Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair

Abstract

SUMMARY Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ~95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa -induced acute lung injury in mice, that non-canonical Notch ligand Dlk1 (delta-like 1 homolog) is essential for AT2-to-AT1 differentiation. Notch signaling was activated in AT2 at the onset of repair but later suppressed by Dlk1. Deletion of Dlk1 in AT2 induced persistent Notch activation, resulting in stalled transition to AT1 and accumulation of an intermediate cell population that expressed low levels of both AT1 and AT2 markers. Thus, Dlk1 expression leads to precisely timed inhibition of Notch signaling and activates AT2-to-AT1 differentiation, leading to alveolar repair.

TAZ is required for lung alveolar epithelial cell differentiation after injury

“…Similar to our findings, that study showed that inadequate alveolar repair after acute injury contributed to increased fibrogenesis; in contrast to our findings, alveolar repair in the S pneumoniae model was dependent on both YAP and TAZ expression. Another recent study using a Pseudomonas aeruginosa acute infection model suggested a role for Dlk-1 in downregulating Notch signaling to promote AEC2-AEC1 differentiation (41). Thus, multiple developmental pathways, including Wnt, Hippo, and Notch, work together to mediate tissue repair after alveolar injury.…”

Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair

“…To study the mechanisms of alveolar repair, we used a mouse lung injury model generated by intratracheal injection (i.t.) of PA (Liu et al, 2011;Sadikot et al, 2006), which is characterized by severe inflammation and alveolar damage 24 to 48 h postinjury and AT2-mediated repair 3-7 days post-injury (Finn et al, 2019;Liu et al, 2015). Based on our previously described endothelial barrier reparative properties of S1P (Natarajan et al, 2013;Tauseef et al, 2008), we further tested the role of S1P as an angiocrine mediator of alveolar epithelial repair in the PA model.…”

Notch Transduction in Non-Small Cell Lung Cancer

“…Noticeably, this latter work also disclosed that unlike Notch1 or Notch3, which displayed increased levels, Notch2 was decreased in advanced tumors in the Kras G12D NSCLC model, where it furthermore displayed a tumor suppressor function through modulation of the Wnt/β-catenin pathway [82]. Notch2 is the predominant receptor activated in AT2 cells and is required for their proliferation and maturation [7], and absence of the Wnt-downstream target Dlk1 (delta-like 1 homolog)-which also participates in lung development and inhibits endogenous Notch signaling-in AT2 cells during AT2 to AT1 repair-induced transition causes Notch activity upregulation and results in a stalled differentiation of AT2 to AT1 cells as well as in accumulation of an intermediate cell type [83]. While the observations above are discernibly contrasting in regard to an oncogenic role for Notch2 in NSCLC initiation and progression, the inductive exertion of transition states in AT2 cells [83] and its implication in EMT [79], as well as its predominant function in AT2 cell maturation and differentiation [7], and the fact that AT2 cells have been shown to functionally serve as cells-of-origin of NSCLC [63,84] (Figure 2), strongly warrants further exploration into the cell-specific, gain-and loss-of-function effects of this receptor in postnatal lung function and oncogenesis.…”