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Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects

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A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10663

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Special Issue Editor

Dr. Hassan Rashidi

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Guest Editor

1. Department of Developmental Biology & Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
2. Institute for Liver and Digestive Health, University College London, London NW3 2PF, UK
Interests: regenerative medicine; stem cell research; tissue engineering; hepatic differentiation; liver regeneration

Special Issue Information

Dear Colleagues,

Liver disease is an escalating global health issue and one of the leading causes of premature mortality. To date, liver transplantation is the only curative treatment for individuals with inherited liver disorders and end-stage liver disease. However, donor organ shortage, allogeneic rejection, adverse effects associated with long-term immunosuppression, and the increasing number of patients requiring transplants are major limitations.

The development of alternative approaches to treat liver disease has remained an unmet clinical need. Cell- and gene-based therapeutic approaches have been suggested as potential alternatives to liver transplantation to treat a range of inherited and acquired liver diseases.

This Special Issue entitled Cell- and Gene-Based Therapeutic Strategies for Liver Disease; Recent Advances and Prospects, therefore aims to highlight the most recent advances in the field by bringing together contributions from experts on stem cell biology, bioprocessing, scale-up and manufacturing of cell-based therapies, tissue engineering, and gene therapy.

Topics of interest include, but are not limited to, the following:

Methodologies for the generation of human pluripotent stem cell-derived parenchymal and non-parenchymal derivatives;
Design, manufacture, and testing of bioartificial liver (BAL) devices;
Gene therapy approaches to treat inherited monogenic liver disease;
Additive manufacturing process to manufacture functional tissue;
Tissue engineering approaches and scaffold design to treat liver disease;
Role of parenchymal and non-parenchymal derivatives in the normal function of the liver and pathogenicity, including fibrosis and non-alcoholic fatty liver disease (NAFLD);
Advanced experimental tools to predict drug-induced liver injury (DILI) of lead compounds more accurately and to assess safety of gene therapy viral vectors.

Dr. Hassan Rashidi
Guest Editor

Manuscript Submission Information

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Keywords

liver
hepatocytes
cholangiocytes
gene therapy
cell therapy

Published Papers (5 papers)

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Research

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15 pages, 2646 KiB

Open AccessArticle

Manufacturing and Functional Characterization of Bioengineered Liver Grafts for Extracorporeal Liver Assistance in Acute Liver Failure

by Victoria L. Nelson, Aron R. Stumbras, R. Noelle Palumbo, Shawn A. Riesgraf, Marie S. Balboa, Zachary A. Hannah, Isaac J. Bergstrom, Christopher J. Fecteau, John R. Lake, John J. Barry and Jeff J. Ross

Bioengineering 2023, 10(10), 1201; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10101201 - 16 Oct 2023

Viewed by 1119

Abstract

Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF. Full article

(This article belongs to the Special Issue Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects)

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13 pages, 2183 KiB

Open AccessArticle

Ultrasound Histotripsy on a Viable Perfused Whole Porcine Liver: Histological Aspects, Including 3D Reconstruction of the Histotripsy Site

by Saied Froghi, Andrew Hall, Arif Hanafi Bin Jalal, Matheus Oliveira de Andrade, Layla Mohammad Hadi, Hassan Rashidi, Pierre Gélat, Nader Saffari, Brian Davidson and Alberto Quaglia

Bioengineering 2023, 10(3), 278; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10030278 - 21 Feb 2023

Viewed by 1691

Abstract

Non-invasive therapeutic-focused ultrasound (US) can be used for the mechanical dissociation of tissue and is described as histotripsy. We have performed US histotripsy in viable perfused ex vivo porcine livers as a step in the development of a novel approach to hepatocyte cell transplantation. The histotripsy nidus was created with a 2 MHz single-element focused US transducer, producing 50 pulses of 10 ms duration, with peak positive and negative pressure values of P+ = 77.7 MPa and P− = –13.7 MPaat focus, respectively, and a duty cycle of 1%. Here, we present the histological analysis, including 3D reconstruction of histotripsy sites. Five whole porcine livers were retrieved fresh from the abattoir using human transplant retrieval and cold static preservation techniques and were then perfused using an organ preservation circuit. Whilst under perfusion, histotripsy was performed to randomly selected sites on the live. Fifteen lesional sites were formalin-fixed and paraffin-embedded. Sections were stained with Haematoxylin and Eosin and picro-Sirius red, and they were also stained for reticulin. Additionally, two lesion sites were used for 3D reconstruction. The core of the typical lesion consisted of eosinophilic material associated with reticulin loss, collagen damage including loss of birefringence to fibrous septa, and perilesional portal tracts, including large portal vein branches, but intact peri-lesional hepatic plates. The 3D reconstruction of two histotripsy sites was successful and confirmed the feasibility of this approach to investigate the effects of histotripsy on tissue in detail. Full article

(This article belongs to the Special Issue Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects)

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20 pages, 3481 KiB

Open AccessArticle

Liver Ultrasound Histotripsy: Novel Analysis of the Histotripsy Site Cell Constituents with Implications for Histotripsy Application in Cell Transplantation and Cancer Therapy

by Saied Froghi, Matheus Oliveira de Andrade, Layla Mohammad Hadi, Pierre Gelat, Hassan Rashidi, Alberto Quaglia, Barry Fuller, Nader Saffari and Brian Davidson

