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IJMSInternational Journal of Molecular Sciences
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30 September 2023

16 Pages

Transcriptional Regulation of Airway Epithelial Cell Differentiation: Insights into the Notch Pathway and Beyond

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Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain
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Int. J. Mol. Sci.2023, 24(19), 14789;https://doi.org/10.3390/ijms241914789
This article belongs to the Topic Stem Cell Differentiation and Applications
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Abstract

The airway epithelium is a critical component of the respiratory system, serving as a barrier against inhaled pathogens and toxins. It is composed of various cell types, each with specific functions essential to proper airway function. Chronic respiratory diseases can disrupt the cellular composition of the airway epithelium, leading to a decrease in multiciliated cells (MCCs) and an increase in secretory cells (SCs). Basal cells (BCs) have been identified as the primary stem cells in the airway epithelium, capable of self-renewal and differentiation into MCCs and SCs. This review emphasizes the role of transcription factors in the differentiation process from BCs to MCCs and SCs. Recent advancements in single-cell RNA sequencing (scRNAseq) techniques have provided insights into the cellular composition of the airway epithelium, revealing specialized and rare cell types, including neuroendocrine cells, tuft cells, and ionocytes. Understanding the cellular composition and differentiation processes within the airway epithelium is crucial for developing targeted therapies for respiratory diseases. Additionally, the maintenance of BC populations and the involvement of Notch signaling in BC self-renewal and differentiation are discussed. Further research in these areas could provide valuable insights into the mechanisms underlying airway epithelial homeostasis and disease pathogenesis.

1. Introduction

The airway epithelium plays a vital role in maintaining optimal respiratory function throughout the airway, from the trachea to the alveoli. It possesses innate immunological properties and acts as a barrier to eliminate inhaled pathogens and toxins, thereby preserving lung homeostasis [1,2]. This epithelium consists of various cell types, each contributing to specific functions essential to proper airway function [3].
Previous studies have established that basal cells (BCs) are the primary stem cells in the respiratory tract, possessing self-renewal capabilities and the capacity to differentiate into both multiciliated cells (MCCs) and secretory cells (SCs) [4]. However, chronic respiratory diseases can disrupt the mucociliary dynamics of the epithelium, leading to a decrease in the number of MCCs and an increase in the number of SCs [5,6]. Additionally, viral infections such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can produce an alteration in the normal regeneration of the respiratory epithelium, promoting the proliferation of basal cells [7,8].
The processes of MCC and SC differentiation require the activation of a transcriptional program that specifies cell fate. Among regulatory pathways, NOTCH signaling provides the differentiation of basal cells into secretory cells types, while its inhibition is required for the differentiation of multiciliated cells [9,10].
The generation of multiciliated cells involves a program in which two master transcription regulators participate, GMNC (geminin coiled-coil domain containing) and MCIDAS (multi-ciliate differentiation and DNA synthesis) associated cell cycle protein, under the inhibitory regulatory control of GEMININ and NOTCH [11,12,13]. Their induction of essential multiciliogenesis genes [e.g., TP73 (tumor protein 73), MYB (myeloblastosis), RFX (regulatory factor X) and FOXJ1 (forkhead box J1)] results in downstream centriole amplification and basal body docking. Additionally, ciliogenesis is also accompanied by the up-regulation of multiple axonemal dyneins and other motile cilia proteins [14,15,16,17,18,19].
Recent studies have revealed that the NOTCH pathway can switch on the HEY1 (Hairy/enhancer-of-split related with YRPW motif protein 1) transcriptor factor to repress the multiciliated cell gene expression program and acquire a secretory cell precursor identity [20]. Besides HEY1, the differentiation of SCs involves the contribution of several transcription factors, such as SAM-pointed-domain-containing Ets-like factor (SPDEF), FOXA2 (forkhead box A2), TTF-1 (thyroid transcription factor 1), FOXM1 (forkhead box M1), RUNX2 (RUNX family transcription factor), and Krüppel-Like Factors (KLF5 and KLF4), among others [21,22,23,24,25,26,27,28].
Several recent reviews have reported different issues about airway epithelium differentiation [7,29,30,31,32,33]. The present review will focus on providing an overview of airway epithelial differentiation pathways. Specifically, this review aims to emphasize the pivotal role of various transcription factors involved in the differentiation process from BCs to MCCs and SCs within the airway epithelium. Furthermore, we highlight the relevant role of the NOTCH pathway to determine epithelial cell fate.
Regarding the search strategy to perform this review, we searched PubMed, Scopus, Web of Science and Google Scholar using different keywords and the combinations of each of them. On the one hand, the criteria for study inclusion were (1) human and mice studies; (2) airway epithelial cells; (3) processes involved in airway epithelium differentiation; (4) experimental in vitro models of cell differentiation; (5) publication year from 2002 to 2023; (6) English language; (7) papers with available abstract. On the other hand, exclusion criteria were (1) studies in other species (e.g., zebrafish, xenopus); (2) studies in other cellular models (e.g., skin cells, renal cells); (3) studies focusing on epithelial cells’ development; (4) studies focusing on cancer cells and other respiratory pathology; (5) papers outside the topic.
Two reviewers (G.C.L. and D.A.B.) independently screened the articles for relevance based on titles and abstracts. Then, the full texts of the retrieved studies were evaluated by all the authors. The management and organization of the bibliographic sources were carried out using the computer program Mendeley (www.mendeley.com) (accessed on 10 July 2023). The extracted information and results were analyzed and summarized, and then they were included in this review.

