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2000
Volume 25, Issue 12
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666
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Abstract

Background

Hippo signaling regulates the behavior and fate of mesenchymal stem cells (MSCs), which are crucial for the repair and cure of acute respiratory distress syndrome (ARDS). However, whether 2-deoxy-D-glucose (2-DG), a specific activator of Hippo signaling, would further enhance the reparative effect of MSCs in ARDS remains unclarified.

Objective

This study aimed to determine whether 2-DG could promote the proliferation, differentiation, migration, and resistance to oxidative stress of mouse bone marrow-derived MSCs (mBMSCs).

Methods

mBMSCs were isolated from C57BL/6 mice and differentiated into alveolar type II epithelial (ATII) cells by noncontact coculture. The specific activator and inhibitor 2-DG and 4-[(5,10-dimethyl-6-Oxo-6,10-dihydro-5h-pyrimido[5,4-B]thieno[3,2-E][1,4]diazepin-2-Yl)amino]benzenesulfonamide (XMU-MP-1) were used to activate and inhibit Hippo signaling, respectively. Oxidative stress-induced injuries were induced by HO treatment.

Results

We observed that 2-DG activated Hippo signaling and promoted mBMSC proliferation in a dose-dependent manner. 2-DG also promoted the differentiation of mBMSCs into ATII cells and enhanced not only the horizontal and vertical migration of mBMSCs but also mBMSC homing to injured lung tissue. HO treatment inhibited Hippo signaling and reduced the viability of mBMSCs by decreasing the Bcl-2/Bax ratio, but 2-DG activated Hippo signaling and conferred mBMSCs with resistance to oxidative stress by increasing the Bcl-2/Bax ratio. However, XMU-MP-1 suppressed these effects to some extent.

Conclusion

Through Hippo signaling, 2-DG promoted the proliferation, migration, differentiation, and resistance to oxidative stress of mBMSCs, suggesting a novel strategy for enhancing the reparative effects of MSCs in ARDS.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-02-26
2025-12-20

