Anti-fibrogenic effect of umbilical cord-derived mesenchymal stem cell-conditioned media in human esophageal fibroblasts.


Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
27 Sep 2024
Historique:
received: 18 03 2024
accepted: 13 09 2024
medline: 28 9 2024
pubmed: 28 9 2024
entrez: 27 9 2024
Statut: epublish

Résumé

Esophageal fibrosis can develop due to caustic or radiation injuries. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are known to mitigate fibrosis in various organs. However, the potential effects of UC-MSCs on human esophageal fibrosis remain underexplored. This study investigated the anti-fibrogenic properties and mechanisms of UC-MSC-derived conditioned media (UC-MSC-CM) on human esophageal fibroblasts (HEFs). HEFs were treated with TGF-β1 and then cultured with UC-MSC-CM, and the expression levels of extracellular matrix (ECM) components, RhoA, myocardin related transcription factor A (MRTF-A), serum response factor (SRF), Yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ) were measured. UC-MSC-CM suppressed TGF-β1-induced fibrogenic activation in HEFs, as evidenced by the downregulation of ECM. UC-MSC-CM diminished the expression of RhoA, MRTF-A, and SRF triggered by TGF-β1. In TGF-β1-stimulated HEFs, UC-MSC-CM decreased the nuclear localization of MRTF-A and YAP. Additionally, UC-MSC-CM diminished the TGF-β1-induced nuclear expressions of YAP and TAZ, while concurrently enhancing the cytoplasmic presence of phosphorylated YAP. Furthermore, UC-MSC-CM reduced TGF-β1-induced phosphorylation of Smad2. These findings suggest that UC-MSC-CM may inhibit TGF-β1-induced fibrogenic activation in HEFs by targeting the Rho-mediated MRTF/SRF and YAP/TAZ pathways, as well as the Smad2 pathway. This indicates its potential as a stem cell therapy for esophageal fibrosis.

Identifiants

pubmed: 39333200
doi: 10.1038/s41598-024-73091-7
pii: 10.1038/s41598-024-73091-7
doi:

Substances chimiques

Culture Media, Conditioned 0
Transforming Growth Factor beta1 0
rhoA GTP-Binding Protein EC 3.6.5.2
Trans-Activators 0
Transcription Factors 0
MRTFA protein, human 0
YAP-Signaling Proteins 0
YAP1 protein, human 0
Serum Response Factor 0
Adaptor Proteins, Signal Transducing 0
Transcriptional Coactivator with PDZ-Binding Motif Proteins 0
WWTR1 protein, human 0
RHOA protein, human 124671-05-2
Smad2 Protein 0
SRF protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

22233

Informations de copyright

© 2024. The Author(s).