2. Cellular Composition of the Airway Epithelium

At the cellular level, the epithelium of the mouse trachea and human airways primarily consists of BCs, MCCs, and SCs (main airway epithelial cells) (Figure 1) [4,34,35].
Recent advancements in single-cell RNA sequencing (scRNA-seq) techniques have provided valuable insights into the cellular composition of both the mouse and the human airway epithelium [36,37,38]. Consequently, data analysis from RNA-seq studies on airway epithelial tissue has unveiled the presence of specialized and/or rare cell types, such as neuroendocrine cells (NECs), brush cells or tuft cells, and ionocytes [39,40,41,42]. Furthermore, scRNA-seq techniques have identified additional intermediate cell populations, including deuterosomal cells and suprabasal or parabasal cells, in both human and mouse airway epithelia [4,29,43].
Figure 1. Airway epithelial differentiation pathways. The airway epithelium is mainly composed of MCCs, SCs, and BCs, as well as more rare cell types including ionocytes, NECs, tuft cells, and deuterosomal cells, according to recent human scRNAseq studies [29,44]. BCs have the capacity to self-renew and produce all epithelial cell types [33]. NOTCH pathway can regulate cell differentiation processes, where up- and downward red arrows indicate stimulation and suppression, respectively. Self-renewal basal cells are independent of NOTCH, while the activation of NOTCH signaling will determine epithelial cell fate toward secretory (club and goblet) or ciliated cells, for which the level of NOTCH2 signaling is decisive [9]. Club cells can undergo trans-differentiation into ciliated cells, through NOTCH 1/2 pathway inhibition. For each cell (sub)type, its function and the most important cellular markers are indicated. TP63, KRT5, KRT6C, KRT14 and KRT15 are basal cell markers, while supra-basal cells are distinguished by the expression of KRT4, KRT13, KRT16 and KRT23. The deuterosomal cells express CDC20B, CCNO, FOXN4, and DEUP1, and mature ciliated cells are distinguished by the expression of FOXJ1, MYB, RFX2/3, and TP73. Club cells are characterized by the expression of SCGB1A1, and SCGB3A2, and mature goblet cells express SPDEF, MUC5B, and MUC5AC. Supra-basal cells can also differentiate into ionocytes (FOXI1+ and CFTR+), NECs (PSMD5 and NGF), or tuft cells (POUF2F2+ and TRPM5+). Tuft cells in turn can differentiate either to ionocytes or to neuroendocrine cells. While NOTCH signaling seems to be involved in ionocytes’ and tuft cells’ differentiation, it is still unclear (?) which signaling pathways are involved in NECs’ lineage. Moreover, “Hillocks” TP63+/KRT13+ basal cells give rise to SCGB1A1+/KRT13+ club cells [9]. Created with BioRender.com (accessed on 10 July 2023).

