SARS-CoV-2 Infection and Lung Regeneration

Abstract

The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.

Keywords: cell therapy; lung injury; mesenchymal stem cells; post-acute sequelae of COVID-19; resident epithelial stem/progenitor cells.

FIG 1

General epithelial populations in mammalian lungs. Pseudostratified epithelium is observed in the trachea of both human and mice. Basal cells are situated on basal membrane and serve as stem cells. Basal cells are restricted to the tracheal region in mice but distributed from proximal to distal axis in human lungs. Club cells and ciliated cells represent two of the most predominant cell types in conducting airways. Bronchioalveolar stem cells (BASCs) are found in distal conducting airways of mice but not human. Alveolar epithelia in human is similar to that in mice, including AT1 and AT2 cells. Markers and functions of each epithelial cell type are also indicated.

FIG 2

SARS-CoV-2 induced lung pathology and treating strategy. SARS-CoV-2 infection causes massive damage to lung epithelium, followed by inflammation storms and possible tissue disruptions. Lung stem/progenitor cells (LSPC) are injured due to the surface expression of ACE2. Monotherapy may not be sufficient to restore lung homeostasis. Combined interventions can be considered including targeted therapy with anti-SARS-CoV-2 infection drugs or monoclonal antibodies, inflammation suppression and host immunity boosts such as corticosteroids, lung structural recovery with LSPC, or MSC therapy. In addition, supportive treatments (for example, mechanical ventilation) are also necessary in the clinical care of COVID-19 patients.