Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

Chiahsuan, Chin; Ranjithkumar, R.; Sanborn, Kristina; Fleming, Timothy P.; Wheatcroft, Stephen; Kearney, Mark T.; Tokman, Sofya; Walia, Rajat; Smith, Michael A.; Flint, David; Mohanakumar, Thalachallour; Bremner, Ross M.; Sureshbabu, Angara

doi:10.1016/j.xcrm.2023.100945

Cited by 22 publications

(13 citation statements)

References 63 publications

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“…Ager Cre was reported to label AT2 cells (15). A recent paper also showed the expression of IGFBP2 in AT2 cells (38).…”

Section: Discussionmentioning

confidence: 96%

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture

Shen,

Chen,

Liu

et al. 2023

Preprint

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Alveolar epithelial regeneration is critical for normal lung function and becomes dysregulated in disease. While alveolar type 2 (AT2) and club cells are known distal lung epithelial progenitors, determining if alveolar epithelial type 1 (AT1) cells also contribute to alveolar regeneration has been hampered by lack of highly specific mouse models labeling AT1 cells. To address this, the Gramd2CreERT2 transgenic strain was generated and crossed to RosamTmG mice. Extensive cellular characterization, including distal lung immunofluorescence and cytospin staining, confirmed that GRAMD2+ AT1 cells are highly enriched for green fluorescent protein (GFP). Interestingly, Gramd2CreERT2 GFP+ cells were able to form organoids in organoid co-culture with Mlg fibroblasts. Temporal scRNAseq revealed that Gramd2+ AT1 cells transition through numerous intermediate lung epithelial cell states including basal, secretory and AT2 cell in organoids while acquiring proliferative capacity. Our results indicate that Gramd2+ AT1 cells are highly plastic suggesting they may contribute to alveolar regeneration.

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“…Ager Cre was reported to label AT2 cells (15). A recent paper also showed the expression of IGFBP2 in AT2 cells (38).…”

Section: Discussionmentioning

confidence: 96%

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture

Shen,

Chen,

Liu

et al. 2023

Preprint

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“…Currently, the endotracheal route is the most common route of administration. [162][163][164][165] In mouse models, body weight-based dosing typically ranges from 1.25 to 4 U/kg. Regarding the frequency of administration, bleomycin can be administered either as a single dose or as repeated low doses.…”

Section: Bleomycin-induced Lung Injury Modelmentioning

confidence: 99%

“…The bleomycin‐induced mouse lung injury model has multiple modes of administration, such as intraperitoneal (ip), intravenous (iv), intratracheal (it), and subcutaneous. Currently, the endotracheal route is the most common route of administration 162–165 . In mouse models, body weight‐based dosing typically ranges from 1.25 to 4 U/kg.…”

Section: Research Models Of Lung Injury and Regenerationmentioning

confidence: 99%

Lung regeneration: diverse cell types and the therapeutic potential

Chen,

Li,

et al. 2024

MedComm

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Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

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“…Another soluble signaling factor of the SASP that plays a significant role in senescence and influences how it affects the microenvironment is the insulin‐like growth factor (IGF), which is one of the ligands in the IGF receptor network. The IGF‐binding protein (IGFBP) family, consisting of IGFBP 1−7 and their regulators IGFBP‐rP1 and IGFBP‐rP2 (also known as connective tissue growth factor), is aberrantly expressed and plays decisive roles in controlling cell senescence in a variety of cell types 54,160–163 . IGF signaling also influences proliferation, survival, and migration of epithelial cells, and its overexpression seems to play a role in the etiology of many cancers 164–166 .…”

Section: Morphological Features Of Senescence and Their Role In Tumor...mentioning

confidence: 99%

“…The IGF‐binding protein (IGFBP) family, consisting of IGFBP 1−7 and their regulators IGFBP‐rP1 and IGFBP‐rP2 (also known as connective tissue growth factor), is aberrantly expressed and plays decisive roles in controlling cell senescence in a variety of cell types. 54 , 160 , 161 , 162 , 163 IGF signaling also influences proliferation, survival, and migration of epithelial cells, and its overexpression seems to play a role in the etiology of many cancers. 164 , 165 , 166 In a recent observational analysis of 20 prospective studies with Mendelian randomization, IGF‐I was positively associated with higher risk of prostate cancer, with possibly earlier onset of disease of an overall more aggressive type.…”

Section: Morphological Features Of Senescence and Their Role In Tumor...mentioning

confidence: 99%

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

Jin,

Duan,

et al. 2024

MedComm

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Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor‐promoting effect of senescence is mainly elicited by a senescence‐associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A “one‐two‐punch” therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.

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Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

Cited by 22 publications

References 63 publications

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture

Lung regeneration: diverse cell types and the therapeutic potential

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

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Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

Cited by 22 publications

References 63 publications

GRAMD2+alveolar type I cell plasticity facilitates cell state transitions in organoid culture

GRAMD2+alveolar type I cell plasticity facilitates cell state transitions in organoid culture

Lung regeneration: diverse cell types and the therapeutic potential

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

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Product

Resources

About

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture

GRAMD2⁺alveolar type I cell plasticity facilitates cell state transitions in organoid culture