Skip to content
2000
Volume 20, Issue 6
  • ISSN: 1574-888X
  • E-ISSN: 2212-3946

Abstract

Background

Mesenchymal Stem Cells (MSCs) are pivotal in immunomodulation, hematopoiesis, and tissue repair. The interplay between MSCs and the pathological microenvironment influences their proliferation and differentiation. Transforming Growth Factor-Beta 1 (TGF-β1) serves as a key cytokine in the MSC microenvironment. This study aimed to scrutinize the impact of TGF-β1 on human placenta-derived MSCs of fetal origin (fPMSCs) and elucidate its underlying mechanism.

Methods

fPMSCs were isolated, and surface markers were identified by flow cytometry. Cell proliferation in fPMSCs was assessed using Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2’-Deoxy Uridine (EdU). Apoptosis was detected Annexin V/PI staining, and apoptosis-related proteins were detected by western blot. Endoplasmic reticulum (ER) stress-related proteins were detected by western blot, and Flou-4 AM staining was utilized to assess intracellular Ca2+ levels under TGF-β1 exposure. The impact of 4-PBA treatment on ER stress and apoptosis was assessed by western blot and Annexin V/PI staining. Additionally, the PERK and p-PERK expressions were evaluated Western blot.

Results

CCK-8 and EdU assays revealed inhibited proliferation of fPMSCs under TGF-β1 exposure. Annexin V/PI staining demonstrated a significant induction of apoptosis in fPMSCs following TGF-β1 treatment. Furthermore, TGF-β1 treatment significantly elevated intracellular Ca2+ levels and the expressions of GRP78, p-eIF2α, and CHOP. Interruption of ER stress with 4-PBA mitigated TGF-β1-induced apoptosis in fPMSCs. Moreover, TGF-β1 increased p-PERK expression. Inhibition of PERK autophosphorylation with GSK2606414 suppressed TGF-β1-induced apoptosis and ER stress in fPMSCs.

Conclusion

Our findings indicated that TGF-β1 induced ER stress-dependent apoptosis in fPMSCs through the PERK signaling pathway. These results offer insights into enhancing the therapeutic efficacy of fPMSCs by modulating TGF-β1-induced apoptosis.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cscr/10.2174/011574888X299292240827092254
2025-07-01
2026-02-05

