In Vitro Human Liver Model of Nonalcoholic Steatohepatitis by Coculturing Hepatocytes, Endothelial Cells, and Kupffer Cells

Ceri Anne E. Suurmond, Soufian Lasli, Floor W. van den Dolder, Aly Ung, Han Jun Kim, Praveen Bandaru, Kang Ju Lee, Hyun Jong Cho, Samad Ahadian, Nureddin Ashammakhi, Mehmet R. Dokmeci, Junmin Lee*, Ali Khademhosseini

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

The liver has a complex and unique microenvironment with multiple cell–cell interactions and internal vascular networks. Although nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with multiple phases, no proper model could fully recapitulate the in vivo microenvironment to understand NAFLD progression. Here, an in vitro human liver model of NAFLD by coculturing human hepatocytes, umbilical vein endothelial cells (HUVECs), and Kupffer cells (KCs) into spheroids is presented. Analysis of indirect cross-talk using conditioned media between steatotic spheroids—composed of hepatocellular carcinoma-derived cells (HepG2) and HUVECs—and mouse KCs reveals that the latter can be activated showing increased cell area, elevated production of reactive oxygen species (ROS), and proinflammatory cytokines. Spheroids incorporating human KCs (HKCs) can also be induced into steatotic stage by supplementing fat. Steatotic spheroids with/without HKCs show different levels of steatotic stages through lipid accumulation and ROS production. Steatotic spheroids made from an immortalized hepatic progenitor cell line (HepaRG) compared to those made from HepG2 cells display similar trends of functionality, but elevated levels of proinflammatory cytokines, and improved reversibility of steatosis. The in vitro human liver system proposed makes strides in developing a model to mimic and monitor the progression of NAFLD.

Original languageEnglish
Article number1901379
JournalAdvanced healthcare materials
Volume8
Issue number24
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • cocultures
  • liver-on-a-chip
  • nonalcoholic fatty liver disease (NAFLD)
  • nonalcoholic steatohepatitis (NASH)
  • spheroids

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