Bioengineering 2023, 10(2), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10020276 - 20 Feb 2023

Cited by 2 | Viewed by 2220

Abstract

Introduction: Allogenic hepatocyte transplantation is an attractive alternative to whole-organ transplantation, particularly for the treatment of metabolic disorders and acute liver failure. However, the shortage of human donor organs for cell isolation, the low cell yield from decellularisation regimes, and low engraftment rates from portal administration of donor cells have restricted its clinical application. Using ultrasound histotripsy to provide a nidus in the liver for direct cell transplantation offers a new approach to overcoming key limitations in current cell therapy. We have analysed the liver cavity constituents to assess their potential as a site for cell delivery and implantation. Methods: Using human organ retrieval techniques, pig livers were collected from the abattoir and transported in ice-cold storage to the laboratory. Following 2 h of cold storage, the livers were flushed with organ preservation solution and placed on an organ perfusion circuit to maintain viability. Organs were perfused with Soltran™ organ preservation solution via the portal vein at a temperature of 24–30 °C. The perfusion circuit was oxygenated through equilibration with room air. Perfused livers (

n = 5

) were subjected to ultrasound histotripsy, producing a total of 130 lesions. Lesions were generated by applying 50 pulses at 1 Hz pulse repetition frequency and 1% duty cycle using a single element 2 MHz bowl-shaped transducer (Sonic Concepts, H-148). Following histotripsy, a focal liver lesion was produced, which had a liquid centre. The fluid from each lesion was aspirated and cultured in medium (RPMI) at 37 °C in an incubator. Cell cultures were analysed at 1 and 7 days for cell viability and a live-dead assay was performed. The histotripsy sites were excised following aspiration and H&E staining was used to characterise the liver lesions. Cell morphology was determined by histology. Results: Histotripsy created a subcapsular lesion (~5 mm below the liver capsule; size ranging from 3 to 5 mm), which contained a suspension of cells. On average, 61×10⁴ cells per mL were isolated. Hepatocytes were present in the aspirate, were viable at 24 h post isolation and remained viable in culture for up to 1 week, as determined by phalloidin/DAPI cell viability stains. Cultures up to 21 days revealed metabolically active live hepatocyte. Live-dead assays confirmed hepatocyte viability at 1 week (Day 1: 12% to Day 7: 45% live cells; p < 0.0001), which retained metabolic activity and morphology, confirmed on assay and microscopy. Cell Titre-Glo^TM showed a peak metabolic activity at 1 week (average luminescence 24.6 RLU; p < 0.0001) post-culture compared with the control (culture medium alone), reduced to 1/3 of peak level (7.85 RLU) by day 21. Conclusions: Histotripsy of the liver allows isolation and culture of hepatocytes with a high rate of viability after 1 week in culture. Reproducing these findings using human livers may lead to wide clinical applications in cell therapy. Full article

(This article belongs to the Special Issue Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects)

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Review

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14 pages, 300 KiB

Open AccessReview

The Current Role and Future Applications of Machine Perfusion in Liver Transplantation

by Sebastian M. Staubli, Carlo D. L. Ceresa and Joerg M. Pollok

Bioengineering 2023, 10(5), 593; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10050593 - 15 May 2023

Cited by 1 | Viewed by 1272

Abstract

The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and have allowed for the prediction of graft function through the analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and to provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts. Full article

(This article belongs to the Special Issue Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects)

27 pages, 1209 KiB

Open AccessReview

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

by Mahsa Ghasemzad, Mahdieh Hashemi, Zohre Miri Lavasani, Nikoo Hossein-khannazer, Haleh Bakhshandeh, Roberto Gramignoli, Hani Keshavarz Alikhani, Mustapha Najimi, Saman Nikeghbalian and Massoud Vosough

Bioengineering 2022, 9(8), 392; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering9080392 - 15 Aug 2022

Cited by 4 | Viewed by 3392

Abstract

The majority of monogenic liver diseases are autosomal recessive disorders, with few being sex-related or co-dominant. Although orthotopic liver transplantation (LT) is currently the sole therapeutic option for end-stage patients, such an invasive surgical approach is severely restricted by the lack of donors and post-transplant complications, mainly associated with life-long immunosuppressive regimens. Therefore, the last decade has witnessed efforts for innovative cellular or gene-based therapeutic strategies. Gene therapy is a promising approach for treatment of many hereditary disorders, such as monogenic inborn errors. The liver is an organ characterized by unique features, making it an attractive target for in vivo and ex vivo gene transfer. The current genetic approaches for hereditary liver diseases are mediated by viral or non-viral vectors, with promising results generated by gene-editing tools, such as CRISPR-Cas9 technology. Despite massive progress in experimental gene-correction technologies, limitations in validated approaches for monogenic liver disorders have encouraged researchers to refine promising gene therapy protocols. Herein, we highlighted the most common monogenetic liver disorders, followed by proposed genetic engineering approaches, offered as promising therapeutic modalities. Full article

(This article belongs to the Special Issue Cell- and Gene-Based Therapeutic Strategies for Liver Disease: Recent Advances and Prospects)

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