  • From This Site

    /content/journals/cscr/10.2174/011574888X299292240827092254
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. AbumareeM.H. AbomarayF.M. AlshabibiM.A. AlAskarA.S. KalionisB. Immunomodulatory properties of human placental mesenchymal stem/stromal cells.Placenta201759879510.1016/j.placenta.2017.04.00328411943
     [Google Scholar]
  2. BarzegarM. WangY. EshaqR.S. YunJ.W. BoyerC.J. CananziS.G. WhiteL.A. ChernyshevO. KelleyR.E. MinagarA. StokesK.Y. LuX.H. AlexanderJ.S. Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.EBioMedicine20216310316110.1016/j.ebiom.2020.10316133348090
     [Google Scholar]
  3. LinY. DongS. YeX. LiuJ. LiJ. ZhangY. TuM. WangS. YingY. ChenR. WangF. NiF. ChenJ. DuB. ZhangD. Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels.Stem Cell Res. Ther.20221316610.1186/s13287‑022‑02717‑235135594
     [Google Scholar]
  4. HanX. WangJ. LiR. HuangM. YueG. GuanL. DengY. CaiW. XuJ. Placental mesenchymal stem cells alleviate podocyte injury in diabetic kidney disease by modulating mitophagy via the sirt1-pgc-1alpha-tfam pathway.Int. J. Mol. Sci.2023245469610.3390/ijms2405469636902127
     [Google Scholar]
  5. LiuJ. GaoJ. LiangZ. GaoC. NiuQ. WuF. ZhangL. Mesenchymal stem cells and their microenvironment.Stem Cell Res. Ther.202213142910.1186/s13287‑022‑02985‑y35987711
     [Google Scholar]
  6. de AraujoF.V. TGF-beta and mesenchymal stromal cells in regenerative medicine, autoimmunity and cancer.Cytokine Growth Factor Rev.2018253710.1016/j.cytogfr.2018.06.002
     [Google Scholar]
  7. XuJ. LiuJ. GanY. DaiK. ZhaoJ. HuangM. HuangY. ZhuangY. ZhangX. High-dose TGF-β1 impairs mesenchymal stem cell–mediated bone regeneration via Bmp2 inhibition.J. Bone Miner. Res.202035116718010.1002/jbmr.387131487395
     [Google Scholar]
  8. ZhangF. RenT. WuJ. TGF-β1 induces apoptosis of bone marrow-derived mesenchymal stem cells via regulation of mitochondrial reactive oxygen species production.Exp. Ther. Med.20151031224122810.3892/etm.2015.259026622469
     [Google Scholar]
  9. GhemrawiR. KhairM. Endoplasmic reticulum stress and unfolded protein response in neurodegenerative diseases.Int. J. Mol. Sci.20202117612710.3390/ijms2117612732854418
     [Google Scholar]
  10. ChenT. ZhuH. WangY. ZhaoP. ChenJ. SunJ. ZhangX. ZhuG. Apoptosis of bone marrow mesenchymal stromal/stem cells via the MAPK and endoplasmic reticulum stress signaling pathways.Am. J. Transl. Res.20181082555256630210692
     [Google Scholar]
  11. KowalczukA. MaryczK. Kornicka-GarbowskaK. KornickaJ. Bujalska-ZadrożnyM. GroborzS. Cannabidiol (CBD) protects adipose-derived mesenchymal stem cells (ASCs) against endoplasmic reticulum stress development and its complications.Int. J. Environ. Res. Public Health202219171086410.3390/ijerph19171086436078578
     [Google Scholar]
  12. ChengS. LiuX. GongF. DingX. ZhouX. LiuC. ZhaoF. LiX. ShiJ. Dexamethasone promotes the endoplasmic reticulum stress response of bone marrow mesenchymal stem cells by activating the PERK-Nrf2 signaling pathway.Pharmacol. Res. Perspect.202193e0079110.1002/prp2.79134038621
     [Google Scholar]
  13. GuoN.F. QiuZ. ChenX.L. ChenX. HuangJ.B. LiuJ. Prostaglandin E2 receptor subtypes 1 and 2 play a role in TGF-β1-induced renal fibrosis by regulating endoplasmic reticulum stress.Eur. Rev. Med. Pharmacol. Sci.20202494954496210.26355/eurrev_202005_2118632432758
     [Google Scholar]
  14. ShinJ.M. KangJ.H. ParkJ.H. YangH.W. LeeH.M. ParkI.H. TGF-β1 activates nasal fibroblasts through the induction of endoplasmic reticulum stress.Biomolecules202010694210.3390/biom1006094232580467
     [Google Scholar]
  15. WangL. YangY. ZhuY. MaX. LiuT. ZhangG. FanH. MaL. JinY. YanX. WeiJ. LiY. Characterization of placenta-derived mesenchymal stem cells cultured in autologous human cord blood serum.Mol. Med. Rep.20126476076610.3892/mmr.2012.100022824952
     [Google Scholar]
  16. ZhouW. LiL. TaoJ. MaC. XieY. DingL. HouS. ZhangZ. XueD. LuoJ. ZhuY. Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential.Mol. Immunol.2022151294010.1016/j.molimm.2022.08.01436075140
     [Google Scholar]
  17. SongM. MaL. ZhuY. GaoH. HuR. Umbilical cord mesenchymal stem cell-derived exosomes inhibits fibrosis in human endometrial stromal cells via miR-140-3p/FOXP1/Smad axis.Sci. Rep.2024141832110.1038/s41598‑024‑59093‑538594471
     [Google Scholar]
  18. ZhangY. ZhongY. LiuW. ZhengF. ZhaoY. ZouL. LiuX. PFKFB3-mediated glycometabolism reprogramming modulates endothelial differentiation and angiogenic capacity of placenta-derived mesenchymal stem cells.Stem Cell Res. Ther.202213139110.1186/s13287‑022‑03089‑335918720
     [Google Scholar]
  19. XiaT. LiaoY.Q. LiL. SunL.Y. DingN.S. WuY.L. LuK.L. 4-PBA attenuates fat accumulation in cultured spotted seabass fed high-fat-diet via regulating endoplasmic reticulum stress.Metabolites20221212119710.3390/metabo1212119736557235
     [Google Scholar]
  20. GunduC. ArruriV.K. SherkhaneB. KhatriD.K. SinghS.B. GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells.Curr Res in Pharmacol and Drug Disc2022310008710.1016/j.crphar.2022.10008735146419
     [Google Scholar]
  21. VasanthanJ. GurusamyN. RajasinghS. SigamaniV. KirankumarS. ThomasE.L. RajasinghJ. Role of human mesenchymal stem cells in regenerative therapy.Cells20201015410.3390/cells1001005433396426
