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2000
Volume 26, Issue 7
  • ISSN: 1389-2037
  • E-ISSN: 1875-5550

Abstract

Introduction

preconditioning increases the therapeutic potential of mesenchymal stem cells (MSCs) in terms of antioxidant activity, growth factor production, homing, differentiation, and immunomodulation. Therefore, it is considered an effective strategy to be used before transplantation and therapeutic application of MSCs. Histone deacetylase inhibitor (HDACi), valproic acid (VPA), has been reported to induce hepatic differentiation in MSCs. Although individual studies have shown that preconditioning and epigenetic modification enhance the survival and differentiation of MSCs, the combined effects of these therapies have not been fully explored. This study aims to investigate the combined effect of hydrogen peroxide (HO) preconditioning and HDACi (valproic acid) on the differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) into hepatic-like cells.

Methods

MSCs were first preconditioned with HO and then cultured with VPA. The migration and proliferation potential of the treated cells were evaluated using wound healing and colony- forming unit assays. Furthermore, the expression of hepatic genes () and proteins (AFP, ALB, TAT) was evaluated in all treated groups.

Results

The combined therapy group exhibited enhanced cell migration and proliferation, as evidenced by wound healing and colony-forming unit assays. Additionally, the combined treatment group showed higher expression of hepatic genes and TAT protein, suggesting an improved differentiation of stem cells into hepatocytes.

Conclusion

In conclusion, the combination of HO and VPA emerges as an important factor in promoting hepatocyte differentiation. However, further studies are required to optimize this protocol for future therapeutics.

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2025-01-03
2025-09-02
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References

