Stem cells and lung regeneration

Abstract

The ability to replace defective cells in an airway with cells that can engraft, integrate, and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.

Keywords: airway epithelium; basal cells; cell therapy; differentiation; pulmonary neuroendocrine cells.

Fig. 1.

Illustration of putative stem/progenitor cells and their niches in the adult murine lung. The lung can be divided into three major levels of conducting airways (the trachea, bronchi, and bronchioles) plus the gas-exchanging alveoli. Distinct region-specific stem/progenitor cell niches are thought to exist along the proximal-distal axis of the airway. These include the submucosal gland (SMG) ducts in the proximal trachea, basal cells within intercartilaginous zones of the trachea and primary bronchi, neuroepithelial bodies (NEBs) in the intralobar bronchi and bronchioles, and the bronchioalveolar duct junction (BADJ) and alveolar spaces within the alveoli. Progenitor/stem cells (marked in red and listed) reside in their respective local niches, and these environments enable them to maintain their stem/progenitor properties and control their ability to differentiate into various progeny cell types. BV, blood vessel; BASC, bronchioalveolar stem cell. [From Lynch et al. (117), reprinted by permission from Springer Nature.]

Fig. 2.

Illustration of basal stem cells and their putative differentiated progeny in the human lung. 1) Basal cells (BC) self-renew and are capable of giving rise to all cell types present on the surface airway epithelium through an intermediate BC precursor. 2) A subset of these BCs that display intracellular Notch commit to a secretory cell lineage while low-level c-myb expression in the same population will differentiate to preciliated and multiciliated cells (MCCs) subsequently. Other identified pathways that induce this lineage relationship include signal transducer and activator of transcription 3 (STAT3)/IL-6 or inhibitory miR-449. 3) club-like cells (CCs) share a common pathway with BCs when differentiating into MCCs but can also renew the MCCs through a goblet cell (GC) intermediate. Alveolar type II and bronchiolar cells are additional contributions from CCs. 4) If BCs are ablated, club-like cells (CCs) have been demonstrated to dedifferentiate to renew BCs. 5) BCs can also give rise to self-renewing neuroendocrine cells as well as brush cells and ionocytes. KRT, cytokeratin; ASCL1, achaete-scute homolog 1; CGRP, calcitonin gene-related peptide; FOX, forkhead box protein; CFTR, cystic fibrosis transmembrane conductance regulator; PGP9.5, protein gene product 9.5; RGS13, regulator of G protein signalling 13; SCGB1A1, secretoglobin family 1A member 1/club cell secretory protein/club cell 10 kDa protein secretory club cells; SP-C, surfactant protein C; MUC, mucin; TFCP2, transcription factor CP2; SSEA-1, stage specific embryonic antigen 1.

Fig. 3.

Schematic of the submucosal gland as a stem cell niche. The submucosal gland is a convoluted tubuloacinar structure beneath the surface airway epithelium beginning with an invagination that then undergoes a series of branching (dotted lines represent additional branches). Specific cells reside in the four identified domains, which are the ciliated ducts, collecting ducts, mucous tubules, and serous acini. Myoepithelial cells (MECs) are a population of self-renewing stem cells that produce glandular serous and mucous cells at steady state. Following severe airway surface injury, MECs express lymphoid enhancer factor (Lef-1) that promotes proliferation into ductal cells and migration to the surface to adopt a basal cell morphology. These cells have a lineage bias toward multiciliated cells and secretory goblet cells and are less likely to renew into secretoglobin family 1A member 1/club cell secretory protein/club cell 10 kDa protein (SCGB1A1⁺) secretory club cells.

Fig. 4.

Schematic of putative progenitors of the alveolar epithelium. Alveolar type II cells (AT2) cells secrete surfactants essential for alveolar function, such as surfactant protein C (pro-SP-C). During lung homeostasis, AT2 cells also function as self-renewing alveolar progenitor cells, in addition to differentiating into AT1 cells, which facilitate gas exchange. Renewal vs. differentiation is regulated by the bone morphogenetic protein (BMP) signaling pathway. In response to acute lung injury, airway epithelial progenitors [club-like cells, bronchioalveolar stem cells (BASCs), and distal airway stem cells (DASCs)] are capable of rapid proliferation and, in response to Wnt and FGF signaling, they can differentiate into AT1 and AT2 cells, respectively (10). Studies in mice suggest that airway club cells self-renew and generate ciliated cells and alveolar cells during homeostasis, whereas severe damage to lung epithelium triggers the expansion and differentiation of BASCs, which regenerates the pool of AT2 and club cells (17) SCGB1A1, secretoglobin family 1A member 1/club cell secretory protein/club cell 10 kDa protein secretory club cells; SSEA-1, stage specific embryonic antigen 1; Fgf, fibroblast growth factor; KRT, cytokeratin; SFTPC, surfactant protein C; TM4SF1, transmembrane 4L six family member 1; LAMP3, lysosomal-associated membrane protein 3; ABCA3, ATP-binding cassette subfamily A member 3; PDPN, podoplanin; HOPX, homeodomain-only protein; AGER, advanced glycosylation end product-specific receptor; AQP5, aquaporin 5.