     [Google Scholar]
  22. WuJ. NiuJ. LiX. WangX. GuoZ. ZhangF. TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production.BMC Dev. Biol.20141412110.1186/1471‑213X‑14‑2124886313
     [Google Scholar]
  23. KawamuraH. NakatsukaR. MatsuokaY. SumideK. FujiokaT. AsanoH. IidaH. SonodaY. TGF-beta signaling accelerates senescence of human bone-derived CD271 and SSEA-4 double-positive mesenchymal stromal cells.Stem Cell Rep201892093210.1016/j.stemcr.2018.01.030
     [Google Scholar]
  24. WalendaG. AbnaofK. JoussenS. MeurerS. SmeetsH. RathB. HoffmannK. FröhlichH. ZenkeM. WeiskirchenR. WagnerW. TGF-beta1 does not induce senescence of multipotent mesenchymal stromal cells and has similar effects in early and late passages.PLoS One2013810e7765610.1371/journal.pone.007765624147049
     [Google Scholar]
  25. KimY.I. RyuJ.S. YeoJ.E. ChoiY.J. KimY.S. KoK. KohY.G. Overexpression of TGF-β1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells.Biochem. Biophys. Res. Commun.201445041593159910.1016/j.bbrc.2014.07.04525035928
     [Google Scholar]
  26. ZhouW. ParkI. PinsM. KozlowskiJ.M. JovanovicB. ZhangJ. LeeC. IlioK. Dual regulation of proliferation and growth arrest in prostatic stromal cells by transforming growth factor-beta1.Endocrinology2003144104280428410.1210/en.2003‑055412959966
     [Google Scholar]
  27. XuX. LaiY. HuaZ.C. Apoptosis and apoptotic body: Disease message and therapeutic target potentials.Biosci. Rep.2019391BSR2018099210.1042/BSR2018099230530866
     [Google Scholar]
  28. KaloniD. DiepstratenS.T. StrasserA. KellyG.L. BCL-2 protein family: Attractive targets for cancer therapy.Apoptosis2023281-2203810.1007/s10495‑022‑01780‑736342579
     [Google Scholar]
  29. LiL. WangS. ZhouW. Balance cell apoptosis and pyroptosis of caspase-3-activating chemotherapy for better antitumor therapy.Cancers20221512610.3390/cancers1501002636612023
     [Google Scholar]
  30. RahiM.S. IslamM.S. JerinI. JahangirC.A. HasanM.M. HoqueK.M.F. RezaM.A. Differential expression of Bax-Bcl-2 and PARP-1 confirms apoptosis of EAC cells in Swiss albino mice by Morus laevigata.J. Food Biochem.2020448e1334210.1111/jfbc.1334232578902
     [Google Scholar]
  31. Di ConzaG. HoP.C. ER stress responses: An emerging modulator for innate immunity.Cells20209369510.3390/cells903069532178254
     [Google Scholar]
  32. van VlietA.R. GargA.D. AgostinisP. Coordination of stress, Ca 2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum.Biol. Chem.2016397764965610.1515/hsz‑2016‑010826872313
     [Google Scholar]
  33. IbrahimI.M. AbdelmalekD.H. ElfikyA.A. GRP78: A cell’s response to stress.Life Sci.201922615616310.1016/j.lfs.2019.04.02230978349
     [Google Scholar]
  34. SamantaS. YangS. DebnathB. XueD. KuangY. RamkumarK. LeeA.S. LjungmanM. NeamatiN. The hydroxyquinoline analogue YUM70 inhibits GRP78 to induce ER stress–mediated apoptosis in pancreatic cancer.Cancer Res.20218171883189510.1158/0008‑5472.CAN‑20‑154033531374
     [Google Scholar]
  35. RiazT.A. JunjappaR.P. HandigundM. FerdousJ. KimH.R. ChaeH.J. Role of endoplasmic reticulum stress sensor IRE1α in cellular physiology, calcium, ROS signaling, and metaflammation.Cells202095116010.3390/cells905116032397116
     [Google Scholar]
  36. ChenC.A. ChangJ.M. ChangE.E. ChenH.C. YangY.L. Crosstalk between transforming growth factor-β1 and endoplasmic reticulum stress regulates alpha-smooth muscle cell actin expression in podocytes.Life Sci.201820991410.1016/j.lfs.2018.07.05030059670
     [Google Scholar]
  37. PaoH.P. LiaoW.I. TangS.E. WuS.Y. HuangK.L. ChuS.J. Suppression of endoplasmic reticulum stress by 4-PBA protects against hyperoxia-induced acute lung injury via up-regulating claudin-4 expression.Front. Immunol.20211267431610.3389/fimmu.2021.67431634122432
     [Google Scholar]
  38. NarayananS. EleselaS. RaskyA.J. MorrisS.H. KumarS. LombardD. LukacsN.W. ER stress protein PERK promotes inappropriate innate immune responses and pathogenesis during RSV infection.J. Leukoc. Biol.2022111237938910.1002/JLB.3A0520‑322RR33866604
     [Google Scholar]
  39. AxtenJ.M. MedinaJ.R. FengY. ShuA. RomerilS.P. GrantS.W. LiW.H. HeerdingD.A. MinthornE. MenckenT. AtkinsC. LiuQ. RabindranS. KumarR. HongX. GoetzA. StanleyT. TaylorJ.D. SigethyS.D. TomberlinG.H. HassellA.M. KahlerK.M. ShewchukL.M. GampeR.T. Discovery of 7-methyl-5-(1-[3-(trifluoromethyl)phenyl]acetyl-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).J. Med. Chem.20127193720710.1021/jm300713s22827572
     [Google Scholar]
/content/journals/cscr/10.2174/011574888X299292240827092254
Loading
TGF-β1 Induces Endoplasmic Reticulum Stress-dependent Apoptosis in Human Placental Mesenchymal Stem Cells of Fetal Origin through PERK Signaling Pathway
Curr Stem Cell Res Ther 20, 699 (2025); https://doi.org/10.2174/011574888X299292240827092254
/content/journals/cscr/10.2174/011574888X299292240827092254
/content/journals/cscr/10.2174/011574888X299292240827092254
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): apoptosis; endoplasmic reticulum stress; mesenchymal stem cell; PERK signaling pathway; placenta; TGF-β1

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test