Références

Zhang, Y. et al. Mitomycin C inhibits esophageal fibrosis by regulating cell apoptosis and autophagy via lncRNA-ATB and miR-200b. Front. Mol. Biosci. 8, 675757. https://doi.org/10.3389/fmolb.2021.675757 (2021).
doi: 10.3389/fmolb.2021.675757
Mizushima, T. et al. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointest. Endosc. 86, 542–552e1. https://doi.org/10.1016/j.gie.2017.01.024 (2017).
doi: 10.1016/j.gie.2017.01.024
Biancheri, P. et al. The role of transforming growth factor (TGF)-beta in modulating the immune response and fibrogenesis in the gut. Cytokin Growth Factor Rev.25, 45–55. https://doi.org/10.1016/j.cytogfr.2013.11.001 (2014).
doi: 10.1016/j.cytogfr.2013.11.001
Derynck, R. & Zhang, Y. E. Smad-dependent and smad-independent pathways in TGF-beta family signalling. Nature425, 577–584. https://doi.org/10.1038/nature02006 (2003).
doi: 10.1038/nature02006
Mu, Y., Gudey, S. K. & Landström, M. Non-smad signaling pathways. Cell. Tissue Res.347, 11–20. https://doi.org/10.1007/s00441-011-1201-y (2012).
doi: 10.1007/s00441-011-1201-y
Koo, J. B. et al. Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts. BMC Gastroenterol.17, 73. https://doi.org/10.1186/s12876-017-0627-4 (2017).
doi: 10.1186/s12876-017-0627-4
Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol.308, L344–L357. https://doi.org/10.1152/ajplung.00300.2014 (2015).
doi: 10.1152/ajplung.00300.2014
Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol.63, 679–688. https://doi.org/10.1016/j.jhep.2015.04.011 (2015).
doi: 10.1016/j.jhep.2015.04.011
Martin, K. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat. Commun.7, 12502. https://doi.org/10.1038/ncomms12502 (2016).
doi: 10.1038/ncomms12502
Seo, E. et al. The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis. Sci. Rep.6, 31931. https://doi.org/10.1038/srep31931 (2016).
doi: 10.1038/srep31931
Szeto, S. G. et al. YAP/TAZ are mechanoregulators of TGF-β-Smad signaling and renal fibrogenesis. J. Am. Soc. Nephrol.27, 3117–3128. https://doi.org/10.1681/ASN.2015050499 (2016).
doi: 10.1681/ASN.2015050499
Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol. Rev.94, 1287–1312. https://doi.org/10.1152/physrev.00005.2014 (2014).
doi: 10.1152/physrev.00005.2014
Samadi, P., Saki, S., Manoochehri, H. & Sheykhhasan, M. Therapeutic applications of mesenchymal stem cells: a comprehensive review. Curr. Stem Cell. Res. Ther.16, 323–353. https://doi.org/10.2174/1574888X15666200914142709 (2021).
doi: 10.2174/1574888X15666200914142709
Yin, F., Wang, W. Y. & Jiang, W. H. Human umbilical cord mesenchymal stem cells ameliorate liver fibrosis in vitro and in vivo: from biological characteristics to therapeutic mechanisms. World J. Stem Cells11, 548–564. https://doi.org/10.4252/wjsc.v11.i8.548 (2019).
doi: 10.4252/wjsc.v11.i8.548
Musiał-Wysocka, A., Kot, M. & Majka, M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transpl.28, 801–812. https://doi.org/10.1177/0963689719837897 (2019).
doi: 10.1177/0963689719837897
Røsland, G. V. et al. Long-term cultures of bone marrow–derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res.69, 5331–5339. https://doi.org/10.1158/0008-5472.CAN-08-4630 (2009).
doi: 10.1158/0008-5472.CAN-08-4630
Walczak, P. et al. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke39, 1569–1574. https://doi.org/10.1161/STROKEAHA.107.502047 (2008).
doi: 10.1161/STROKEAHA.107.502047
Choi, Y. J. et al. Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A. Stem Cell. Res. Ther.10, 291. https://doi.org/10.1186/s13287-019-1385-8 (2019).
doi: 10.1186/s13287-019-1385-8
Hou, L. et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223–3p/NLRP3 axis. Ecotoxicol. Environ. Saf.251, 114537. https://doi.org/10.1016/j.ecoenv.2023.114537 (2023).
doi: 10.1016/j.ecoenv.2023.114537
Moodley, Y. et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am. J. Pathol.175, 303–313. https://doi.org/10.2353/ajpath.2009.080629 (2009).
doi: 10.2353/ajpath.2009.080629
Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell12, 2730–2741. https://doi.org/10.1091/mbc.12.9.2730 (2001).
doi: 10.1091/mbc.12.9.2730
An, S. Y. et al. Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology152, 1174–1186. https://doi.org/10.1053/j.gastro.2016.12.003 (2017).
doi: 10.1053/j.gastro.2016.12.003
Knipe, R. S., Tager, A. M. & Liao, J. K. The rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol. Rev.67, 103–117. https://doi.org/10.1124/pr.114.009381 (2015).
doi: 10.1124/pr.114.009381
Small, E. M. et al. Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ. Res.107, 294–304. https://doi.org/10.1161/CIRCRESAHA.110.223172 (2010).
doi: 10.1161/CIRCRESAHA.110.223172
Makita, R. et al. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am. J. Physiol. Ren. Physiol.294, F542–F553. https://doi.org/10.1152/ajprenal.00201.2007 (2008).
doi: 10.1152/ajprenal.00201.2007
Mitani, A. et al. Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. Am. J. Respir. Crit. Care Med.180, 326–338. https://doi.org/10.1164/rccm.200812-1827OC (2009).
doi: 10.1164/rccm.200812-1827OC