2.1. Main Airway Epithelial Cells

In this subsection, the three main airway epithelium cells (BCs, SCs and MCCs) are described in detail.
Firstly, as outlined above, BCs reside in the airway epithelium. They comprise approximately 30% of the airway epithelium and are anchored to the basal lamina through desmosomes [10,45,46,47,48]. Extensive research has demonstrated that BCs serve as the primary stem cells, with remarkable regenerative potential for the airway epithelium, acting as precursors for specialized cell types [4,39,41,47,49].
Molecularly, BCs are characterized by the expression of transformation-related protein P63 (TP63), as well as cytoskeletal proteins Keratin 5 (KRT5), KRT6C, KRT14, and KRT15 [45,47,50] (Figure 1). TP63, a member of the p53 family of transcription factors, plays a crucial role in BC development. Studies using mutant mice lacking this protein have shown an absence of BCs in the pseudostratified epithelium of the trachea [51,52].
Within the BC population, there are parabasal or suprabasal cells that have detached from the basal lamina to contribute to cell renewal [10]. Previous investigations have confirmed that the transition from basal to suprabasal cells is driven by the endogenous activation of NOTCH3 signaling in murine tracheal and proximal airways (e.g., [43]) (Figure 1). Suprabasal cells are characterized by the expression of KRT4, KRT13, KRT16, and KRT23, and they exhibit lower levels of p63 compared to BCs [29] (Figure 1). These intermediate cells have the potential to differentiate into MCCs, into SCs, or directly into tuft cells [4,10,43,49].
Another group of relevant epithelial cells are SCs, which are interspersed among other cell types in the airway epithelium and play a crucial role in secreting mucus into the respiratory tract lumen, facilitating the trapping of suspended particles [53]. As depicted in Figure 1, SCs encompass a heterogeneous population, including club cells (previously known as Clara cells) and goblet cells [53]. Club cells, which have been extensively studied, exhibit mature states characterized by the presence of the secretoglobins SCGB1A1 and SCGB3A2 [54]. Goblet cells, on the other hand, are molecularly identified through the expression of mucin 5AC (MUC5AC), mucin 5B (MUC5B), and SPDEF [55].
Finally, the third type of main cells of the respiratory epithelium are MCCs. They are specialized airway epithelial cells characterized by the presence of multiple motile cilia on their apical surface. These cells play a crucial role in facilitating the movement of mucus that coats the epithelium, which aids in trapping particles and pathogens [56,57]. Consequently, dysfunction in MCCs can lead to recurrent respiratory infections [58]. As depicted in Figure 1, several molecular markers associated with MCC cells, such as FOXJ1, RFX2, RFX3, MYB, and p73, are instrumental in regulating the expression of numerous proteins involved in MCC differentiation [32].