  1. HuC. WuZ. LiL. Pre-treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases.J. Cell. Mol. Med.2020241404910.1111/jcmm.1478831691463
    [Google Scholar]
  2. WangL. ChenY.M. GeorgeD. SmetsF. SokalE.M. BremerE.G. SorianoH.E. Engraftment assessment in human and mouse liver tissue after sex-mismatched liver cell transplantation by real-time quantitative PCR for Y chromosome sequences.Liver Transpl.20028982282810.1053/jlts.2002.3489112200785
    [Google Scholar]
  3. IansanteV. MitryR.R. FilippiC. FitzpatrickE. DhawanA. Human hepatocyte transplantation for liver disease: current status and future perspectives.Pediatr. Res.2018831-223224010.1038/pr.2017.28429149103
    [Google Scholar]
  4. Martin-RendonE. SweeneyD. LuF. GirdlestoneJ. NavarreteC. WattS.M. 5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies.Vox Sang.200895213714810.1111/j.1423‑0410.2008.01076.x18557828
    [Google Scholar]
  5. AugelloA. De BariC. The regulation of differentiation in mesenchymal stem cells.Hum. Gene Ther.201021101226123810.1089/hum.2010.17320804388
    [Google Scholar]
  6. KhatlaniT. AlgudiriD. AlenziR. Al SubayyilA.M. AbomarayF.M. BahattabE. AlAskarA.S. KalionisB. El-MuzainiM.F. AbumareeM.H. Preconditioning by hydrogen peroxide enhances multiple properties of human decidua basalis mesenchymal stem/multipotent stromal cells.Stem Cells Int.2018201811310.1155/2018/648079329795719
    [Google Scholar]
  7. Garrido-PascualP. Alonso-VaronaA. CastroB. BurónM. PalomaresT. H2O2-preconditioned human adipose-derived stem cells (HC016) increase their resistance to oxidative stress by overexpressing Nrf2 and bioenergetic adaptation.Stem Cell Res. Ther.202011133510.1186/s13287‑020‑01851‑z31900237
    [Google Scholar]
  8. TompkinsY.H. LiuG. KimW.K. Impact of exogenous hydrogen peroxide on osteogenic differentiation of broiler chicken compact bones derived mesenchymal stem cells.Front. Physiol.202314112435510.3389/fphys.2023.112435536776980
    [Google Scholar]
  9. GuoL. DuJ. YuanD. ZhangY. ZhangS. ZhangH. MiJ. NingY. ChenM. WenD. SunJ. LiuD. ZengL. ZhangA. JiangJ. HuangH. Optimal H2O2 preconditioning to improve bone marrow mesenchymal stem cells’ engraftment in wound healing.Stem Cell Res. Ther.202011143410.1186/s13287‑020‑01910‑533032649
    [Google Scholar]
  10. BaiH. FangC.W. ShiY. ZhaiS. JiangA. LiY.N. WangL. LiuQ.L. ZhouG.Y. CaoJ.H. LiJ. YangX.K. QinX.J. Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice.Cell Death Dis.202314321610.1038/s41419‑023‑05744‑w36977674
    [Google Scholar]
  11. SiesH. Role of metabolic H2O2 generation: redox signaling and oxidative stress.J. Biol. Chem.2014289138735874110.1074/jbc.R113.54463524515117
    [Google Scholar]
  12. MahmoudiT. AbdolmohammadiK. BashiriH. MohammadiM. RezaieM.J. FathiF. FakhariS. RezaeeM.A. JaliliA. RahmaniM.R. TayebiL. Hydrogen peroxide preconditioning promotes protective effects of umbilical cord vein mesenchymal stem cells in experimental pulmonary fibrosis.Adv. Pharm. Bull.2019101728010.15171/apb.2020.00932002364
    [Google Scholar]
  13. SnykersS. VanhaeckeT. De BeckerA. PapeleuP. VinkenM. Van RietI. RogiersV. Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow.BMC Dev. Biol.2007712410.1186/1471‑213X‑7‑2417407549
    [Google Scholar]
  14. LiX. LiL. PandeyR. ByunJ.S. GardnerK. QinZ. DouY. The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptional network.Cell Stem Cell201211216317810.1016/j.stem.2012.04.02322862943
    [Google Scholar]
  15. RashidS. QaziR.M. MalickT.S. SalimA. KhanI. IlyasA. HaneefK. Effect of valproic acid on the hepatic differentiation of mesenchymal stem cells in 2D and 3D microenvironments.Mol. Cell. Biochem.2021476290991910.1007/s11010‑020‑03955‑933111212
    [Google Scholar]
  16. TariqueS. NaeemN. SalimA. AinuddinJ.A. HaneefK. The role of epigenetic modifiers in the hepatic differentiation of human umbilical cord derived mesenchymal stem cells.Biol. Futur.202273449550210.1007/s42977‑022‑00145‑036512201
    [Google Scholar]
  17. AnS.Y. HanJ. LimH.J. ParkS.Y. KimJ.H. DoB.R. KimJ.H. Valproic acid promotes differentiation of hepatocyte-like cells from whole human umbilical cord-derived mesenchymal stem cells.Tissue Cell201446212713510.1016/j.tice.2013.12.00624472423
    [Google Scholar]
  18. RashidS. SalimA. QaziR.M. MalickT.S. HaneefK. Sodium butyrate induces hepatic differentiation of mesenchymal stem cells in 3D collagen scaffolds.Appl. Biochem. Biotechnol.202219483721373210.1007/s12010‑022‑03941‑535499693
