrate that tenascin-C is a biomarker and a mediator of kidney fibrogenesis by impairing tubular integrity. Tenascin-C was found to be increased in kidney biopsies from patients with chronic kidney disease (CKD). In a cohort of 225 patients with CKD, the urinary tenascin-C level was markedly elevated, compared to 39 healthy individuals. Moreover, the level of urinary tenascin-C in CKD was correlated with the severity of kidney dysfunction and fibrosis. In mouse model of acute kidney injury-to-CKD induced by ischemia/reperfusion, depletion of tenascin-C preserved tubular integrity and ameliorated renal fibrotic lesions. In vitro, tenascin-C impaired tubular cell integrity by inducing partial epithelial-mesenchymal transition. Using decellularized kidney tissue scaffolds, we found that tenascin-C-enriched scaffolds facilitated tubular epithelial-mesenchymal transition ex vivo. Mechanistically, tenascin-C specifically induced integrins αvβ6 in tubular cells and activated focal adhesion kinase (FAK). Blocking αvβ6 integrins or inhibition of FAK restored tubular integrity by repressing epithelial-mesenchymal transition and alleviated kidney fibrosis. Thus, our studies underscore that tenascin-C is a noninvasive biomarker of kidney fibrogenesis and a pathogenic mediator that impairs tubular integrity. Hence, blockade of the tenascin-C/αvβ6 integrin/FAK signal cascade may be a novel strategy for therapeutic intervention of kidney fibrosis.
10.1016/j.kint.2020.01.026
Tenascin-C Is a Major Component of the Fibrogenic Niche in Kidney Fibrosis.
Fu Haiyan,Tian Yuan,Zhou Lili,Zhou Dong,Tan Roderick J,Stolz Donna B,Liu Youhua
Journal of the American Society of Nephrology : JASN
Kidney fibrosis initiates at certain focal sites in which the fibrogenic niche provides a specialized microenvironment that facilitates fibroblast activation and proliferation. However, the molecular identity of these fibrogenic niches is poorly characterized. Here, we determined whether tenascin-C (TNC), an extracellular matrix glycoprotein, is a component of the fibrogenic niche in kidney fibrosis. , TNC expression increased rapidly in kidneys subjected to unilateral ureteral obstruction or ischemia/reperfusion injury and predominantly localized at the foci rich in fibroblasts in renal interstitium. , TNC selectively promoted renal interstitial fibroblast proliferation, bromodeoxyuridine incorporation, and the expression of proliferation-related genes. The mitogenic activity of TNC required the integrin/focal adhesion kinase/mitogen-activated protein kinase signaling cascade. Using decellularized extracellular matrix scaffolds, we found that TNC-enriched scaffolds facilitated fibroblast proliferation, whereas TNC-deprived scaffolds inhibited proliferation. Matrix scaffold prepared from fibrotic kidney also promoted greater fibroblast proliferation than did scaffolds prepared from healthy kidney. Conversely, small interfering RNA-mediated knockdown of TNC repressed injury-induced fibroblast expansion and renal fibrosis. These studies identify TNC as a major constituent of the fibrogenic niche that promotes fibroblast proliferation, and illustrate a pivotal role for the TNC-enriched microenvironment in kidney fibrogenesis.
10.1681/ASN.2016020165
Decellularized kidney scaffold-mediated renal regeneration.
Yu Y L,Shao Y K,Ding Y Q,Lin K Z,Chen B,Zhang H Z,Zhao L N,Wang Z B,Zhang J S,Tang M L,Mei J
Biomaterials
Renal regeneration approaches offer great potential for the treatment of chronic kidney disease, but their availability remains limited by the clinical challenges they pose. In the present study, we used continuous detergent perfusion to generate decellularized (DC) rat kidney scaffolds. The scaffolds retained intact vascular trees and overall architecture, along with significant concentrations of various cytokines, but lost all cellular components. To evaluate its potential in renal function recovery, DC scaffold tissue was grafted onto partially nephrectomized rat kidneys. An increase of renal size was found, and regenerated renal parenchyma cells were observed in the repair area containing the grafted scaffold. In addition, the number of nestin-positive renal progenitor cells was markedly higher in scaffold-grafted kidneys compared to controls. Moreover, radionuclide scan analysis showed significant recovery of renal functions at 6 weeks post-implantation. Our results provide further evidence to show that DC kidney scaffolds could be used to promote renal recovery in the treatment of chronic kidney disease.
