Decellularized liver matrix as substrates for rescue of acute hepatocytes toxicity

Abstract

More and more scholars regard the lesion of liver cirrhosis as a series of progressive clinical stages. Besides, liver cirrhosis is a late stage of scarring (fibrosis) of the liver, and has long been a common cause of death for the global adult population, thus, the treatment of liver cirrhosis is a key point investigated in the biomedical field. Here, we propose a novel hypothesis; if decellularized liver matrix (DLM) is possible injected into the injurant‐induced fiberized liver via the hepatic portal vein to thoroughly repair the liver, it may be an effective therapeutic method for liver fibrosis or even liver cirrhosis. This study mixed rat DLM with gelatin‐hydroxyphenylpropionic acid (Glt‐HPA) to form a three‐dimensional structure to simulate the in vivo liver environment, and cultured the primary rat hepatocytes in it. Afterward, the hepatocytes were treated using D‐galactosamine (GaIN), CHCl3, and CCl4‐containing medium to simulate the toxin‐mediated liver fibrosis in vitro. Finally, they were cultured in a DLM‐containing medium to observe the viability and functions of the damaged hepatocytes, and the hypothesis of this research was proved, meaning that Glt‐HPA‐DLM acting on damaged hepatocytes may repair them. Results have shown that Glt‐HPA‐DLM was effective for hepatocytes culture and repaired injured hepatocytes from GaIN, CHCl3, and CCl4 (albumin synthesis was increased by 219, 108, and 12%, respectively, whereas relative lactate dehydrogenase activity was reduced by 38, 68, and 67%, after 5 days of culture, separately). This research shows promising effects against hepatic fibrosis and may have potential for liver cirrhosis in vivo.

Upgrading Hepatic Differentiation and Functions on 3D Printed Silk–Decellularized Liver Hybrid Scaffolds

“…Several studies have used the DCL ECM in a solubilized form to generate 3D injectable hydrogels. 7,11 The viability and functionality of hepatocytes have been shown to be significantly improved in DCL hydrogels compared to those observed in collagen hydrogels. 39 Recent studies have also reported 3D bioprinting of liver cells, in which bioprinted hepatocytes and nonparenchymal cells in 3D architecture have been reported to be metabolically and functionally active.…”

“…For example, decellularized liver (DCL) tissue and hydrogels based on DCL extracellular matrix (ECM) have been used extensively for liver tissue engineering, where all of the cellular and immunogenic components of ECM proteins are removed only to retain the native ECM. 7 Recently, a few studies have reported three-dimensional (3D) cultures of hepatocytes along with other liver cells, including endothelial and stellate cells, to form a functional liver construct. 8−10 Minami et al developed a 3D liver tissue equivalent using human-induced pluripotent stem cells and rat DCL-based scaffolds that expressed albumin (ALB) and cytochrome P450 3A4 (CYP3A4) genes after 48 h of recellularization.…”

“…Furthermore, rapid loss in the proliferation rate of hepatocytes has been observed 3–5 days postisolation due to their tendency to undergo dedifferentiation, the loss of characteristic hepatocyte morphology and functionality. − Different biomaterial scaffolds and culture strategies are being tested to optimize hepatocyte cultures in vitro . For example, decellularized liver (DCL) tissue and hydrogels based on DCL extracellular matrix (ECM) have been used extensively for liver tissue engineering, where all of the cellular and immunogenic components of ECM proteins are removed only to retain the native ECM . Recently, a few studies have reported three-dimensional (3D) cultures of hepatocytes along with other liver cells, including endothelial and stellate cells, to form a functional liver construct. − Minami et al developed a 3D liver tissue equivalent using human-induced pluripotent stem cells and rat DCL-based scaffolds that expressed albumin (ALB) and cytochrome P450 3A4 (CYP3A4) genes after 48 h of recellularization .…”

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

“…In order to develop a completely competent transplantable organ utilizing BEL, the two stages of decellularization and recellularization are necessary ( Badylak et al, 2011 ; Baptista et al, 2011 ). Decellularization seeks to create a biocompatible decellularized scaffold that preserves the three-dimensional architecture and biochemical content of the original tissue while removing the cellular material to decrease the immunological reactivity ( Uygun et al, 2010 ; Debnath et al, 2020 ; Hou et al, 2020 ; Moulisova et al, 2020 ). Enzymes and chemicals, along with mechanical agitation, freezing/thawing, and sonication, are various strategies for decellularization by disturbing cells and liberating their substance.…”

Regenerative medicine for the hepatobiliary system: A review

“…Recent reports document that decellularized liver scaffolds promote liver regeneration after partial hepatectomy 95 and rescue of acute hepatocyte toxicity. 96 Decellularized liver matrix-modified scaffolds have been shown as a substrate for hepatocyte culture 97 as well as potential hepatocyte carriers in BAL support systems and implantable liver constructs. 98 These studies provide further proof that this technology may one day deliver viable constructs for drug discovery and toxicology applications, as well as for transplantation.…”