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Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation.

ABSTRACT: Decellularized extracellular matrix scaffold, widely utilized for organ engineering, often undergoes matrix decomposition after transplantation and produces byproducts that cause inflammation, leading to clinical failure. Here we propose a strategy using nano-graphene oxide to modify the biophysical properties of decellularized liver scaffolds. Notably, we demonstrate that scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of matrix metalloproteinase activity and increased mechanical rigidity. We find that M2-like macrophage polarization is promoted within the crosslinked scaffolds, which reduces graft-elicited inflammation. Moreover, we show that low activities of matrix metalloproteinases, attributed to both nano-graphene oxide and tissue inhibitors of metalloproteinases expressed by M2c, can protect the crosslinked scaffolds against in vivo degradation. Lastly, we demonstrate that bioengineered livers fabricated with the crosslinked scaffolds remain functional, thereby effectively regenerating damaged livers after transplantation into liver failure mouse models. Overall, nano-graphene oxide crosslinking prolongs allograft survival and ultimately improves therapeutic effects of bioengineered livers, which offer an alternative for donor organs.

SUBMITTER: Kim DH

PROVIDER: S-EPMC9925774 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation.

Kim Da-Hyun DH Kim Min-Ji MJ Kwak Seon-Yeong SY Jeong Jaemin J Choi Dongho D Choi Soon Won SW Ryu Jaechul J Kang Kyung-Sun KS

Nature communications 20230213 1

Decellularized extracellular matrix scaffold, widely utilized for organ engineering, often undergoes matrix decomposition after transplantation and produces byproducts that cause inflammation, leading to clinical failure. Here we propose a strategy using nano-graphene oxide to modify the biophysical properties of decellularized liver scaffolds. Notably, we demonstrate that scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of matrix ...[more]

PMID: 36781854

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Project description:Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental. We found that liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia-reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. Conclusion: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic MMP inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells.

Project description:BackgroundThe invasive and complicated procedures involving the use of traditional stem cells limit their application in bone tissue engineering. Cell-free, tissue-engineered bones often have complex scaffold structures and are usually engineered using several growth factors (GFs), thus leading to costly and difficult preparations. Urine-derived stem cells (USCs), a type of autologous stem cell isolated noninvasively and with minimum cost, are expected to solve the typical problems of using traditional stem cells to engineer bones. In this study, a graphene oxide (GO)-modified silk fibroin (SF)/nanohydroxyapatite (nHA) scaffold loaded with USCs was developed for immunomodulation and bone regeneration.MethodsThe SF/nHA scaffolds were prepared via lyophilization and cross-linked with GO using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxy succinimide (NHS). Scaffolds containing various concentrations of GO were characterized using scanning electron microscopy (SEM), the elastic modulus test, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectrometer (XPS). Examinations of cell adhesion, proliferation, viability, morphology, alkaline phosphatase activity, and osteogenesis-related gene expression were performed to compare the osteogenesis-related biological behaviors of USCs cultured on the scaffolds. The effect of USC-laden scaffolds on the differentiation of macrophages was tested using ELISA, qRT-PCR, and immunofluorescence staining. Subcutaneous implantations in rats were performed to evaluate the inflammatory response of the USC-laden scaffolds after implantation. The scaffolds loaded with USCs were implanted into a cranial defect model in rats to repair bone defects. Micro-computed tomography (μCT) analyses and histological evaluation were performed to evaluate the bone repair effects.ResultsGO modification enhanced the mechanical properties of the scaffolds. Scaffolds containing less than 0.5% GO had good biocompatibility and promoted USC proliferation and osteogenesis. The scaffolds loaded with USCs induced the M2-type differentiation and inhibited the M1-type differentiation of macrophages. The USC-laden scaffolds containing 0.1% GO exhibited the best capacity for promoting the M2-type differentiation of macrophages and accelerating bone regeneration and almost bridged the site of the rat cranial defects at 12 weeks after surgery.ConclusionsThis composite system has the capacity for immunomodulation and the promotion of bone regeneration and shows promising potential for clinical applications of USC-based, tissue-engineered bones.

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Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation.

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Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation.

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