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Re-Endothelialization of Decellularized Liver Scaffolds: A Step for Bioengineered Liver Transplantation.

ABSTRACT: Bioengineered livers (BELs) are an attractive therapeutic alternative to address the donor organ shortage for liver transplantation. The goal of BELs technology aims at replacement or regeneration of the native human liver. A variety of approaches have been proposed for tissue engineering of transplantable livers; the current review will highlight the decellularization-recellularization approach to BELs. For example, vascular patency and appropriate cell distribution and expansion are critical components in the production of successful BELs. Proper solutions to these components of BELs have challenged its development. Several strategies, such as heparin immobilization, heparin-gelatin, REDV peptide, and anti-CD31 aptamer have been developed to extend the vascular patency of revascularized bioengineered livers (rBELs). Other novel methods have been developed to enhance cell seeding of parenchymal cells and to increase graft functionality during both bench and in vivo perfusion. These enhanced methods have been associated with up to 15 days of survival in large animal (porcine) models of heterotopic transplantation but have not yet permitted extended survival after implantation of BELs in the orthotopic position. This review will highlight both the remaining challenges and the potential for clinical application of functional bioengineered grafts.

SUBMITTER: Li K

PROVIDER: S-EPMC8960611 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Re-Endothelialization of Decellularized Liver Scaffolds: A Step for Bioengineered Liver Transplantation.

Li Kewei K Tharwat Mohammad M Larson Ellen L EL Felgendreff Philipp P Hosseiniasl Seyed M SM Rmilah Anan Abu AA Safwat Khaled K Ross Jeffrey J JJ Nyberg Scott L SL

Frontiers in bioengineering and biotechnology 20220310

Bioengineered livers (BELs) are an attractive therapeutic alternative to address the donor organ shortage for liver transplantation. The goal of BELs technology aims at replacement or regeneration of the native human liver. A variety of approaches have been proposed for tissue engineering of transplantable livers; the current review will highlight the decellularization-recellularization approach to BELs. For example, vascular patency and appropriate cell distribution and expansion are critical c ...[more]

PMID: 35360393

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Project description:BackgroundConstructing tissue-engineered kidneys using decellularized kidney scaffolds (DKS) has attracted widespread attention as it is expected to be the key to solving the shortage of donor kidneys. However, thrombosis and the host inflammatory response are unfavorable factors that hider the re-endothelialization and vascularization of the decellularized scaffolds.MethodsHeparin was immobilized into the DKS using the method of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) activation. Fourier-transform infrared (FTIR) spectra were used to verify the heparinization of DKS. Human umbilical vein endothelial cells (HUVECs) were seeded and cultured in the DKS, then the sliced scaffolds were transplanted subcutaneously into nude mouse. Scanning electron microscopy and a series of histochemical stains including hematoxylin and eosin (H&E), elastic Verhöeff-Van Gieson (EVG), Sirius red, Masson's trichrome, and toluidine blue (TB) staining were used for morphological characterization. The qRT-PCR analysis, immunohistochemistry (IHC), and immunofluorescence (IF) staining were used to determine the expression of related molecular markers.ResultsThe rat DKS completely retained the extracellular matrix and heparinized modification. The H&E staining results showed there were more HUVECs covering the internal surfaces of tubular structures in the HEP-DKS group compared with the DKS group. The IF analysis results revealed that CD31, Ki67, and CD206 had higher positive rates in HUVECs in the HEP-DKS group compared to the DKS group. Both groups of scaffolds showed blood vessel formation via H&E staining, and there were more blood vessels in the HEP-DKS group compared with the native DKS group (P<0.05). The qRT-PCR results showed that the levels of IL-1β, IL-6, and TNF-α in the HEP-DKS group were significantly lower than those of the native DKS group, while the expression level of IL-10 was significantly higher than that in the native DKS group (P<0.05).ConclusionsHeparin modification improves the re-endothelialization and vascular regeneration of the DKS through anticoagulation in vitro and in vivo. The anti-inflammatory effect of heparin on the transplanted host was initially confirmed, and it is considered that this effect may play a non-negligible role in promoting DKS re-endothelialization and angiogenesis. Heparinized DKS is therefore a promising candidate for kidney tissue engineering.

Project description:Engineering of functional vascularized liver tissues holds great promise in addressing donor organ shortage for transplantation. Whole organ decellularization is a cell removal method that retains the native vascular structures of the organ such that it can be anastomosed with the recipient circulation after recellularization with healthy cells. However, a main hurdle to successful implantation of bioengineered organ is the inability to efficiently re-endothelialize the vasculature with a functional endothelium, resulting in blood clotting which is the primary cause of failure in early transplant studies. Here, we present an efficient approach for enhancing re-endothelialization of decellularized rat liver scaffolds by conjugating the REDV cell-binding domain to improve attachment of endothelial cells (EC) on vascular wall surfaces. In order to facilitate expression and purification of the peptide, REDV was fused with elastin-like peptide (ELP) that confers thermally triggered aggregation behavior to the fusion protein. After validating the adhesive properties of the REDV-ELP peptide, we covalently coupled REDV-ELP to the blood vasculature of decellularized rat livers and seeded EC using perfusion of the portal vein. We showed that REDV-ELP increased cell attachment, spreading and proliferation of EC within the construct resulting in uniform endothelial lining of the scaffold vasculature. We further observed that REDV-ELP conjugation dramatically reduced platelet adhesion and activation. Altogether, our results demonstrate that this method allowed functional re-endothelialization of liver scaffold and show great potential toward the generation of functional bioengineered liver for long-term transplantation.Statement of significanceThere is a critical need for novel organ replacement therapies as the grafts for transplantation fall short of demand. Recent advances in tissue engineering, through the use of decellularized scaffolds, have opened the possibility that engineered grafts could be used as substitutes for donor livers. However, successful implantation has been challenged by the inability to create a functional vasculature. Our research study reports a new strategy to increase efficiency of endothelialization by increasing the affinity of the vascular matrix for endothelial cells. We functionalized decellularized liver scaffold using elastin-like peptides grafted with REDV cell binding domain. We showed that REDV-ELP conjugation improve endothelial cell attachment and proliferation within the scaffold, demonstrating the feasibility of re-endothelializing a whole liver vasculature using our technique.

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Re-Endothelialization of Decellularized Liver Scaffolds: A Step for Bioengineered Liver Transplantation.

Publications

Re-Endothelialization of Decellularized Liver Scaffolds: A Step for Bioengineered Liver Transplantation.

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