10.1016/j.biomaterials.2014.04.074
Biomimetic Porous PLGA Scaffolds Incorporating Decellularized Extracellular Matrix for Kidney Tissue Regeneration.
Lih Eugene,Park Ki Wan,Chun So Young,Kim Hyuncheol,Kwon Tae Gyun,Joung Yoon Ki,Han Dong Keun
ACS applied materials & interfaces
Chronic kidney disease is now recognized as a major health problem, but current therapies including dialysis and renal replacement have many limitations. Consequently, biodegradable scaffolds to help repairing injured tissue are emerging as a promising approach in the field of kidney tissue engineering. Poly(lactic-co-glycolic acid) (PLGA) is a useful biomedical material, but its insufficient biocompatibility caused a reduction in cell behavior and function. In this work, we developed the kidney-derived extracellular matrix (ECM) incorporated PLGA scaffolds as a cell supporting material for kidney tissue regeneration. Biomimetic PLGA scaffolds (PLGA/ECM) with different ECM concentrations were prepared by an ice particle leaching method, and their physicochemical and mechanical properties were characterized through various analyses. The proliferation of renal cortical epithelial cells on the PLGA/ECM scaffolds increased with an increase in ECM concentrations (0.2, 1, 5, and 10%) in scaffolds. The PLGA scaffold containing 10% of ECM has been shown to be an effective matrix for the repair and reconstitution of glomerulus and blood vessels in partially nephrectomized mice in vivo, compared with only PLGA control. These results suggest that not only can the tissue-engineering techniques be an effective alternative method for treatment of kidney diseases, but also the ECM incorporated PLGA scaffolds could be promising materials for biomedical applications including tissue engineered scaffolds and biodegradable implants.
10.1021/acsami.6b03771
Hypoxia-inducible Factor-1α directs renal regeneration induced by decellularized scaffolds.
Yu Yaling,Cui Haomin,Chen Chuan,Wen Gen,Xu Jia,Zheng Binbin,Zhang Jianse,Wang Chunyang,Chai Yimin,Mei Jin
Biomaterials
Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope. Using the isobaric tag for relative and absolute quantitation, we performed proteomics analysis and found that hypoxia-inducible factor (HIF)-1α may be a key factor involved in induced renal regeneration. Dimethyloxyallyl glycine (DMOG), a propyl hydroxylase inhibitor, was applied to stabilize constitutive expression of HIF-1α protein, and small interfering RNA was used to inhibit gene expression. Administration of DMOG to decellularized scaffold-grafted rats improved the induced renal regeneration, whereas siHif1α transfection decreased the regeneration capacity. These findings revealed the critical role of HIF-1α in renal regeneration and provided important insights into our understanding of kidney development and the treatment of various kidney diseases.
10.1016/j.biomaterials.2018.02.045
A Bioinspired Scaffold with Anti-Inflammatory Magnesium Hydroxide and Decellularized Extracellular Matrix for Renal Tissue Regeneration.
ACS central science
Kidney diseases are a worldwide public health issue. Renal tissue regeneration using functional scaffolds with biomaterials has attracted a great deal of attention due to limited donor organ availability. Here, we developed a bioinspired scaffold that can efficiently induce renal tissue regeneration. The bioinspired scaffold was designed with poly(lactide--glycolide) (PLGA), magnesium hydroxide (Mg(OH)), and decellularized renal extracellular matrix (ECM). The Mg(OH) inhibited materials-induced inflammatory reactions by neutralizing the acidic microenvironment formed by degradation products of PLGA, and the acellular ECM helped restore the biological function of kidney tissues. When the PLGA/ECM/Mg(OH) scaffold was implanted in a partially nephrectomized mouse model, it led to the regeneration of renal glomerular tissue with a low inflammatory response. Finally, the PLGA/ECM/Mg(OH) scaffold was able to restore renal function more effectively than the control groups. These results suggest that the bioinspired scaffold can be used as an advanced scaffold platform for renal disease treatment.
