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Effect of Notch1 signaling in hiPSC-derived cardiomyocytes differentiation

Grant number: 23/05709-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2023
Effective date (End): February 28, 2027
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:José Eduardo Krieger
Grantee:Nikolas Dresch Ferreira
Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated scholarship(s):23/15481-6 - VALIDATION OF CANDIDATE ENHANCERS OF CARDIAC SPECIFIC GENES, BE.EP.DD

Abstract

Current protocols for differentiating human induced pluripotent stem cells (hiPSCs) into cardiomyocytes (CMs) for cellular therapy still need improvement due to the occurrence of arrhythmias in preclinical trials, which limits their therapeutic application. This is mainly attributed to the insufficient maturation and electrophysiological heterogeneity of CMs obtained with current differentiation methods. In this regard, to investigate one of the mechanisms responsible for the specialization of hiPSC-CMs, we evaluated in an anterior project the role of the Notch1 pathway in generating working CMs. Our results demonstrate that inhibiting the Notch1 pathway during cardiac progenitor formation can modulate CM morphology, marker expression, and electrophysiological behavior. However, the observed variability in electrical profiles suggests that the cells may represent different developmental stages or distinct subpopulations. Based on our findings and functional comparisons, we hypothesize that this treatment led to increased electrical maturation and a phenotype resembling working CMs. Therefore, we requested an update from Master's to Doctoral level in the qualifying exam, to allow for a longer period of work involving more advanced techniques such as transcriptomics, functional analysis in isolated cells, and immunofluorescence, after pharmacological and genetic inhibition of the Notch1 pathway during the optimized differentiation protocol. Our research will contribute to a better understanding of key mechanisms involved in hiPSC-CM differentiation, leading to the development of safer and more effective cellular therapies for cardiac regeneration. Furthermore, we plan to apply for the overseas research internship grant (BEPE-DD) to work at Dr. Sean Wu's laboratory at Stanford University, USA, to further investigate the time-dependent effect of the Notch1 pathway in hiPSC-CM differentiation. (AU)

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