Self-Organized Liver Microtissue on a Bio-Functional Surface: The Role of Human Adipose-Derived Stromal Cells in Hepatic Function

Abstract

<jats:p>The maintenance of hepatocyte function is a critical research topic in liver tissue engineering. Although an increasing number of strategies have been developed, liver tissue engineering using hepatocytes as a therapeutic alternative remains challenging owing to its poor efficacy. In this study, we developed a multicellular hepatic microtissue to enhance the function of induced hepatic precursor cells. Mouse induced hepatic precursor cells (miHeps) were self-organized in 3D with human adipose-derived stem cells (hASCs) on a bio-functional matrix. We found that hepatic phenotypes, such as levels of albumin, asialoglycoprotein receptor-1, and cytochrome P450, were enhanced in miHeps-hASC microtissue comprising miHeps and hASCs relative to two-dimensional-cultured miHeps-hASCs. Additionally, the secretome of 3D-cultured hASCs increased the hepatic function of mature miHeps. Furthermore, hepatic gene expression was reduced in mature miHeps treated with conditioned media of hypoxia-inducible factor 1α (HIF1α)-depleted hASCs relative to that with conditioned media of control hASCs. Our results suggested that the hepatic function of 3D-co-cultured miHeps could be enhanced by HIF1α-dependent factors secreted from stromal cells. This study provides an insight into the factors regulating hepatic function and shows that self-organized hepatic microtissue could act as liver spheroids for liver regenerative medicine and liver toxicity tests.</jats:p>

Systematic review on spheroids from adipose‐derived stem cells: Spontaneous or artefact state?

“…In a biofunctional matrix of PS coated with basic fibroblast growth factor (FGF2) and maltose binding protein, Hong et al generated functional 3D hepatocytes with hASCs as supporting cells that were cocultured with mouse induced hepatic precursor cells (miHeps) (Hong et al, 2020 ).…”

“…generated functional 3D hepatocytes with hASCs as supporting cells that were cocultured with mouse induced hepatic precursor cells (miHeps) (Hong et al, 2020).…”

Engineered liver tissue in vitro to mimic liver functions and its biomedical applications

“…The development of MPCCs was inspired by earlier studies of physical homomorphic (hepatocellularhepatocellular) and heteromorphic (hepatocellular-stromal) interactions regulating hepatocyte function in vitro. [62][63][64][65] Previous researchers found that some functions could be temporarily induced when epithelial cell types from the liver were cocultured with primary human liver cells. However, in these studies, the two types of cells were randomly distributed.…”

Cell competition promotes metastatic intestinal cancer through a multistage process

“…Next, we aimed to develop a model which better resembles the overall organ structure of the liver and allows us to study liver-cancer interactions in a self-organizing matrix-free environment. We were inspired by reported microtissues from organs such as brain 45 , heart 46 and liver [47][48][49][50] that were previously used to study the tissue development and response to injury. For this, pieces of hepatocyte-like differentiated organoids were aggregated in a U-bottom plate to obtain self-organizing liver microtissues with a size of 1-2mm (Figure 6A).…”