The Regenerative Power of Stem Cells: Treating Bleomycin-Induced Lung Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with no known cure, characterized by the formation of scar tissue in the lungs, leading to respiratory failure. Although the exact cause of IPF remains unclear, the condition is thought to result from a combination of genetic and environmental factors. One of the most widely used animal models to study IPF is the bleomycin-induced lung injury model in mice. In this model, the administration of the chemotherapeutic agent bleomycin causes pulmonary inflammation and fibrosis, which closely mimics the pathological features of human IPF. Numerous recent investigations have explored the functions of various categories of stem cells in the healing process of lung injury induced by bleomycin in mice, documenting the beneficial effects and challenges of this approach. Differentiation of stem cells into various cell types and their ability to modulate tissue microenvironment is an emerging aspect of the regenerative therapies. This review article aims to provide a comprehensive overview of the role of stem cells in repairing bleomycin-induced lung injury. It delves into the mechanisms through which various types of stem cells, including mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and lung resident stem cells, exert their therapeutic effects in this specific model. We have also discussed the unique set of intermediate markers and signaling factors that can influence the proliferation and differentiation of alveolar epithelial cells both during lung repair and homeostasis. Finally, we highlight the challenges and opportunities associated with translating stem cell therapy to the clinic for IPF patients. The novelty and implications of this review extend beyond the understanding of the potential of stem cells in treating IPF to the broader field of regenerative medicine. We believe that the review paves the way for further advancements in stem cell therapies, offering hope for patients suffering from this debilitating and currently incurable disease.

Keywords: alveoli; bleomycin; differentiation; proliferation; pulmonary fibrosis; regeneration.

Figure 1

An illustration of AT2-AT1 cell transition during fibrotic lung injury. The figure represents the process of AT2-AT1 cell transition during fibrotic lung injury. AT2 cells are shown to proliferate after the lung injury, where a fraction of these cells differentiating into mature AT1 cells. Also included are the representative cell types involved in the repair process (top right). Created with BioRender.com.

Figure 2

Lineage-tracing of cells during the repair phase of an injured lung by the Cre-ERT2 system. (a) Schematic representation of the Cre-ERT2 system. The presence of a stop codon flanked by loxP sites inhibits the expression of the reporter transgene (tdTomato). Upon tamoxifen treatment, the expressed Cre mediates site-specific recombination between loxP sites, which removes the intervening stop codon, and the reporter is expressed. (b) Lineage-tracing using Cre-ERT2 system enriches and identifies intermediate stages of transdifferentiated AT2 stem cells. Some of the identified intermediates are shown for representation. Similar enrichment can also be achieved using stem cell surface markers such as CD34, CD45, and Thy1. Created with BioRender.com.

Figure 3

Mechanotransduction-Mediated Signaling in AT2-AT1 Transition. The figure illustrates the signaling factors and progenitor stem cells involved in the AT2-AT1 transition in fibrotic lungs, as well as the role of the mesenchymal niche microenvironment in this process. The complex mechanical signaling pathways that control this transition are depicted, with a focus on the involvement of the small Rho GTPase family member Cdc42 in regulating the STAT-3 and STAT-1 signaling pathways. The effects of mechanotransduction on Wnt, Sox2, EGF, β-catenin, and Nkx2 proteins in the lung mesenchyme, which can alter lung development and repair, have also been demonstrated (bottom right). Created with BioRender.com.