This week we profile a recent publication in the American Journal of Physiology-Lung Cellular and Molecular Physiology from the labs of Drs. Finn Hawkins (pictured, right), Darrell Kotton, Elke Mühlberger, and Ruobing Wang (left).
Can you provide a brief overview of your lab’s current research focus?
This work is a collaborative effort between the Hawkins, Kotton, Mühlberger and Wang laboratories. The Wang laboratory, based at Boston Children’s Hospital, uses induced pluripotent stem cell (iPSC)-based platforms and gene-editing techniques to study pediatric lung diseases, focusing mainly on cystic fibrosis (CF) and is currently studying how CF diseased airway epithelium responds differentially to emerging and common pathogens that affects cystic fibrosis patients. The Hawkins and Kotton labs, based at the Center for Regenerative Medicine of Boston University and Boston Medical Center, focus on iPSC-modeling of lung development and disease. The Mühlberger laboratory, in Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL), studies highly pathogenic emerging viruses.
What is the significance of the findings in this publication?
The COVID-19 pandemic caused by SARS-CoV-2 has caused widespread morbidity and death since its emergence and represents an ongoing urgent research priority. The airway epithelium is a major initial target for SARS-CoV-2 and plays a central role in this disease. A hurdle in the response of the research community to the pandemic is access to human in vitro models of the organs most affected by SARS-CoV-2. In this study, we used polarized, mucociliary airway epithelial cultures generated from human iPSCs for COVID-19 disease modeling. The advantages of this platforms are 1) the potential for a near unlimited source of airway cells to study infection in one the most important targets of SARS-CoV-2 infection, 2) the capacity to generate physiologically relevant airway cultures from any individual of interest, and 3) the ability to interrogate the molecular mechanisms of infection, particularly the genes, variants and pathways associated with severe disease. In this manuscript we confirm that the iPSC-airway express SARS-CoV-2 entry factors ACE2 and TMPRSS2 and demonstrate that this airway epithelium is permissive to SARS-CoV-2 infection via multiciliated cells. Following infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses. We also demonstrate that this platform is suitable for testing the efficacy of anti-viral therapies. The now routine generation of iPSCs from any individual of interest and the ability to genetically engineer iPSCs suggest the application of this platform to broad research pursuits including; (1) in-vitro drug testing, (2) studying the mechanisms of viral infection and propagation in airway epithelium with different SARS-CoV-2 variants, and (3) studying the contributions of genetic determinants of disease severity using gene-editing and functional genomics.
What are the next steps for this research?
We are currently studying how the cystic fibrosis (CF) airway responds to SARS-CoV-2 using the iPSC-airway platform. This will allow us to assess CF epithelial intrinsic responses to SARS-CoV-2, which can generate useful insights that may aid practice guidelines and direct therapy specific for CF patients during the current COVID-19 pandemic. We will also intend to extend the study of pathogens using the iPSC-airway platform to include current and future SARS-CoV-2 variants, as well as clinically-relevant CF pathogens such as influenza A (subtype H1N1), and Pseudomonas aeruginosa.
If you’d like to mention your funding sources, please list them.
Wang
- Cystic Fibrosis Foundation
- Gilead Sciences
- Alfred and Gilda Slifka Fund
- CF/MS fund
- NIH/NHLBI
Hawkins
- -NIH/NHLBI
- Evergrande MassCPR
Kotton
- Evergrande MassCPR
- Cystic Fibrosis Foundation
- NIH/NHLBI
Mühlberger
- Fast Grants
- Evergrande MassCPR
- NIH
