Abstract
Tissue engineering of a transplantable liver could provide an alternative to donor livers for transplant, solving the problem of escalating donor shortages. One of the challenges for tissue engineers is the extracellular matrix (ECM); a finely controlled in vivo niche which supports hepatocytes. Polymers and decellularized tissue scaffolds each provide some of the necessary biological cues for hepatocytes, however, neither alone has proved sufficient. Enhancing microenvironments using bioactive molecules allows researchers to create more appropriate niches for hepatocytes. We combined decellularized human liver tissue with electrospun polymers to produce a niche for hepatocytes and compared the human liver ECM to its individual components; Collagen I, Laminin-521 and Fibronectin. The resulting scaffolds were validated using THLE-3 hepatocytes. Immunohistochemistry confirmed retention of proteins in the scaffolds. Mechanical testing demonstrated significant increases in the Young’s Modulus of the decellularized ECM scaffold; providing significantly stiffer environments for hepatocytes. Each scaffold maintained hepatocyte growth, albumin production and influenced expression of key hepatic genes, with the decellularized ECM scaffolds exerting an influence which is not recapitulated by individual ECM components. Blended protein:polymer scaffolds provide a viable, translatable niche for hepatocytes and offers a solution to current obstacles in disease modelling and liver tissue engineering.
Highlights
According to the NHS, liver disease is one of the top five causes of premature death in the UK, with incidence rising sharply by 20% over the last decade[1]
Protein:polymer scaffolds containing human liver extracellular matrix (ECM) exert a significant positive influence on the gene expression profile, albumin production, attachment, and survival of liver cells which cannot be recapitulated by individual ECM components
HRL521 scaffolds were significantly more elastic than both hBTC1 and human plasma fibronectin (hFN) scaffolds (Table 1). Such results demonstrate that the mechanical influence of varying ECM compositions influence on cell behaviour and function cannot be discounted in studies and must be considered when analysing biological results
Summary
According to the NHS, liver disease is one of the top five causes of premature death in the UK, with incidence rising sharply by 20% over the last decade[1]. As part of the push for a solution to this problem, tissue engineers are focussing on creating niche microenvironments for main cell type of the liver, the hepatocyte, which support cell survival and function and could be used to treat patients in the future[5,6,7,8,9]. Such an environment would allow for the study of new pharmaceuticals to treat human disease more effectively[10]. Each protein individually represents a small fraction of the bioactive molecules present in the ECM and when used in isolation cannot recapitulate the healthy hepatic matrix[24,29,30]
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