    [Google Scholar]
  19. GladyA. VandebroekA. YasuiM. Human keratinocyte-derived extracellular vesicles activate the MAPKinase pathway and promote cell migration and proliferation in vitro.Inflamm. Regen.2021411410.1186/s41232‑021‑00154‑x33526070
    [Google Scholar]
  20. ZhangS. YangY. FanL. ZhangF. LiL. The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future.Ann. Transl. Med.20208856510.21037/atm.2020.03.21832775366
    [Google Scholar]
  21. Bretón-RomeroR. LamasS. Hydrogen peroxide signaling in vascular endothelial cells.Redox Biol.2014252953410.1016/j.redox.2014.02.00524634835
    [Google Scholar]
  22. LiuP. XieX. WuH. LiH. ChiJ. LiuX. LuoJ. TangY. XuC. Conditioned medium of mesenchymal stem cells pretreated with H2O2 promotes intestinal mucosal repair in acute experimental colitis.Sci. Rep.20221212077210.1038/s41598‑022‑24493‑y36456585
    [Google Scholar]
  23. DengX. JingD. LiangH. ZhengD. ShaoZ. H2O2 damages the stemness of rat bone marrow-derived mesenchymal stem cells: developing a “stemness loss” model.Med. Sci. Monit.2019255613562010.12659/MSM.91401131353362
    [Google Scholar]
  24. YamamotoY. TerataniT. YamamotoH. QuinnG. MurataS. IkedaR. KinoshitaK. MatsubaraK. KatoT. OchiyaT. Recapitulation of in vivo gene expression during hepatic differentiation from murine embryonic stem cells.Hepatology200542355856710.1002/hep.2082516104048
    [Google Scholar]
  25. JonesE.A. Clement-JonesM. JamesO.F.W. WilsonD. Differences between human and mouse alpha-fetoprotein expression during early development.J. Anat.2001198555555910.1046/j.1469‑7580.2001.19850555.x11430694
    [Google Scholar]
  26. SeminoC.E. MerokJ.R. CraneG.G. PanagiotakosG. ZhangS. Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds.Differentiation2003714-526227010.1046/j.1432‑0436.2003.7104503.x12823227
    [Google Scholar]
  27. BishiD.K. MathapatiS. VenugopalJ.R. GuhathakurtaS. CherianK.M. RamakrishnaS. VermaR.S. Trans-differentiation of human mesenchymal stem cells generates functional hepatospheres on poly(l-lactic acid)-co-poly(ε-caprolactone)/collagen nanofibrous scaffolds.J. Mater. Chem. B Mater. Biol. Med.20131323972398410.1039/c3tb20241k32261223
    [Google Scholar]
  28. HeZ.P. TanW.Q. TangY.F. FengM.F. Differentiation of putative hepatic stem cells derived from adult rats into mature hepatocytes in the presence of epidermal growth factor and hepatocyte growth factor.Differentiation2003714-528129010.1046/j.1432‑0436.2003.7104505.x12823229
    [Google Scholar]
  29. FangS. QiuY. MaoL. ShiX. YuD. DingY. Differentiation of embryoid-body cells derived from embryonic stem cells into hepatocytes in alginate microbeads in vitro.Acta Pharmacol. Sin.200728121924193010.1111/j.1745‑7254.2007.00713.x18031606
    [Google Scholar]
  30. QinL. DaiX. YinY. Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.Mol. Cell. Neurosci.201675273510.1016/j.mcn.2016.06.00427343825
    [Google Scholar]
  31. WangX. NiC. JiangN. WeiJ. LiangJ. ZhaoB. LinX. Generation of liver bipotential organoids with a small-molecule cocktail.J. Mol. Cell Biol.202012861862910.1093/jmcb/mjaa01032232340
    [Google Scholar]
  32. WenX. JiaoL. TanH. MAPK/ERK pathway as a central regulator in vertebrate organ regeneration.Int. J. Mol. Sci.2022233146410.3390/ijms2303146435163418
    [Google Scholar]
  33. PerugorriaM.J. OlaizolaP. LabianoI. Esparza-BaquerA. MarzioniM. MarinJ.J.G. BujandaL. BanalesJ.M. Wnt–β-catenin signalling in liver development, health and disease.Nat. Rev. Gastroenterol. Hepatol.201916212113610.1038/s41575‑018‑0075‑930451972
    [Google Scholar]
  34. NasiriF. JohariB. AmiriF. Habibi RoudkenarM. MolaeiS. BahadoriM. H2O2-Preconditioned umbilical cord-derived mesenchymal stem cells ameliorate liver regeneration in acute liver failure-induced mice.Anatomical Sci. J.20171414350
    [Google Scholar]
  35. RothU. CurthK. UntermanT.G. KietzmannT. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway.J. Biol. Chem.200427942623263110.1074/jbc.M30839120014612449
    [Google Scholar]
  36. AkintolaA.A. van HeemstD. Insulin, aging, and the brain: mechanisms and implications.Front. Endocrinol. (Lausanne)201561310.3389/fendo.2015.0001325705204
    [Google Scholar]
  37. YehM.M. BoschD.E. DaoudS.S. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases.World J. Gastroenterol.201925304074409110.3748/wjg.v25.i30.407431435165
    [Google Scholar]
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