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References

  1. ConfalonieriM. SaltonF. FabianoF. Acute respiratory distress syndrome.Eur. Respir. Rev.20172614416011610.1183/16000617.0116‑2016 28446599
     [Google Scholar]
  2. BellaniG. LaffeyJ.G. PhamT. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA2016315878880010.1001/jama.2016.0291 26903337
     [Google Scholar]
  3. HorieS. MastersonC. DevaneyJ. LaffeyJ.G. Stem cell therapy for acute respiratory distress syndrome.Curr. Opin. Crit. Care2016221142010.1097/MCC.0000000000000276 26645555
     [Google Scholar]
  4. GutierrezM.T. LaffeyJ.G. PelosiP. RoccoP.R.M. Cell-based therapies for the acute respiratory distress syndrome.Curr. Opin. Crit. Care201420112213110.1097/MCC.0000000000000061 24300620
     [Google Scholar]
  5. XiangB. ChenL. WangX. ZhaoY. WangY. XiangC. Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of lps-induced acute lung injury.Int. J. Mol. Sci.201718468910.3390/ijms18040689 28346367
     [Google Scholar]
  6. WalterJ. WareL.B. MatthayM.A. Mesenchymal stem cells: Mechanisms of potential therapeutic benefit in ARDS and sepsis.Lancet Respir. Med.20142121016102610.1016/S2213‑2600(14)70217‑6 25465643
     [Google Scholar]
  7. GuptaN. KrasnodembskayaA. KapetanakiM. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia.Thorax201267653353910.1136/thoraxjnl‑2011‑201176 22250097
     [Google Scholar]
  8. KellnerM. NoonepalleS. LuQ. SrivastavaA. ZemskovE. BlackS.M. ROS signaling in the pathogenesis of acute lung injury (ali) and acute respiratory distress syndrome (ards).Adv. Exp. Med. Biol.201796710513710.1007/978‑3‑319‑63245‑2_8 29047084
     [Google Scholar]
  9. JacksonM. KrasnodembskayaA. Analysis of mitochondrial transfer in direct co-cultures of human monocyte-derived macrophages (mdm) and mesenchymal stem cells (msc).Bio Protoc.201779e225510.21769/BioProtoc.2255 28534038
     [Google Scholar]
  10. HayesM. CurleyG. AnsariB. LaffeyJ.G. Clinical review: Stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype?Crit. Care201216220510.1186/cc10570 22424108
     [Google Scholar]
  11. MiyamuraN. HataS. ItohT. YAP determines the cell fate of injured mouse hepatocytes in vivo.Nat. Commun.2017811601710.1038/ncomms16017 28681838
     [Google Scholar]
  12. WangY.Y. YuW. ZhouB. Hippo signaling pathway in cardiovascular development and diseases.Yi Chuan201739757658710.16288/j.yczz.17‑039 28757472
     [Google Scholar]
  13. TangY. WeissS.J. Snail/Slug-YAP/TAZ complexes cooperatively regulate mesenchymal stem cell function and bone formation.Cell Cycle201716539940510.1080/15384101.2017.1280643 28112996
     [Google Scholar]
  14. WangW. XiaoZ.D. LiX. AMPK modulates Hippo pathway activity to regulate energy homeostasis.Nat. Cell Biol.201517449049910.1038/ncb3113 25751139
     [Google Scholar]
  15. FanF. HeZ. KongL.L. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration.Sci. Transl. Med.20168352352ra10810.1126/scitranslmed.aaf2304 27535619
     [Google Scholar]
  16. SunW. LiuM. LiY. HuX. ChenG. ZhangF. Xanthorrhizol inhibits mitochondrial damage, oxidative stress and inflammation in LPS-induced MLE-12 cells by regulating MAPK pathway.Tissue Cell202384102170t10.1016/j.tice.2023.102170 37494831
     [Google Scholar]
  17. DesaiN. LudginJ. GoldbergJ. FalconeT. Development of a xeno-free non-contact co- culture system for derivation and maintenance of embryonic stem cells using a novel human endometrial cell line.J. Assist. Reprod. Genet.201330560961510.1007/s10815‑013‑9977‑1 23575766
     [Google Scholar]
  18. VaranouA. PageC.P. MingerS.L. Human embryonic stem cells and lung regeneration.Br. J. Pharmacol.2008155331632510.1038/bjp.2008.333 18724383
     [Google Scholar]
  19. JohnsonR. HalderG. The two faces of Hippo: Targeting the Hippo pathway for regenerative medicine and cancer treatment.Nat. Rev. Drug Discov.2014131637910.1038/nrd4161 24336504
     [Google Scholar]
  20. ZhangQ. MengF. ChenS. Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade.Nat. Cell Biol.201719436237410.1038/ncb3496 28346439
     [Google Scholar]
  21. ZhaoB. TumanengK. GuanK.L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal.Nat. Cell Biol.201113887788310.1038/ncb2303 21808241
     [Google Scholar]
  22. CuiC.B. CooperL.F. YangX. KarsentyG. AukhilI. Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ.Mol. Cell. Biol.20032331004101310.1128/MCB.23.3.1004‑1013.2003 12529404
     [Google Scholar]
  23. MokhtariR.B. AshayeriN. BaghaieL. The hippo pathway effectors yap/taz-tead oncoproteins as emerging therapeutic targets in the tumor microenvironment.Cancers20231513346810.3390/cancers15133468 37444578
     [Google Scholar]
  24. LiL. DongL. ZhangJ. GaoF. HuiJ. YanJ. Mesenchymal stem cells with downregulated Hippo signaling attenuate lung injury in mice with lipopolysaccharide induced acute respiratory distress syndrome.Int. J. Mol. Med.20184331241125210.3892/ijmm.2018.4047 30628652
     [Google Scholar]
  25. MisraJ.R. IrvineK.D. The hippo signaling network and its biological functions.Annu. Rev. Genet.2018521658710.1146/annurev‑genet‑120417‑031621 30183404
     [Google Scholar]
  26. ChangH.A. YangO.R.Z. SuJ.M. YAP nuclear translocation induced by HIF-1α prevents DNA damage under hypoxic conditions.Cell Death Discov.20239138510.1038/s41420‑023‑01687‑5 37863897
