Unlocking lung regeneration: insights into progenitor cell dynamics and metabolic control DOI Creative Commons

Jiaying Yang,

Yawen Li, Ying Huang

et al.

Cell Regeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Dec. 16, 2024

Abstract Regenerative responses are particularly important in the lungs, which critical for gas exchange and frequently challenged by environmental insults. The lung progenitor cells play a central role regeneration response, their dysfunction is associated with various diseases. Understanding mechanisms regulating cell function essential developing new therapeutic approaches to promote regeneration. This review summarizes recent advancements field of regeneration, focusing on metabolic control function. We discuss lineage plasticity cell–cell signaling under different physiological conditions. Additionally, we highlight connection between diseases, emphasizing need develop strategies regenerative medicine improve capacity.

Language: Английский

Lung repair and regeneration: Advanced models and insights into human disease DOI Creative Commons
Maria C. Basil, Konstantinos–Dionysios Alysandratos, Darrell N. Kotton

et al.

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(4), P. 439 - 454

Published: March 15, 2024

Language: Английский

Citations

16
A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease DOI Creative Commons
Kyungtae Lim,

Eimear N Rutherford,

Livia Delpiano

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: 44(3), P. 639 - 664

Published: Jan. 15, 2025

Alveolar type 2 (AT2) cells maintain lung health by acting as stem and producing pulmonary surfactant. AT2 dysfunction underlies many diseases, including interstitial disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung modeling dissection underlying mechanisms remain challenging due to complexities deriving maintaining human ex vivo. Here, we describe development mature, expandable organoids derived fetal lungs are phenotypically stable, can differentiate into AT1-like cells, genetically manipulable. We use these test key effectors SFTPC maturation identified a forward genetic screen E3 ligase ITCH, demonstrating that their depletion phenocopies pathological redistribution seen for SFTPC-I73T variant. In summary, demonstrate novel alveolar organoid model it identify necessary health.

Language: Английский

Citations

1
Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells DOI Creative Commons

I. A. Govorova,

Sofya Nikitochkina, Е. A. Vorotelyak

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 27, 2024

Abstract A cell is a dynamic system in which various processes occur simultaneously. In particular, intra- and intercellular signaling pathway crosstalk has significant impact on cell’s life cycle, differentiation, proliferation, growth, regeneration, and, consequently, the normal functioning of an entire organ. Hippo YAP/TAZ nucleocytoplasmic shuttling play pivotal role development, homeostasis, tissue particularly lung cells. Intersignaling communication core components localization. This review describes between key pathways (WNT, SHH, TGFβ, Notch, Rho, mTOR) using cells as example highlights remaining unanswered questions.

Language: Английский

Citations

7
Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells DOI Creative Commons
Yuko Ohnishi,

Atsushi Masui,

Takahiro Suezawa

et al.

Stem Cell Reports, Journal Year: 2024, Volume and Issue: 19(4), P. 529 - 544

Published: March 28, 2024

Alveolar type 2 (AT2) epithelial cells are tissue stem capable of differentiating into alveolar 1 (AT1) for injury repair and maintenance lung homeostasis. However, the factors involved in human AT2-to-AT1 cell differentiation not fully understood. Here, we established SFTPCGFP AGERmCherry-HiBiT dual-reporter induced pluripotent (iPSCs), which detected with high sensitivity identified inducing AT1 from AT2 their progenitor cells. We also an "on-gel" spheroid culture suitable medium-throughput screening. Among 274 chemical compounds, several single including LATS-IN-1, converted Moreover, YAP/TAZ signaling activation AKT suppression synergistically recapitulated induction transcriptomic, morphological, functionally mature Our findings provide novel insights development regenerative medicine.

Language: Английский

Citations

6
PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells DOI Creative Commons

Dennis Reininger,

Katrin Fundel‐Clemens, Christoph H. Mayr

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(23), P. 4766 - 4781

Published: Aug. 25, 2024

Background and Purpose The PDE4 family is considered a prime target for therapeutic intervention in several fibro‐inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), preferential PDE4B inhibitor. Experimental Approach In addition to clinically relevant parameters idiopathic pulmonary fibrosis (IPF; lung function measurement/high‐resolution computed tomography scan/AI‐Ashcroft score), whole‐lung homogenates from male Wistar rat model were analysed by next‐generation sequencing (NGS). Data matched with public domain data derived human IPF samples investigate how well reflected IPF. scored top counter‐regulated genes following treatment single cells validated disease markers discovered using disease‐relevant vitro assay Key Results Nerandomilast improved decline bleomycin‐treated animals. NGS study, most transcripts deregulated bleomycin normalised treatment. Most notably, significant number that identified also found animal reversed nerandomilast. Mapping single‐cell revealed strongest effects on mesenchymal, epithelial endothelial cell populations. primary culture system, disease‐related (bio)markers inhibited concentration‐dependent manner. Conclusions Implications This study further supports available knowledge about anti‐inflammatory/antifibrotic provides novel insights into mode action signalling pathways influenced fibrosis.

