Impacts of STI1 modulation on Wnt signaling and pluripotency status

• Grant number: 22/14445-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2023
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Samuel Ribeiro Soares
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/15557-4 - Prion protein and its partners: emerging targets for glioblastoma stem cell based-therapy, AP.JP2

Abstract

Pluripotency is the transient ability to differentiate in the three embryonic leaflets, which varies according to the stages of early embryonic development. The pluripotent status characteristic of pluripotent stem cells (PSCs) is regulated by a network of characteristic transcription factors (TFs) that change according to pro-differentiation or pro-pluripotency stimuli. Alongside these TFs, several signaling pathways also participate in the maintenance of this status, especially the canonical WNT pathway, which regulates various aspects of embryogenesis. PSCs require a high degree of fidelity of their protein homeostasis mechanisms, especially the heat shock proteins HSP70 and HSP90, capable of forming a complex with each other, mediated by the co-chaperone STI1. Depletion of STI1 in murine embryos triggers malformation of the neural tube, limbs and increased caspase-3 activity, evidencing its importance in early development, which remains sparsely described. Furthermore, members of the HSP90-STI1-HSP70 complex play a prominent role in stabilizing central TFs for pluripotency, in addition to interacting with WNT signaling and directly influencing the modulation of the protein complex responsible for ²-catenin degradation in tumor models. Although interactions between STI1 and WNT signaling have already been described in cancer models, the characterization of this phenomenon in PSCs is poorly understood and, similarly, the impacts of STI1 in the early stages of embryonic development and in pluripotency still remain partially known.Therefore, we will use murine PSCs as a model of embryonic development in order to characterize the impacts of STI1 modulation on WNT signaling and pluripotency status. For this, we will mimic the different stages of pluripotency in PSCs and analyze markers of cell proliferation and death, as well as the expression of pluripotency markers and WNT signaling that may be impacted by the modulation of STI1, in order to assess the activation and activity of these pathways. Our analysis will be conducted under different conditions of pharmacological intervention to determine how the canonical WNT signaling can influence the maintenance of pluripotency. Thus, the present study will contribute to the understanding of the role of STI1 in the control of molecular mechanisms related to pluripotency status with potential application for new therapeutic approaches.