Lung regeneration: diverse cell types and the therapeutic potential

Abstract

Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

Keywords: cellular composition; lung regeneration; molecular mechanisms; research models; therapeutic potential.

FIGURE 1

The balance of the lung repair process. Under homeostatic conditions, various cells in the lungs work in an orderly manner and perform gas exchange functions normally. Upon injury, a variety of cells are activated, such as fibroblasts, immune cells, and epithelial cells, triggering an inflammatory response and secretion of extracellular matrix, which ultimately leads to impaired gas exchange. AT1: type I alveolar epithelial cell, AT2: type II alveolar epithelial cell; PCEC, pulmonary capillary endothelial cell; RBC, red blood cell.

FIGURE 2

Sources of type I alveolar epithelial cells during lung regeneration. Type I alveolar epithelial cells are the specific units of lung tissue that perform the function of gas exchange. After injury, to rapidly restore lung function, in addition to type II alveolar epithelial precursor cells, other cell types of the respiratory system (such as bronchioalveolar stem cells and respiratory airway secretory cells) also rapidly transdifferentiate to supplement the number of AT1 cells. AEP, Wnt‐responsive alveolar epithelial progenitor; AT2, type 2 alveolar epithelial cell; H2‐K1, MHC class I marker; LNEPs, lineage negative epithelial progenitors; PATS, pre‐alveolar type‐1 transitional cell state; RASC, respiratory airway secretory cells; TM4SF1, transmembrane 4 L six family 1.

FIGURE 3

Cellular and molecular mechanisms in the process of pulmonary fibrosis. When the repair process loses control, multiple cell types, such as PCECs, macrophages, neutrophils, and platelets, are abnormally activated. The activated cells release various proinflammatory cytokines, activate fibroblasts, excessively secrete extracellular matrix, and destroy the structure and function of lung tissue. 12‐HETE, 12‐hydroxyeicosatetraenoic acid; AT2, type 2 alveolar epithelial cell; CXCR7, chemokine (C‐X‐C motif) receptor 7; CXCL4, platelet factor 4; ECM, extracellular matrix; Jag1, jagged canonical Notch ligand 1; SDF1, C‐X‐C motif chemokine ligand 12.