Language: Английский

Citations

5
Extracellular stiffness regulates site-specific lung development DOI Creative Commons

Zhiying Liao,

Junjie Lv,

Dong Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Extracellular matrix (ECM) stiffness plays a crucial role in regulating cell fate and maturation, but its influence on lung development is limited known. Here we utilized stiffness-tunable gelatin methacryloyl (GelMA) hydrogels to investigate how ECM influences site-specific stem cell-derived organoid model. We found increased promoted NKX2-1+ progenitor cells (LPCs) generation. In airway organoids (hAWOs), stiff directed proximal differentiation enriched with goblet, ciliated, basal cells; whereas the decreased favored emergence of secretory proximal-distal transition zone distal airway. alveolar (hALOs), enhanced AT2 AT1 transition. Moreover, infection assays Omicron BA.1.1 Delta variants recapitulated proximal-to-distal tropism SARS-CoV-2 lung. Transcriptomic sequencing revealed regulates via Hippo, TGF-β, HIF Wnt pathways. These findings advance mechanism understanding provide novel mechanical regulation for generating organoids.

Language: Английский

Citations

0
Cell therapy: A beacon of hope in the battle against pulmonary fibrosis DOI Open Access
Ruyan Wan, Yanli Liu,

Jingwen Yan

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 28, 2025

Abstract Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts pathological remodeling the extracellular matrix, with poor prognosis limited treatment options. Lung transplantation currently only approach that can extend life expectancy patients; however, its applicability severely restricted due to donor shortages patient‐specific limitations. Therefore, search for novel therapeutic strategies imperative. In recent years, stem cells have shown great promise in field regenerative medicine their self‐renewal capacity multidirectional differentiation potential, growing body literature supports efficacy cell therapy PF treatment. This paper systematically summarizes research progress various types PF. Furthermore, it discusses primary methods clinical outcomes PF, based on both preclinical data. Finally, current challenges key factors consider are objectively analyzed, future directions improving this proposed, providing new insights references patients.

Language: Английский

Citations

0
A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma DOI Creative Commons
Antonella F. M. Dost, Katarína Balážová,

Carla Pou Casellas

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Chronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the epithelium. Here, we describe a feeder- serum-free primary adult human organoid model investigate how influences regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an type 2 (AT2) maturation protocol enhances surfactant production supports tubular myelin formation. Introducing LATS inhibitor condition induces 1 (AT1) differentiation maintaining AT2 cells. Using this platform, find that interferon-gamma exerts cytotoxic effects on AT1 cells promoting growth regenerating illustrating single inflammatory stimulus can have divergent epithelial cell types. These findings underscore nuanced influence pro-inflammatory cytokines Our provides reductionist platform for mechanistic studies, aimed identify strategies enhance

Language: Английский

Citations

0
Biomaterial-based 3D human lung models replicate pathological characteristics of early pulmonary fibrosis DOI Creative Commons
Alicia E. Tanneberger, Rachel Blomberg,

Anton D. Kary

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by tissue scarring that disrupts gas exchange. Epithelial cell dysfunction, fibroblast activation, excessive extracellular matrix deposition drive this pathology ultimately leads to respiratory failure. Mechanistic studies have shown repeated injury alveolar epithelial cells initiates an aberrant wound-healing response in surrounding fibroblasts through secretion of mediators like transforming growth factor-β, yet the precise biological pathways contributing progression are not fully understood. To better study these interactions there critical need for models replicate cellular heterogeneity, geometry, biomechanics distal microenvironment. In study, induced pluripotent stem cell-derived type II (iATII) human were arranged micro-architecture embedded soft or stiff poly(ethylene glycol) norbornene (PEG-NB) hydrogels recapitulated mechanical properties healthy fibrotic tissue, respectively. The co-cultured then exposed pro-fibrotic biochemical cues, including inflammatory cytokines factors. iATIIs exhibited differentiation gene expression patterns consistent with trends observed during IPF vivo . A design experiments statistical analysis identified combined cue exposure as most effective condition modeling vitro Finally, treatment Nintedanib, one only two Food Drug Administration (FDA)-approved drugs IPF, was assessed. Treatment reduced indicated downregulation key activation genes, upregulated several genes. These findings demonstrate 3D co-culture hold tremendous potential advancing our understanding identifying novel therapeutic targets. Statement significance This leverages advanced biomaterials biofabrication techniques engineer physiologically relevant, patient-specific, sex-matched fibrosis, addressing pre-clinical drug screening platforms. successfully replicated features tissue. Tuning microenvironmental stiffness PEG-NB match values exposing iATII pro-inflammatory cues recreated hallmark characteristics pathogenesis, loss, well activation. utility further validated demonstrating responsiveness clinically available IPF. highlight transformative well-defined biomaterial-based elucidating complex mechanisms accelerating discovery chronic diseases idiopathic fibrosis. Graphical abstract

Language: Английский

Citations

0
Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis DOI

Mikael G. Pezet,

J Torres,

Tania A. Thimraj

et al.

Nature Biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

Citations

0