FGF2 promotes the expansion of parietal mesothelial progenitor pools and inhibits BMP4-mediated smooth muscle cell differentiation

Our plain-English summary of FGF2 promotes the expansion of parietal mesothelial progenitor pools and inhibits BMP4-mediated smooth muscle cell differentiation, by Y. Hwang, Y. Shimamura, J. Tanaka, et al (Frontiers in Cell and Developmental Biology, 2024).

The study

• Authors: Y. Hwang, Y. Shimamura, J. Tanaka, A. Miura, A. Sawada, H. Sarmah, D. Shimizu, Y. Kondo, H. Lee, F. Martini, Z. Ninish, K.S. Yan, K. Yamada, M. Mori
• Journal: Frontiers in Cell and Developmental Biology
• Published: 2024;12:1387237
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelial cells, in the outermost layer of internal organs, are essential for both organ development and homeostasis. Although the parietal mesothelial cell is the primary origin of mesothelioma that may highjack developmental signaling, the signaling pathways that orchestrate developing parietal mesothelial progenitor cell (MPC) behaviors, such as MPC pool expansion, maturation, and differentiation, are poorly understood. To address it, we established a robust protocol for culturing WT1+ MPCs isolated from developing pig and mouse parietal thorax. Quantitative qPCR and immunostaining analyses revealed that BMP4 facilitated MPC differentiation into smooth muscle cells (SMCs). In contrast, FGF2 significantly promoted MPC progenitor pool expansion but blocked the SMC differentiation. BMP4 and FGF2 counterbalanced these effects, but FGF2 had the dominant impact in the long-term culture. A Wnt activator, CHIR99021, was pivotal in MPC maturation to CALB2+ mesothelial cells, while BMP4 or FGF2 was limited. Our results demonstrated central pathways critical for mesothelial cell behaviors.

Copyright © 2024 Hwang, Shimamura, Tanaka, Miura, Sawada, Sarmah, Shimizu, Kondo, Lee, Martini, Ninish, Yan, Yamada and Mori.

In plain English

This was a laboratory study of cells. It involved no asbestos exposure or human participants, though the authors reanalyzed published single-cell data from developing human and mouse lungs. The authors noted that mesothelioma tends to arise from parietal mesothelial cells, which line the chest wall. They studied which growth signals control immature (progenitor) and mature forms of these cells. They developed a method to grow these cells from the chest walls of fetal Yucatan miniature pigs (embryonic day 80) and fetal mice (day 17.5). They then treated the pig cells with growth factors. In long-term culture, FGF2 kept the progenitor marker WT1 at more than 5 times its level in untreated cells. After 3 days, BMP4 raised the share of cells with the smooth muscle marker α-SMA from 7.8% to 31.4%; FGF2 and PDGF-BB lowered it to 2.5% and 3.2%. FGF2 countered BMP4's effect. A Wnt activator, CHIR99021, gave the largest rise in the maturity marker CALB2. The authors concluded the results showed central pathways for mesothelial cell behavior. Their suggestion about targeting FGF2 in mesothelioma was untested speculation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture study using cells isolated from pig and mouse fetuses, plus reanalysis of previously published single-cell RNA-seq data from developing human and mouse lungs; not an asbestos exposure study and no human participants
• Who was studied: Parietal mesothelial progenitor cells taken from the chest walls of embryonic day 80 Yucatan miniature pig fetuses, and from embryonic day 17.5 mouse fetuses (CD-1 and WT1 lineage-tracing mice); work done at Columbia University
• Exposure: No asbestos exposure. Cells were treated with growth factors and small molecules: FGF2 (20 ng/mL), PDGF-BB (15 ng/mL), BMP4 (50 ng/mL) and CHIR99021 (3 uM), plus inhibitors, for 3, 10 or 14 days
• Main results:
  • In pig cells grown on gelatin-coated dishes, 76.7% were WT1+ progenitor cells and 7.5% were α-SMA+ cells
  • In short-term (3-day) pig cell culture, FGF2 and PDGF-BB each produced a more than four-fold increase in the proportion of proliferating Ki67+WT1+ progenitor cells compared with control
  • In long-term pig cell culture, FGF2 kept WT1 mRNA expression more than 5-fold above control, while PDGF-BB did not significantly change WT1 mRNA over time
  • BMP4 increased the proportion of α-SMA+ (smooth muscle marker) pig cells from 7.8% plus or minus 1.7% in controls to 31.4% plus or minus 1.4%; the BMP inhibitor dorsomorphin reduced it to 6.7% plus or minus 3.0%
  • FGF2 and PDGF-BB reduced the proportion of α-SMA+ pig cells (control 7.8%, FGF2 2.5%, PDGF-BB 3.2%)
  • Combining FGF2 or PDGF-BB with BMP4 lowered α-SMA mRNA expression compared with BMP4 alone
  • The Wnt activator CHIR99021 gave the largest increase in CALB2 mRNA (a maturity marker); long-term CHIR treatment lost WT1+ progenitor pools but relatively sustained CALB2 expression
  • The authors reanalyzed previously published single-cell RNA-seq data from developing human and mouse lung tissue to look for maturation markers shared across species
• The authors' conclusion: The authors concluded that their results demonstrated central pathways critical for mesothelial cell behaviors. In the discussion they speculated, without testing it, that targeting FGF2 and its downstream signals may be critical for controlling FGF2-high mesothelioma.
• Limitations the authors state:
  • The authors could not expand cells from embryonic day 40 or earlier, so the work focused on day-80 chest wall cells
  • Harvesting progenitor cells only from the lungs was difficult because the cultures contained various other cell types
  • In the WT1 lineage-tracing mice, fewer than 1% of cells were WT1+ after sorting, making expansion difficult; further optimization is required
  • MSLN protein was not detected in developing lungs and thorax with three different antibodies, which was inconsistent with the RNA data

Topics

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, Mesothelioma, Thorax.

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