Glia-Like Cells from Late-Passage Human MSCs Protect Against Ischemic Stroke Through IGFBP-4

  • Jeong-Woo Son
  • Jihye Park
  • Ye Eun Kim
  • Jieun Ha
  • Dong Woo Park
  • Mi-Sook ChangEmail author
  • Seong-Ho KohEmail author


Stem cell therapy is considered to be a promising future treatment for intractable neurological diseases, although all the clinical trials using stem cells have not yet shown any good results. Early passage mesenchymal stem cells (MSCs) have been used in most clinical trials because of the issues on safety and efficacy. However, it is not easy to get plenty of cells enough for the treatment and it costs too much. Lots of late passage MSCs can be obtained at lower cost but their efficacy would be a big hurdle for clinical trials. If late passage MSCs with better efficacy could be used in clinical trials, it could be a new and revolutionary solution to reduce cost and enhance easier clinical trials. In the present study, it was investigated whether late passage MSCs could be induced into glia-like cells (ghMSCs); ghMSCs had better efficacy and they protected neurons and the brain from ischemia, and insulin-like growth factor binding protein-4 (IGFBP-4) played a critical role in beneficial effect of ghMSCs. ghMSCs were induced from MSCs and treated in in vitro and in vivo models of ischemia. They effectively protected neurons from ischemia and restored the brain damaged by cerebral infarction. These beneficial effects were significantly blocked by IGFBP-4 antibody. The current study demontsrated that late passage hMSCs can be efficiently induced into ghMSCs with better neuroprotective effect on ischemic stroke. Moreover, the results indicate that IGFBP-4 released from ghMSCs may serve as one of the key neuronal survival factors secreted from ghMSCs.


Cell death Growth factor Ischemia Mesenchymal stem cells Neuronal protection 


Funding Information

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI17C2160).


  1. 1.
    Nguyen H, Zarriello S, Coats A, Nelson C, Kingsbury C, Gorsky A, Rajani M, Neal EG et al (2018) Stem cell therapy for neurological disorders: a focus on aging. Neurobiol Dis 126:85–104. CrossRefPubMedGoogle Scholar
  2. 2.
    Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R et al (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1(1):55–70. CrossRefPubMedGoogle Scholar
  3. 3.
    Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448(7151):313–317. CrossRefPubMedGoogle Scholar
  4. 4.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. CrossRefGoogle Scholar
  5. 5.
    Luo J, Zhao S, Wang J, Luo L, Li E, Zhu Z, Liu Y, Kang R et al (2018) Bone marrow mesenchymal stem cells reduce ureteral stricture formation in a rat model via the paracrine effect of extracellular vesicles. J Cell Mol Med 22(9):4449–4459. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hofer HR, Tuan RS (2016) Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 7(1):131. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Yoon DS, Choi Y, Choi SM, Park KH, Lee JW (2015) Different effects of resveratrol on early and late passage mesenchymal stem cells through beta-catenin regulation. Biochem Biophys Res Commun 467(4):1026–1032. CrossRefPubMedGoogle Scholar
  8. 8.
    Ikegame Y, