Abnormal respiratory progenitors in fibrotic lung injury

Abstract

Recent advances in single-cell RNA sequencing (scRNA-seq) and epithelium lineage labeling have yielded identification of multiple abnormal epithelial progenitor populations during alveolar type 2 (ATII) cell differentiation into alveolar type 1 (ATI) cells during regenerative lung post-fibrotic injury. These abnormal cells include basaloid/basal-like cells, ATII transition cells, and persistent epithelial progenitors (PEPs). These cells occurred and accumulated during the regeneration of distal airway and alveoli in response to both chronic and acute pulmonary injury. Among the alveolar epithelial progenitors, PEPs express a distinct Krt8+ phenotype that is rarely found in intact alveoli. However, post-injury, the Krt8+ phenotype is seen in dysplastic epithelial cells. Fully understanding the characteristics and functions of these newly found, injury-induced abnormal behavioral epithelial progenitors and the signaling pathways regulating their phenotype could potentially point the way to unique therapeutic targets for fibrosing lung diseases. This review summarizes recent advances in understanding these epithelial progenitors as they relate to uncovering regenerative mechanisms.

Hamsters are a model for post-COVID-19 alveolar regeneration mechanisms: an opportunity to understand post-acute sequelae of SARS-CoV-2

“…7 D ). The AT2-ADI-AT1 trajectory is regulated by different signaling pathways, including TGF beta -, notch - and wnt beta catenin signaling and involves the EMT process 19,44 . At 5 and 14 dpi, only a few cells with ADI signature showed high positive scores for TGF beta signaling ( Fig.…”

“…For instance, in vitro studies in primary murine cells revealed that a chronic activation of WNT/β-catenin signaling can induce senescence and CK8 expression in ADI cells 44,53 . In addition, persistent Notch activation in AT2 cells induces retarded differentiation of AT2 into AT1 cells, resulting in ADI cell accumulation in a Pseudomonas lung injury model 44,54 . Moreover, persistent TGF-β signaling has been shown to block ADI cells from differentiating into AT1 cells 20 .…”

“…In COVID-19 patients the most prominent airway progenitors supporting alveolar regeneration were reported to be CK5 + basal cell, which form the so-called “keratin 5 pods”. Basal cell expansion, also termed “pod”” is gradually recognized as common feature of epithelial remodeling ( 17,44 . To a lesser extent, more immature CK5 + p63 + basal cells were also reported to support alveolar regeneration in COVID-19 patients 37 .…”

“…It has been demonstrated, that ADI cells exit the cell cycle before their differentiation into AT1 cells. Thus, nuclear TP53 expression in the hamster ADI cells could be an indicator of this transient stage before differentiation and part of a physiologic process 19,21,44 . On the other hand, accumulation of TP53 is also detected in cells with high level of DNA damage.…”

Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis

“…In recent years, the advent of technologies such as single cell RNA sequencing (scRNASeq), spatial transcriptomics and advanced imaging has allowed to identify novel cell types of the lung and subpopulations, as well as transcriptional patterns and dynamics in healthy and diseased tissues. Multiple studies using single cell transcriptomics in combination with lineage tracing, lung injury models and organoid cultures have revealed that depending on the site of the damage (airway vs. alveoli) as well as the type and the extent of injury, different epithelial progenitor populations with the capacity to self-renew and differentiate into the epithelial lineages of the tissue respond to restore tissue homeostasis [ 67 , 69 , 72 , 73 ].…”