Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure
Abstract Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse...
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Nature Portfolio
2024-03-01
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| Online Access: | https://doi.org/10.1038/s41598-024-56547-8 |
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| author | Anchal Chauhan Siddhartha Gangopadhyay Kavita Koshta Sukhveer Singh Dhirendra Singh Vikas Srivastava |
| author_facet | Anchal Chauhan Siddhartha Gangopadhyay Kavita Koshta Sukhveer Singh Dhirendra Singh Vikas Srivastava |
| author_sort | Anchal Chauhan |
| collection | DOAJ |
| description | Abstract Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse offspring. In the present work, we have examined the role of As-conditioned dermal fibroblasts (DFs) in creating pro-tumorigenic niches for Keratinocyte stem cells (KSCs) in the offspring. DFs isolated from prenatally exposed animals showed increased levels of activation markers (α-SMA, Fibronectin, Collagen IV), induction of ten-eleven translocation methylcytosine dioxygenase 1(TET1), and secreted high levels of niche modifying IL-6. This led to enhanced proliferation, migration, and survival of KSCs. Increased IL-6 production in As-conditioned fibroblast was driven through TET1 mediated 5-mC to 5-hmC conversion at -698/-526 and -856/-679 region on its promoter. IL-6 further acted through downstream activation of JAK2-STAT3 signaling, promoting epithelial-to-mesenchymal transition (EMT) in KSCs. Inhibition of pSTAT3 induced by IL-6 reduced the EMT process in KSCs resulting in a significant decrease in their proliferation, migration, and colony formation. Our results indicate that IL-6 produced by prenatally conditioned fibroblasts plays a major role in regulating the KSC niche and promoting skin tumor development in As-exposed offspring. |
| first_indexed | 2024-04-24T19:57:19Z |
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| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T19:57:19Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-a34400a200d5412c81981c85924860f12024-03-24T12:17:48ZengNature PortfolioScientific Reports2045-23222024-03-0114111510.1038/s41598-024-56547-8Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposureAnchal Chauhan0Siddhartha Gangopadhyay1Kavita Koshta2Sukhveer Singh3Dhirendra Singh4Vikas Srivastava5Academy of Scientific and Innovative ResearchAcademy of Scientific and Innovative ResearchAcademy of Scientific and Innovative ResearchAcademy of Scientific and Innovative ResearchAnimal Facility, CSIR-Indian Institute of Toxicology Research (CSIR-IITR)Academy of Scientific and Innovative ResearchAbstract Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse offspring. In the present work, we have examined the role of As-conditioned dermal fibroblasts (DFs) in creating pro-tumorigenic niches for Keratinocyte stem cells (KSCs) in the offspring. DFs isolated from prenatally exposed animals showed increased levels of activation markers (α-SMA, Fibronectin, Collagen IV), induction of ten-eleven translocation methylcytosine dioxygenase 1(TET1), and secreted high levels of niche modifying IL-6. This led to enhanced proliferation, migration, and survival of KSCs. Increased IL-6 production in As-conditioned fibroblast was driven through TET1 mediated 5-mC to 5-hmC conversion at -698/-526 and -856/-679 region on its promoter. IL-6 further acted through downstream activation of JAK2-STAT3 signaling, promoting epithelial-to-mesenchymal transition (EMT) in KSCs. Inhibition of pSTAT3 induced by IL-6 reduced the EMT process in KSCs resulting in a significant decrease in their proliferation, migration, and colony formation. Our results indicate that IL-6 produced by prenatally conditioned fibroblasts plays a major role in regulating the KSC niche and promoting skin tumor development in As-exposed offspring.https://doi.org/10.1038/s41598-024-56547-8Inorganic asPrenatal exposureFibroblast activationIL-6EMTStem cell niche |
| spellingShingle | Anchal Chauhan Siddhartha Gangopadhyay Kavita Koshta Sukhveer Singh Dhirendra Singh Vikas Srivastava Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure Scientific Reports Inorganic as Prenatal exposure Fibroblast activation IL-6 EMT Stem cell niche |
| title | Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| title_full | Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| title_fullStr | Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| title_full_unstemmed | Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| title_short | Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| title_sort | activated fibroblasts modify keratinocyte stem niche through tet1 and il 6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure |
| topic | Inorganic as Prenatal exposure Fibroblast activation IL-6 EMT Stem cell niche |
| url | https://doi.org/10.1038/s41598-024-56547-8 |
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