10.1021/acscentsci.8b00812
"Tissue Papers" from Organ-Specific Decellularized Extracellular Matrices.
Advanced functional materials
Using an innovative, tissue-independent approach to decellularized tissue processing and biomaterial fabrication, the development of a series of "tissue papers" derived from native porcine tissues/organs (heart, kidney, liver, muscle), native bovine tissue/organ (ovary and uterus), and purified bovine Achilles tendon collagen as a control from decellularized extracellular matrix particle ink suspensions cast into molds is described. Each tissue paper type has distinct microstructural characteristics as well as physical and mechanical properties, is capable of absorbing up to 300% of its own weight in liquid, and remains mechanically robust ( = 1-18 MPa) when hydrated; permitting it to be cut, rolled, folded, and sutured, as needed. In vitro characterization with human mesenchymal stem cells reveals that all tissue paper types support cell adhesion, viability, and proliferation over four weeks. Ovarian tissue papers support mouse ovarian follicle adhesion, viability, and health in vitro, as well as support, and maintain the viability and hormonal function of nonhuman primate and human follicle-containing, live ovarian cortical tissues ex vivo for eight weeks postmortem. "Tissue papers" can be further augmented with additional synthetic and natural biomaterials, as well as integrated with recently developed, advanced 3D-printable biomaterials, providing a versatile platform for future multi-biomaterial construct manufacturing.
10.1002/adfm.201700992
Rapid 3D bioprinting of decellularized extracellular matrix with regionally varied mechanical properties and biomimetic microarchitecture.
Biomaterials
Hepatocellular carcinoma (HCC), as the fifth most common malignant cancer, develops and progresses mostly in a cirrhotic liver where stiff nodules are separated by fibrous bands. Scaffolds that can provide a 3D cirrhotic mechanical environment with complex native composition and biomimetic architecture are necessary for the development of better predictive tissue models. Here, we developed photocrosslinkable liver decellularized extracellular matrix (dECM) and a rapid light-based 3D bioprinting process to pattern liver dECM with tailorable mechanical properties to serve as a platform for HCC progression study. 3D bioprinted liver dECM scaffolds were able to stably recapitulate the clinically relevant mechanical properties of cirrhotic liver tissue. When encapsulated in dECM scaffolds with cirrhotic stiffness, HepG2 cells demonstrated reduced growth along with an upregulation of invasion markers compared to healthy controls. Moreover, an engineered cancer tissue platform possessing tissue-scale organization and distinct regional stiffness enabled the visualization of HepG2 stromal invasion from the nodule with cirrhotic stiffness. This work demonstrates a significant advancement in rapid 3D patterning of complex ECM biomaterials with biomimetic architecture and tunable mechanical properties for in vitro disease modeling.
10.1016/j.biomaterials.2018.09.026
Organ-Derived Decellularized Extracellular Matrix: A Game Changer for Bioink Manufacturing?
Choudhury Deepak,Tun Han Win,Wang Tianyi,Naing May Win
Trends in biotechnology
The extracellular matrix (ECM) comprises a complex milieu of proteins and other growth factors that provide mechanical, biophysical, and biochemical cues to cells. The ECM is organ specific, and its detailed composition varies across organs. Bioinks are material formulations and biological molecules or cells processed during a bioprinting process. Organ-derived decellularized ECM (dECM) bioinks have emerged as arguably the most biomimetic bioinks. Here, we review bioinks derived from different decellularized organs, the techniques used to obtain these bioinks, and the characterization methods used to evaluate their quality. We emphasize that obtaining a good-quality bioink depends on the choice of organ, animal, and decellularization method. Finally, we explore potential large-scale applications of bioinks and challenges in manufacturing such bioinks.
10.1016/j.tibtech.2018.03.003