Generation of hiPSC-derived cells relevant for COVID19 research and drug screening

• Grant number: 20/12506-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2021
• End date: January 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Lygia da Veiga Pereira
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Carolina Borsoi Moraes ; Lucio Holanda Gondim de Freitas Junior ; Patricia Nolasco Santos

Abstract

The corona virus disease-19 (COVID-19) pandemic is a global emergency that already affects approximately 200 countries and territories worldwide and continues to spread rapidly, making it the greatest challenge facing humanity in a hundred years. Contrary to what happened in other recent pandemics, such as Influenza A H1N1, there are still no drugs that are proven effective against the disease. So far, it is known that the SARS-CoV-2 virus, which causes COVID-19, mainly uses the angiotensin-converting enzyme 2 (ACE2), a component of the renin-angiotensin system, as a receptor for entry into human cells. Infection of cells in the upper and lower airways by the virus results in an acute respiratory syndrome that can worsen, leading to death. Another interesting observation was the presence of cardiac complications in some patients, such as arrhythmia and failure. It is known that people who have previous cardiovascular diseases and diabetes have an increased risk of developing severe forms of the disease, however, the mechanisms of association between these pathologies have not yet been elucidated. A hypothesis yet to be tested would be that the expression of ACE2 is increased in patients with these comorbidities, which would facilitate infection by SARS-CoV-2 in these cases. In the current situation, the extreme urgency for the discovery of effective drugs against the disease obliges researchers to shorten the long process of discovering new treatments. An alternative to the cell types most commonly used in this process - tumor or immortalized lines, often not very relevant to the disease - are type 2 alveolar epithelial cells derived from human induced pluripotent stem cells (hiPSC-AEC2 or iAEC2). In vivo, AEC2 serve as optional progenitors of pulmonary alveoli and are one of the cell types most infected by SARS-CoV-2. The presence of cardiac manifestations in patients affected by COVID-19 also raises the hypothesis of infection of cardiomyocytes (CMs) by the virus. The possibility of generating both cell types from the differentiation of hiPSCs circumvents the existing difficulties in obtaining and maintaining primary AEC2s and CMs, being a promising tool for the study of the disease and possible therapies.Considering our laboratory's experience with hiPSC cultivation and differentiation techniques, we will redirect our efforts towards the generation of cell types relevant to the study of COVID-19, in particular alveolar, endothelial and cardiomyocyte epithelial cells. The cells derived from hiPSCs will be used in screening and validation of drugs capable of inhibiting SARS-CoV-2 infection in collaboration with the group of Prof. Lucio H. Freitas-Junior of ICB-USP, specialized in phenotypic screens on automated High Content Screening (HCS) platforms. (AU)