3D scaffold-free microlivers with drug metabolic function generated by lineage-reprogrammed hepatocytes from human fibroblasts

Lu, Zuyan; Rajan, Shiny Amala Priya; Song, Qisheng; Zhao, Yu; Wan, Meimei; Aleman, Julio; Skardal, Aleksander; Bishop, Colin E.; Atala, Anthony; Lu, Baisong

doi:10.1016/j.biomaterials.2021.120668

Cited by 16 publications

(22 citation statements)

References 48 publications

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“…In these systems, the 3D architecture is obtained through a cellular self-assembling, in which cancer cells synthesize their own extracellular matrix (ECM), allowing for natural modeling of cell–matrix interactions [ 18 ]. Up to now, there are five main scaffold-free techniques, i.e., agitation-based [ 19 , 20 , 21 ], hanging drop [ 22 , 23 ], liquid overlay [ 24 , 25 ], magnetic levitation [ 26 , 27 , 28 ] and microfluidic techniques [ 29 , 30 ] (see Table 1 ). In scaffold-based 3D systems, cell cultures are developed on exogenous structures, made of synthetic or naturally derived polymers, which provide a support for cell growth and mimic ECM conditions.…”

Section: Types Of 3d In Vitro Cancer Modelsmentioning

confidence: 99%

Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment

et al. 2023

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In the last decades three-dimensional (3D) in vitro cancer models have been proposed as a bridge between bidimensional (2D) cell cultures and in vivo animal models, the gold standards in the preclinical assessment of anticancer drug efficacy. 3D in vitro cancer models can be generated through a multitude of techniques, from both immortalized cancer cell lines and primary patient-derived tumor tissue. Among them, spheroids and organoids represent the most versatile and promising models, as they faithfully recapitulate the complexity and heterogeneity of human cancers. Although their recent applications include drug screening programs and personalized medicine, 3D in vitro cancer models have not yet been established as preclinical tools for studying anticancer drug efficacy and supporting preclinical-to-clinical translation, which remains mainly based on animal experimentation. In this review, we describe the state-of-the-art of 3D in vitro cancer models for the efficacy evaluation of anticancer agents, focusing on their potential contribution to replace, reduce and refine animal experimentations, highlighting their strength and weakness, and discussing possible perspectives to overcome current challenges.

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Section: Types Of 3d In Vitro Cancer Modelsmentioning

confidence: 99%

Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment

et al. 2023

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“…Prox1 is a key transcription factor controlling liver development and metabolism. Prox1 expression is essential for hepatoblast migration and hepatocyte cell commitment (Burke & Oliver, 2002; Dudas et al, 2004; Lu et al, 2021; Sosa-Pineda et al, 2000; Velazquez et al, 2021). In the adult liver, Prox1 controls key aspects of lipid metabolism; adult mice lacking Prox1 in hepatocytes show a strong degree of liver steatosis and hepatic injury (Armour et al, 2017; Dittner, 2016; Goto et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Section: Prox1 Is Modified By Sumo At Lysine 556 In Response To Nutri...mentioning

confidence: 99%

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Nunez

Dittner

Becker

et al. 2022

Preprint

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The liver is the major metabolic hub, ensuring appropriate nutrient supply during fasting and feeding. In obesity, accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease. Understanding the signaling mechanisms that enable hepatocytes to quickly adapt to dietary cues, might help to restore balance in liver diseases. Post-translational modification by attachment of the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. Here, we demonstrate that the specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly modified by SUMOylation on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was strongly abolished upon fasting. In a context of diet-induced obesity, Prox1 SUMOylation became insensitive to fasting cues. Hepatocyte-selective knock in of a SUMOylation-deficient Prox1 mutant into mice fed a high fat/high fructose diet led to reduction of systemic cholesterol levels, associated with the induction of bile acid detoxifying pathways in mutant livers during fasting. As appropriate and controlled fasting protocols have been shown to exert beneficial effects on human health, tools to maintain the nutrient-sensitive SUMOylation switch on Prox1 may thus contribute to the development of fasting-based approaches for the maintenance of metabolic health.

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“…Significant progress has been made in achieving a wide range of target cell types, including cardiac muscle cells, 7 neurons, 8 chondrocytes, 9 and hepatocytes. 10 However, low direct transformation efficiency (generally <10% of transformed cells) and functionality issues remain major obstacles to transplantation therapy of the directly reprogramed cells. 11 Different strategies have been exploited to enhance the reprogramming process, including miRNA, 12−14 small molecules, and other chemical signals.…”

Section: Introductionmentioning

confidence: 99%

Direct Reprogramming of Mouse Fibroblasts to Osteoblast-like Cells Using Runx2/Dlx5 Factors on Engineered Stiff Hydrogels

Zhang,

Wang,

Guo

et al. 2023

ACS Appl. Mater. Interfaces

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3D scaffold-free microlivers with drug metabolic function generated by lineage-reprogrammed hepatocytes from human fibroblasts

Cited by 16 publications

References 48 publications

Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment

Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Direct Reprogramming of Mouse Fibroblasts to Osteoblast-like Cells Using Runx2/Dlx5 Factors on Engineered Stiff Hydrogels

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