title: Agathisflavone enhances retinoic acid-induced neurogenesis and its receptors α and β in pluripotent stem cells.
abstract: Flavonoids have key functions in the regulation of multiple cellular processes; however, their effects have been poorly examined in pluripotent stem cells. Here, we tested the hypothesis that neurogenesis induced by all-trans retinoic acid (RA) is enhanced by agathisflavone (FAB, Caesalpinia pyramidalis Tull). Mouse embryonic stem (mES) cells and induced pluripotent stem (miPS) cells growing as embryoid bodies (EBs) for 4 days were treated with FAB (60 μM) and/or RA (2 μM) for additional 4 days. FAB did not interfere with the EB mitotic rate of mES cells, as evidenced by similar percentages of mitotic figures labeled by phospho-histone H3 in control (3.4% ± 0.4%) and FAB-treated groups (3.5% ± 1.1%). Nevertheless, the biflavonoid reduced cell death in both control and RA-treated EBs from mES cells by almost 2-fold compared with untreated EBs. FAB was unable, by itself, to induce neuronal differentiation in EBs after 4 days of treatment. On the other hand, FAB enhanced neuronal differentiation induced by RA in both EBs of mES and miPS. FAB increased the percentage of nestin-labeled cells by 2.7-fold (mES) and 2.4 (miPS) and β-tubulin III-positive cells by 2-fold (mES) and 2.7 (miPS) in comparison to RA-treated EBs only. FAB increased the expression of RA receptors α and β in mES EBs, suggesting that the availability of RA receptors is limiting RA-induced neurogenesis in pluripotent stem cells. This is the first report to describe that naturally occurring biflavonoids regulate apoptosis and neuronal differentiation in pluripotent stem cells.
authors.affiliation: Instituto de Ciências Biomédicas, Laboratório Nacional de Células-Tronco Embrionárias, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Bruna S
authors.initials: BS
authors.lastname: Paulsen
authors.forename: Cleide S
authors.initials: CS
authors.lastname: Souza
authors.forename: Leonardo
authors.initials: L
authors.lastname: Chicaybam
authors.forename: Martin Hernán
authors.initials: MH
authors.lastname: Bonamino
authors.forename: Marcus
authors.initials: M
authors.lastname: Bahia
authors.forename: Silvia Lima
authors.initials: SL
authors.lastname: Costa
authors.forename: Helena L
authors.initials: HL
authors.lastname: Borges
authors.forename: Stevens K
authors.initials: SK
authors.lastname: Rehen
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D044946:Biflavonoids; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta; C079168:agathisflavone; D014212:Tretinoin