Attisano, L. & Wrana, J. L. Signal integration in TGF-β, WNT, and Hippo pathways. F1000Prime Rep. 5, 17 (2013).
Nakamura, R., Hiwatashi, N., Bing, R., Doyle, C. P. & Branski, R. C. Concurrent YAP/TAZ and SMAD signaling mediate vocal Fold fibrosis. Sci. Rep.11, 13484. https://doi.org/10.1038/s41598-021-92871-z (2021).
doi: 10.1038/s41598-021-92871-z
Varelas, X. et al. TAZ controls smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol.10, 837–848. https://doi.org/10.1038/ncb1748 (2008).
doi: 10.1038/ncb1748
Huh, H. D., Kim, D. H., Jeong, H. S. & Park, H. W. Regulation of TEAD transcription factors in cancer biology. Cells8, 600. https://doi.org/10.3390/cells8060600 (2019).
doi: 10.3390/cells8060600
Zhu, T. et al. YAP/TAZ affects the development of pulmonary fibrosis by regulating multiple signaling pathways. Mol. Cell. Biochem.475, 137–149. https://doi.org/10.1007/s11010-020-03866-9 (2020).
doi: 10.1007/s11010-020-03866-9
Small, E. M. The actin–MRTF–SRF gene regulatory axis and myofibroblast differentiation. J. Cardiovasc. Transl. Res.5, 794–804. https://doi.org/10.1007/s12265-012-9397-0 (2012).
doi: 10.1007/s12265-012-9397-0
Mishra, R., Zhu, L., Eckert, R. L. & Simonson, M. S. TGF-β-regulated collagen type I accumulation: role of src-based signals. Am. J. Physiol. Cell. Physiol.292, C1361–C1369. https://doi.org/10.1152/ajpcell.00370.2006 (2007).
doi: 10.1152/ajpcell.00370.2006
Kurose, H. Cardiac fibrosis and fibroblasts. Cells10, 1716. https://doi.org/10.3390/cells10071716
Mosaddad, S. A. et al. Response to mechanical cues by interplay of YAP/TAZ transcription factors and key mechanical checkpoints of the cell: a comprehensive review. Cell. Physiol. Biochem.55, 33–60. https://doi.org/10.33594/000000325 (2021).
doi: 10.33594/000000325
Quack, T. et al. The formin-homology protein SmDia interacts with the src kinase SmTK and the GTPase SmRho1 in the gonads of Schistosoma mansoni. PLoS One4, e6998. https://doi.org/10.1371/journal.pone.0006998 (2009).
doi: 10.1371/journal.pone.0006998
Wada, K. I., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development138, 3907–3914. https://doi.org/10.1242/dev.070987 (2011).
doi: 10.1242/dev.070987
Fang, S. et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cells Transl. Med.5, 1425–1439. https://doi.org/10.5966/sctm.2015-0367 (2016).
doi: 10.5966/sctm.2015-0367
Li, T. et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev.22, 845–854. https://doi.org/10.1089/scd.2012.0395 (2013).
doi: 10.1089/scd.2012.0395
Bian, D., Wu, Y., Song, G., Azizi, R. & Zamani, A. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review. Stem Cell. Res. Ther.13, 24. https://doi.org/10.1186/s13287-021-02697-9 (2022).
doi: 10.1186/s13287-021-02697-9
Labibi, B., Bashkurov, M., Wrana, J. L. & Attisano, L. Modeling the control of TGF-β/smad nuclear accumulation by the hippo pathway effectors, taz/yap. iScience 23, 101416 (2020). https://doi.org/10.1016/j.isci.2020.101416
Sisson, T. H. et al. Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am. J. Pathol.185, 969–986. https://doi.org/10.1016/j.ajpath.2014.12.005 (2015).
doi: 10.1016/j.ajpath.2014.12.005
Johnson, L. A. et al. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β–induced fibrogenesis in human colonic myofibroblasts. Inflamm. Bowel Dis.20, 154–165 (2014).
doi: 10.1097/01.MIB.0000437615.98881.31
Choi, Y. J., Kim, W. R., Kim, D. H., Kim, J. H. & Yoo, J. H. Human umbilical cord/placenta mesenchymal stem cell conditioned medium attenuates intestinal fibrosis in vivo and in vitro. Stem Cell Res. Ther.15, 69 (2024).
doi: 10.1186/s13287-024-03678-4
Kho, A. R. et al. Administration of placenta-derived mesenchymal stem cells counteracts a delayed anergic state following a transient induction of endogenous neurogenesis activity after global cerebral ischemia. Brain Res.1689, 63–74. https://doi.org/10.1016/j.brainres.2018.03.033 (2018).
doi: 10.1016/j.brainres.2018.03.033
Kim, M. J. et al. Human chorionic-plate-derived mesenchymal stem cells and Wharton’s jelly-derived mesenchymal stem cells: a comparative analysis of their potential as placenta-derived stem cells. Cell. Tissue Res.346, 53–64. https://doi.org/10.1007/s00441-011-1249-8 (2011).
doi: 10.1007/s00441-011-1249-8
Oh, S. H. et al. Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model. Exp. Mol. Med.50, 1–12. https://doi.org/10.1038/s12276-018-0041-1 (2018).
doi: 10.1038/s12276-018-0041-1

Auteurs

Yoon Jeong Choi (YJ)

Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam, 13496, South Korea.

Jee Hyun Kim (JH)

Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.

Yeonju Lee (Y)

Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.

Hee Jang Pyeon (HJ)

R&D Division, CHA Biotech Co., Ltd, Seongnam, 13488, South Korea.

In Kyung Yoo (IK)

Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea. ikyoo82@hanmail.net.

Jun Hwan Yoo (JH)

Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea. jhyoo@cha.ac.kr.
Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam, 13496, South Korea. jhyoo@cha.ac.kr.

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