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Título: Adult and iPS-derived non-parenchymal cells regulate liver organoid development through differential modulation of Wnt and TGF-beta
Autor: GOULART, ErnestoCAIRES-JUNIOR, Luiz Carlos deTELLES-SILVA, Kayque AlvesARAUJO, Bruno Henrique SilvaKOBAYASHI, Gerson S.MUSSO, Camila MansoASSONI, Amanda FariaOLIVEIRA, DanylloCALDINI, EliaGERSTENHABER, Jonathan A.RAIA, SilvanoLELKES, Peter I.ZATZ, Mayana
Citación: STEM CELL RESEARCH & THERAPY, v.10, n.1, article ID 258, 11p, 2019
Resumen: 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-beta 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-beta/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.
Aparece en las colecciones:

Artigos e Materiais de Revistas Científicas - FM/MCG
Departamento de Cirurgia - FM/MCG

Artigos e Materiais de Revistas Científicas - FM/MPT
Departamento de Patologia - FM/MPT

Artigos e Materiais de Revistas Científicas - LIM/59
LIM/59 - Laboratório de Biologia Celular


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