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Adult and iPS-derived non-parenchymal cells regulate liver organoid development through differential modulation of Wnt and TGF-β
Goulart, E De Caires-Junior, LC Telles-Silva, KA Araujo, BHS Kobayashi, GS Musso, CM Assoni, AF Oliveira, D Caldini, E Gerstenhaber, JA
Goulart, E
De Caires-Junior, LC
Telles-Silva, KA
Araujo, BHS
Kobayashi, GS
Musso, CM
Assoni, AF
Oliveira, D
Caldini, E
Gerstenhaber, JA
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Journal Article
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2019-08-15
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10.1186/s13287-019-1367-x
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© 2019 The Author(s). Background: Liver organoid technology holds great promises to be used in large-scale population-based drug screening and in future regenerative medicine strategies. Recently, some studies reported robust protocols for generating isogenic liver organoids using liver parenchymal and non-parenchymal cells derived from induced pluripotent stem cells (iPS) or using isogenic adult primary non-parenchymal cells. However, the use of whole iPS-derived cells could represent great challenges for a translational perspective. Methods: Here, we evaluated the influence of isogenic versus heterogenic non-parenchymal cells, using iPS-derived or adult primary cell lines, in the liver organoid development. We tested four groups comprised of all different combinations of non-parenchymal cells for the liver functionality in vitro. Gene expression and protein secretion of important hepatic function markers were evaluated. Additionally, liver development-associated signaling pathways were tested. Finally, organoid label-free proteomic analysis and non-parenchymal cell secretome were performed in all groups at day 12. Results: We show that liver organoids generated using primary mesenchymal stromal cells and iPS-derived endothelial cells expressed and produced significantly more albumin and showed increased expression of CYP1A1, CYP1A2, and TDO2 while presented reduced TGF-β and Wnt signaling activity. Proteomics analysis revealed that major shifts in protein expression induced by this specific combination of non-parenchymal cells are related to integrin profile and TGF-β/Wnt signaling activity. Conclusion: Aiming the translation of this technology bench-to-bedside, this work highlights the role of important developmental pathways that are modulated by non-parenchymal cells enhancing the liver organoid maturation.
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Springer Science and Business Media LLC
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Stem Cell Research and Therapy
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