     [Google Scholar]
  27. JeongH. BaeS. AnS.Y. TAZ as a novel enhancer of MyoD‐mediated myogenic differentiation.FASEB J.20102493310332010.1096/fj.09‑151324 20466877
     [Google Scholar]
  28. HeQ. HuangH.Y. ZhangY.Y. LiX. QianS.W. TangQ.Q. TAZ is downregulated by dexamethasone during the differentiation of 3T3-L1 preadipocytes.Biochem. Biophys. Res. Commun.2012419357357710.1016/j.bbrc.2012.02.074 22374070
     [Google Scholar]
  29. DupontS. MorsutL. AragonaM. Role of YAP/TAZ in mechanotransduction.Nature2011474735017918310.1038/nature10137 21654799
     [Google Scholar]
  30. MendezJ.J. GhaediM. SteinbacherD. NiklasonL.E. Epithelial cell differentiation of human mesenchymal stromal cells in decellularized lung scaffolds.Tissue Eng. Part A20142011-121735174610.1089/ten.tea.2013.0647 24393055
     [Google Scholar]
  31. MaN. GaiH. MeiJ. Bone marrow mesenchymal stem cells can differentiate into type II alveolar epithelial cells in vitro.Cell Biol. Int.201135121261126610.1042/CBI20110026 21542803
     [Google Scholar]
  32. RamírezC.D. VargasC.E. CastilloG.S. Effect of glycolysis inhibition on mitochondrial function in rat brain.J. Biochem. Mol. Toxicol.201226520621110.1002/jbt.21404 22539072
     [Google Scholar]
  33. LiuS. ZhangX. WangW. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.Mol. Cancer202423126110.1186/s12943‑024‑02165‑x 39574178
     [Google Scholar]
  34. PajakB. SiwiakE. SołtykaM. 2-Deoxy-d-glucose and its analogs: From diagnostic to therapeutic agents.Int. J. Mol. Sci.201921123410.3390/ijms21010234 31905745
     [Google Scholar]
  35. OrtizL.A. GambelliF. McBrideC. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc. Natl. Acad. Sci. USA2003100148407841110.1073/pnas.1432929100 12815096
     [Google Scholar]
  36. WangZ. MaQ. LiuQ. Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway.Br. J. Cancer200899101695170310.1038/sj.bjc.6604745 19002187
     [Google Scholar]
  37. WangT. LiuY.P. WangT. XuB.Q. XuB. ROS feedback regulates the microRNA-19-targeted inhibition of the p47 phox -mediated LPS-induced inflammatory response.Biochem. Biophys. Res. Commun.2017489436136810.1016/j.bbrc.2017.05.022 28479245
     [Google Scholar]
  38. MatthayM.A. WareL.B. ZimmermanG.A. The acute respiratory distress syndrome.J. Clin. Invest.201212282731274010.1172/JCI60331 22850883
     [Google Scholar]
  39. LiD. XuY. GaoC.Y. ZhaiY.P. Adaptive protection against damage of preconditioning human umbilical cord-derived mesenchymal stem cells with hydrogen peroxide.Genet. Mol. Res.20141337304731710.4238/2014.February.21.9 24634295
     [Google Scholar]
  40. KimJ.Y. LeeJ.S. HanY.S. Pretreatment with lycopene attenuates oxidative stress-induced apoptosis in human mesenchymal stem cells.Biomol. Ther.201523651752410.4062/biomolther.2015.085 26535076
     [Google Scholar]
  41. CiamporceroE. DagaM. PizzimentiS. Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer.Free Radic. Biol. Med.201811544745710.1016/j.freeradbiomed.2017.12.005 29248722
     [Google Scholar]
  42. PetriS. KörnerS. KiaeiM. Nrf2/ARE signaling pathway: Key mediator in oxidative stress and potential therapeutic target in als.Neurol. Res. Int.201220121710.1155/2012/878030 23050144
     [Google Scholar]
  43. AudoussetC. McGovernT. MartinJ.G. Role of Nrf2 in disease: Novel molecular mechanisms and therapeutic approaches – pulmonary disease/asthma.Front. Physiol.20211272780610.3389/fphys.2021.727806 34658913
     [Google Scholar]
  44. DubeyP.K. MasudaK. NyatiK.K. Arid5a-deficient mice are highly resistant to bleomycin-induced lung injury.Int. Immunol.2017292798510.1093/intimm/dxx004 28379390
     [Google Scholar]
  45. MeiS.H.J. McCarterS.D. DengY. ParkerC.H. LilesW.C. StewartD.J. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1.PLoS Med.200749e26910.1371/journal.pmed.0040269 17803352
     [Google Scholar]
  46. WangF.W. WangZ. ZhangY.M. Protective effect of melatonin on bone marrow mesenchymal stem cells against hydrogen peroxide-induced apoptosis in vitro.J. Cell. Biochem.2013114102346235510.1002/jcb.24582 23824714
     [Google Scholar]
  47. SaitoA. NagaseT. Hippo and TGF-β interplay in the lung field.Am. J. Physiol. Lung Cell. Mol. Physiol.20153098L756L76710.1152/ajplung.00238.2015 26320155
     [Google Scholar]
  48. FahyR.J. LichtenbergerF. McKeeganC.B. NuovoG.J. MarshC.B. WewersM.D. The acute respiratory distress syndrome: A role for transforming growth factor-beta 1.Am. J. Respir. Cell Mol. Biol.200328449950310.1165/rcmb.2002‑0092OC 12654639
     [Google Scholar]
  49. BeyerT.A. WeissA. KhomchukY. Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells.Cell Rep.2013561611162410.1016/j.celrep.2013.11.021 24332857
     [Google Scholar]
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2-DG Promotes the Proliferation, Differentiation, Migration, and Resistance to Oxidative Stress of Mesenchymal Stem Cells through Hippo Signaling
Current Molecular Medicine 25, 1484 (2025); https://doi.org/10.2174/0115665240327407250206112910
/content/journals/cmm/10.2174/0115665240327407250206112910
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  • Article Type:     Research Article
Keyword(s): antioxidative stress; differentiation; Hippo signaling; Mesenchymal stem cells; migration; proliferation

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