BCL-2 Modulates IRE1α Activation to Attenuate Endoplasmic Reticulum Stress and Pulmonary Fibrosis.

BCL-2 family members are known to be implicated in survival in numerous biological settings. Here, we provide evidence that in injury and repair processes in lungs, BCL-2 mainly acts to attenuate endoplasmic reticulum (ER) stress and limit extracellular matrix accumulation. Days after an intratracheal bleomycin challenge, mice lose a fraction of their alveolar type II epithelium from terminal ER stress driven by activation of the critical ER sensor and stress effector IRE1α.

Human distal airways contain a multipotent secretory cell that can regenerate alveoli.

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized.

Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5 basal cells.

Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF.

An inflammatory switch for stem cell plasticity.

Tissue resident stem cells are capable of remarkable plasticity in areas of tissue damage, where inflammatory cells accumulate as part of the reparative response. A study in the lung now provides critical insight on how inflammatory signals alter cell-to-cell Notch signaling within the airway niche to drive stem cell plasticity.

Gli1 mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung.

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been delineated in metaplasia. Here, we show that Gli1 mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5 basal cells.

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis.

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration.

The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future.

The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration. We focus on the cellular compositions within functional niches, cell-cell signaling in homeostatic health, the responses to injury, and new methods to study lung repair and regeneration.

VEGF Drives the Car toward Better Gas Exchange.

How lung epithelium and endothelium co-develop to maintain structural integrity of alveoli remains unclear. In this issue of Developmental Cell, Ellis et al. define how epithelial Vegfa directs development of a distinct endothelial cell population that ultimately plays a critical role in ensuring appropriate alveolar septation during alveologenesis.

Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration.

Lung injury activates specialized adult epithelial progenitors to regenerate the epithelium. Depending on the extent of injury, both remaining alveolar type II cells (AEC2s) and distal airway stem/progenitors mobilize to cover denuded alveoli and restore normal barriers. The major source of airway stem/progenitors other than basal-like cells remains uncertain.

PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer.

PTEN phosphorylation at its C-terminal (C-tail) serine/threonine cluster negatively regulates its tumor suppressor function. However, the consequence of such inhibition and its downstream effects in driving lung cancer remain unexplored. Herein, we ascertain the molecular mechanisms by which phosphorylation compromises PTEN function, contributing to lung cancer.

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by lung remodeling arising from epithelial injury, aberrant fibroblast growth, and excessive deposition of extracellular matrix. Repeated epithelial injury elicits abnormal wound repair and lung remodeling, often associated with alveolar collapse and edema, leading to focal hypoxia. Here, we demonstrate that hypoxia is a physiological insult that contributes to pulmonary fibrosis (PF) and define its molecular roles in profibrotic activation of lung epithelial cells.

Data on evolution of intrinsically disordered regions of the human kinome and contribution of FAK1 IDRs to cytoskeletal remodeling.

We present data on the evolution of intrinsically disordered regions (IDRs) taking into account the entire human protein kinome. The evolutionary data of the IDRs with respect to the kinase domains (KDs) and kinases as a whole protein (WP) are reported. Further, we have reported its post translational modifications of FAK1 IDRs and their contribution to the cytoskeletal remodeling.

Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling.

Therapeutic protein kinase inhibitors are designed on the basis of kinase structures. Here, we define intrinsically disordered regions (IDRs) in structurally hybrid kinases. We reveal that 65% of kinases have an IDR adjacent to their kinase domain (KD).

Presence and utility of intrinsically disordered regions in kinases.

Since aberrant cell signaling pathways underlie majority of pathophysiological morbidities, kinase inhibitors are routinely used for pharmacotherapy. However, most kinase inhibitors suffer from adverse off-target effects. Inhibition of one kinase in a pathogenic signaling pathway elicits multiple compensatory feedback signaling loops, reinforcing the pathway rather than inhibiting it, leading to chemoresistance.

BMP4 sufficiency to induce choroid plexus epithelial fate from embryonic stem cell-derived neuroepithelial progenitors.

Choroid plexus epithelial cells (CPECs) have essential developmental and homeostatic roles related to the CSF and blood-CSF barrier they produce. Accordingly, CPEC dysfunction has been implicated in many neurological disorders, such as Alzheimer's disease, and transplant studies have provided proof-of-concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture.