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Hepatocyte thorns, a novel drug-induced stress response in human and mouse liver spheroids

ABSTRACT: The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of e.g. novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids wherein long slender filaments form after chronic treatment with four different drugs, of which, three are PPARα an-tagonists. The morphology of the thorns varies between donors and compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471, revealed changes in gene and protein expression like those in the spheroids. In addition, similar changes in kera-tin expression were seen following treatment of hepatotoxic drugs including aflatoxin B1, para-cetamol, chlorpromazine, cyclosporine and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems like the spheroids.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Massimiliano Gaetani

LAB HEAD: Massimiliano Gaetani

PROVIDER: PXD033550 | Pride | 2022-05-26

REPOSITORIES: Pride

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			Action	DRS
	2020701_HF2_01_Chris_Spheroids_200622_Vehicle.raw	Raw
	2020701_HF2_02_Chris_Spheroids_200622_GW6451.raw	Raw
	20210827_HF2_01_CP_1_TMT6_F1.raw	Raw
	20210827_HF2_02_CP_1_TMT6_F2.raw	Raw
	20210827_HF2_03_CP_1_TMT6_F3.raw	Raw

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Hepatocyte thorns, a novel drug-induced stress response in human and mouse liver spheroids

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