The role of stem cells in SARS-CoV-2 infection

Abstract

The emergence of SARS-CoV-2, the causative agent of the COVID-19 pandemic, has posed an unprecedented global health crisis, driving rapid advancements in vaccine development and targeted antiviral therapies. Despite these efforts, there remains a critical need for effective therapeutic strategies capable of modulating immune dysregulation and promoting tissue regeneration. Equally important is the development of physiologically relevant in vitro model that recapitulate the structural and functional complexity of the human lung to facilitate the study of viral pathogenesis and therapeutic responses.
Mesenchymal stem cells (MSCs) have gained considerable attention due to their immunomodulatory and regenerative properties, mediated primarily through paracrine signalling. The conditioned medium (MSC-CM), rich in bioactive factors, offers a cell-free therapeutic approach with reduced immunogenicity and ease of application. MSCs and MSC-CM have shown promise in mitigating the hyperinflammatory response and supporting epithelial repair in SARS-CoV-2-infected tissues. This study reveals novel mechanistic insights into the therapeutic effects of MSC-CM on SARS-CoV-2-infected human lung epithelial cells. Using the Calu-3 cell line as a representative model of the respiratory epithelium, MSC-CM was shown to modulate IL-1β-induced apoptosis through the action of IL-1ra and to promote tight junction reassembly via HGF-mediated pathways.
To enhance translational relevance, a human induced pluripotent stem cell (iPSC)-derived lung organoid model was established. These organoids exhibit key cellular characteristics of both airway and alveolar epithelium and are permissive to SARS-CoV-2 infection and replication. The model supported replication of multiple SARS-CoV-2 variants, demonstrating its robustness and versatility for studying strain-specific viral dynamics, and viral-host interactions within a biologically representative lung environment.
In conclusion, this study is the first to characterise the molecular mechanisms underpinning MSC-CM-mediated immunomodulation and epithelial repair in a SARS-CoV-2 cellular model. Additionally, the successful development of an iPSC-derived lung organoid system provides a robust model for investigating pulmonary infectious diseases and evaluating regenerative therapies.

Date of Award	30 Sept 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Wael Kafienah (Supervisor) & Andrew D Davidson (Supervisor)