Building blocks for lung regeneration: Stem cells and niches

Abstract

The respiratory system is an essential organ that performs gas exchange through the blood circulation in mammals. Unlike other organs, the lungs are directly exposed to the external environment, including particulate matter, cigarette smoke, and various pollutants, and are therefore, highly susceptible to damage. The lungs retain regional-specific stem/progenitor cells that quickly mobilize to replace the damaged epithelium. Accumulating evidences suggest that fate decision of stem cells relies on regulatory programs integrated by niches constituting the microenvironment providing diverse signals that regulate stem cell behavior. Therefore, understanding cellular diversity and precise interaction between stem cells and their respective niches is crucial to understand how tissue recovers homeostasis after injury. Here, in this review, we summarize recent progress in cellular and functional identity of stem cells and distinctive niches in the lungs. We also describe the molecular mechanism of genetic and epigenetic program in the regulation of stem cell behavior during tissue regeneration. Lastly, we introduce the three-dimensional lung organoid platforms that provide valuable insights into the mechanisms of lung pathophysiology in human system.

Keywords: Alveolar regeneration; Lung organoids; Lung stem cells; Niches; Transitional cell states.

Fig. 1

Comparative epithelial cell composition and lineage differentiation potential in mouse and human lungs. (A) Schematic illustration depicting epithelial cell types across 4 anatomical regions—proximal airway, small airway, respiratory airway, and alveoli—in mouse and human lungs. Key differences include the presence of respiratory airway secretory cells (RASCs) and alveolar type 0 (AT0) cells in the distal airways of humans, and bronchioalveolar stem cells (BASCs) at the bronchioalveolar duct junction in mice. (B) Diagram summarizing epithelial lineage hierarchies based on developmental and injury-repair models. In the airways, basal cells serve as progenitors for multiple differentiated cell types. In the alveolar compartment, BASCs (in mice) and RASCs (in humans) give rise to AT2 cells, which further differentiate into alveolar type 1 AT1 cells. These lineage trajectories highlight fundamental species-specific differences in epithelial regeneration and plasticity.

Fig. 2

Cellular dynamics of stem cells and their niches during alveolar regeneration. (A) Schematic model of alveolar regeneration. Following injury, IL-1β from interstitial macrophages primes AT2 cells, leading to their transition into intermediate states such as damage-associated transient progenitors (DATPs), pre-alveolar type-1 transitional cells (PATS), or alveolar differentiation intermediates (ADIs). These transitional states are marked by loss of AT2 identity, upregulation of Krt8, Cldn4, and p53 target genes, and a shift toward a squamous morphology. In healthy regeneration, transitional cells resolve into mature AT1 cells. However, under chronic inflammatory conditions—such as pulmonary fibrosis or in lungs of patients with idiopathic pulmonary fibrosis (IPF)—Krt8+ transitional cells persist abnormally, potentially contributing to disease pathogenesis. (B) In the steady-state alveolus, alveolar type 2 (AT2) and type 1 (AT1) cells constitute the epithelial barrier, supported by diverse fibroblast populations and resident immune cells. Lipofibroblasts located beneath AT2 cells contribute to surfactant production through lipid metabolism. Alveolar and interstitial macrophages provide immune surveillance. The underlying vasculature consists of aerocyte (aCap) and general capillary (gCap) endothelial cells forming the alveolar-capillary barrier. (C) Summary of major epithelial, stromal, immune, and endothelial cell populations involved in alveolar homeostasis and regeneration, including transitional and injury-associated states. (D) Following injury, interstitial macrophages and infiltrating monocytes secrete IL-1β, triggering AT2 cells to enter a transitional state known as DATPs. Regulatory T cells (Tregs) contribute to epithelial regeneration through TGF-β and IL-13 signaling. CTHRC1+ myofibroblasts expand and participate in matrix remodeling. Alveolar macrophages, activated by interferon-gamma (IFN-γ), contribute to vascular remodeling. AT1 cells secrete VEGFA to maintain alveolar structure, while endothelial-derived MMP14 and BMP4 promote epithelial regeneration via NFATc1-dependent pathways. Proliferative gCap endothelial cells (ECs) and aCap-like ECs—emerging during injury with partial aCap identity—contribute to vascular reconstruction. Additionally, Ly6G+ macrophages secrete cytokines and chemokines that support tissue repair and inflammation resolution.

Fig. 3

Schematic overview of human lung organoid establishment and applications. (A) Adult human lung tissue is enzymatically dissociated to obtain a single-cell suspension. Epithelial stem/progenitor cells are subsequently isolated using fluorescence-activated (FACS) or magnetic-activated (MACS) cell sorting. These cells are embedded in extracellular matrix–based hydrogels and cultured under defined conditions to generate lung organoids. Depending on the cellular origin and culture conditions, the resulting organoids can differentiate into airway, bronchioalveolar, or alveolar subtypes. (B) Coculture systems allow investigation of interactions between epithelial cells and their surrounding niche, including stromal or immune cells, facilitating the study of cell-cell communication and microenvironmental influence. (C) Organoids serve as a model to explore lineage commitment and differentiation trajectories of lung stem and progenitor cells under homeostatic or injury-mimicking conditions. (D) Patient-derived lung organoids retain clinically relevant cellular and molecular characteristics, enabling disease modeling of genetic and acquired pulmonary disorders. (E) Organoids provide a physiologically relevant platform for preclinical drug screening and evaluation of therapeutic efficacy.