2.2. Intermediate and Specialized and/or Rare Cell Types

Recent studies (e.g., [59]) have identified a population of cells called deuterosomal cells inside the cellular composition and the hierarchy of the airway epithelium, through scRNA-seq, which represent a transitional state during MCCs differentiation (Figure 1). Deuterosomal cells exhibit an intermediate phenotype between SCs and mature MCCs. These cells express specific markers such as CDC20B (cell division cycle 20 homolog B) and DEUP-1 (deuterosome assembly protein 1), which are involved in centriole amplification and the organization of apical microtubules required for cilia formation [12,31].
Additionally, deuterosomal cells [60] also express FOXJ1 but display distinct marker expression compared to mature MCCs, including FOXN4 (Forkhead Box N4), CDC20B, DEUP1, and CCNO (cyclin-O) [60,61]. This intermediate cell type has been observed in both human and mouse airway epithelia [59,60]. Furthermore, CCNO, a member of the cyclin protein family required for cell cycle progression, is involved in the early stages of deuterosome-mediated centriole formation [31]. The expression of both CDC20B and CCNO is regulated by MCIDAS (Multicilin (MCI) and IDAS, encoded by MCIDAS), a key regulator of multiciliogenesis [60,62].
Figure 1 also illustrates the presence of tuft cells (also known as Brush cells), which are specialized and/or rare cell types and are involved in immune responses. These cells are characterized by the expression of common markers such as transient receptor potential cation channel subfamily M member 5 (TRPM5) and POU domain class 2 homeobox 3 (POU2F3) [4,63]. The transcription factor POU2F3 plays a crucial role in the formation and differentiation of tuft cells [63]. Additionally, Bukowy-Bieryllo et al. (2022) [29] suggest that tuft cells may serve as progenitors for NECs and ionocytes (as depicted in Figure 1). However, it must be noted that NECs and pulmonary ionocytes can also directly differentiate from BCs through NOTCH signaling [39,41,64].
In regards to the NECs, they constitute approximately 0.5% of all epithelial cells in human airways and express markers such as PSMD5 (Proteasome 26S Subunit, Non-ATPase 5) and NGF (Nerve Growth Factor) [29,65,66]. These innervated epithelial-resident cells play a role in sensing airway activity and secreting neuropeptides to stimulate immune responses [30]. NECs contribute to immune modulation through chemical secretion and are molecularly characterized by the expression of Chromogranin A (CHGA) and calcitonin gene-related peptide (CGRP) [2,4,35,55]. Similar to basal and club cells, a subset of NECs can undergo reprogramming in response to epithelial damage, assuming alternative cell fates and serving as stem cells to facilitate tissue repair [66,67].
As for pulmonary ionocytes, these cells exhibit high expression levels of FOXI1 and cystic fibrosis transmembrane conductance regulator (CFTR), suggesting their involvement in the regulation of airway surface liquid (as depicted in Figure 1). The CFTR gene encodes a critical chloride channel that is frequently mutated in cystic fibrosis pathology [35,41].
Lastly, Montoro et al. (2018) [39] discovered a novel population of basal progenitor cells, referred to as Hillock basal cells, which express both TP63 and KRT13 (as shown in Figure 1). These Hillock basal cells are known to differentiate into Hillock club cells, exhibiting elevated levels of markers such as Scgb1ab1+ and KRT13+. Although Hillock club cells display high turnover rates, their precise physiological role remains relatively unexplored [39].
Therefore, BCs are the major stem cells of the respiratory tract with the ability to differentiate into ciliated cells, club cells, tuft cells, neuroendocrine cells, and pulmonary ionocytes. For this reason, we will focus this work on reviewing the basal stem cell population maintenance, including both MCC and SC differentiation programs.

3. Basal Stem Cells’ Population Maintenance

As previously indicated, BCs play a crucial role in the development of mammalian airway epithelium, as they possess the ability to self-renew and give rise to all epithelial cell types [33]. NOTCH signaling is highly conserved and plays a relevant role as master regulator of various biological functions. While NOTCH signaling has been implicated in the differentiation of adult airway BCs, their self-renewal appears to be independent of NOTCH [9,10,68]. In addition, Garrido-Jimenez at al. (2021) [69] reported that p53 protein contributes to the self-renewal and differentiation of basal stem cells in mouse and human airway epithelium.

3.1. NOTCH Signaling in Airway Epithelium

The mammalian NOTCH family consists of four receptors (NOTCH1-4) and five ligands (delta-like ligand (DLL) 1, 3, 4, and jagged (JAG) 1 and 2) [70]. Human bronchial epithelial cells express all four NOTCH receptors and all NOTCH ligands, with the exception of DLL3 [71].
Several studies provide ample evidence that NOTCH3 signaling is involved in the generation of parabasal cells, which subsequently differentiate into secretory or ciliated cells through the activation of the NOTCH1 and NOTCH2 pathways [43,72]. Furthermore, the suppression of NOTCH1–NOTCH2 signaling leads to the expansion of MCCs, while the activation of NOTCH signaling determines the fate of lung epithelial cells towards secretory lineages such as club and goblet cells [32,43,71,72]. Recently, the up-regulation of NOTCH signaling was observed in SARS-CoV-2-infected cells [8]. In cells directly infected by SARS-CoV-2, the NOTCH pathway might promote viral entry, and in addition, excessive NOTCH signaling may promote interleukin 6 (IL-6) and inflammatory pathways that can exacerbate the morbidity and severity of COVID-19 [7].
It must be pointed out that NOTCH2 plays a more central role than NOTCH1 in determining the Clara/ciliated cell fate [9]. Additionally, studies have shown that secretory progenitor cells (club cells) can undergo trans-differentiation into ciliated cells, a process involving NOTCH1–NOTCH2 pathway inhibition [31,33,73]. Rock et al. (2011) [10] demonstrated that BC differentiation in the airways relies on NOTCH signaling, as the inhibition of NOTCH signaling using the gamma-secretase inhibitor DBZ resulted in the absence of intermediate cells responsible for generating ciliated and secretory lineages, leaving only TRP63+ BCs in a pseudostratified epithelium.

3.2. p53 Function in BCs' Homeostasis and Differentiation

Recent studies conducted in mouse tracheal epithelial cell culture and human bronchial epithelial cells have highlighted the significance of regulating p53 protein levels in maintaining the self-renewal, differentiation competence, and homeostasis of BCs [69]. In addition, the MDM2/p53 interaction is involved in the regulation of p53 protein levels during BC differentiation, and the disruption of this interaction leads to defects in cell differentiation and alterations in cilia formation [69].

6. Conclusions and Remarks

Several key conclusions and remarks can be made regarding the differentiation programs of BCs and the formation of MCCs and SCs in the airway epithelium.
BCs are crucial for airway development and possess self-renewal capabilities, which are independent of NOTCH signaling. NOTCH signaling, however, plays a role in the differentiation of adult airway BCs. Different NOTCH receptors and ligands are expressed in human bronchial epithelial cells and determine whether lung epithelial cells develop into secretory or ciliated lineages. MCC differentiation can occur through NOTCH signaling inhibition in BCs or the trans-differentiation of SCs.
Specific transcription factors collaborate to regulate the MCC differentiation process, which involves basal body biogenesis, migration, the docking of basal bodies, and the generation of motile cilia. SCs can differentiate from BCs, and NOTCH signaling is involved in generating multipotent suprabasal cells that can further differentiate into secretory or ciliated cells. NOTCH ligands are necessary for this differentiation process. And once again, additional transcription factors are involved in the regulation of gene expression and overall differentiation processes, highlighting the complexity that requires further research to fully understand the differentiation process from BCs.

7. Future Directions

There are several potential future directions for research on the differentiation programs of BCs and the formation of MCCs and SCs in the airway epithelium. Further investigation is needed to understand the precise mechanisms of NOTCH signaling in the differentiation of BCs and their subsequent fate toward secretory or ciliated lineages. This could involve studying the specific interactions between different NOTCH receptors, ligands, and downstream effectors in regulating cell fate determination.
Also, further research can focus on unraveling the complex transcriptional networks involving these factors and identifying additional transcriptional regulators involved in these processes, for example, investigating BC heterogeneity. BCs have been identified as a key cell population involved in airway development and repair. However, it is important to explore the heterogeneity within the BC population and understand whether distinct subpopulations contribute differentially to MCC and SC differentiation.
These studies could also investigate how environmental factors, such as air pollutants or microbial exposures, influence the differentiation programs of BCs and how the formation of MCCs and SCs could provide important insights into respiratory health and disease. Additionally, exploring epigenetic modifications that regulate gene expression during differentiation processes may uncover new mechanisms and potential therapeutic targets.
Overall, further research in these directions will enhance our understanding of the complex differentiation programs in the airway epithelium and may have implications for the development of therapies targeting respiratory diseases and conditions.

Author Contributions

Conceptualization, G.C.-L. and D.A.B.; methodology, G.C.-L. and D.A.B.; software, G.C.-L. and D.A.B.; validation, G.C.-L., D.A.B., S.M.-N. and J.M.C.-G.; formal analysis, G.C.-L. and D.A.B.; investigation, G.C.-L. and D.A.B.; resources, G.C.-L. and D.A.B.; data curation, G.C.-L. and D.A.B.; writing—original draft preparation, G.C.-L., D.A.B., S.M.-N. and J.M.C.-G.; writing—review and editing, G.C.-L., D.A.B., S.M.-N. and J.M.C.-G.; visualization, G.C.-L., D.A.B., S.M.-N. and J.M.C.-G.; supervision, S.M.-N. and J.M.C.-G.; project administration, J.M.C.-G.; funding acquisition, J.M.C.-G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by BFU2017-85547-P, TED2021-130560B-I00 and PID2021-126905NB-I00 grants from the Ministry of Economy, IB18014 from Junta de Extremadura to J.M.C.-G. and GR21140 from Junta de Extremadura to S.M.-N. All Spanish funding is co-sponsored by the European Union FEDER program.

Conflicts of Interest

The authors declare no conflict of interest.

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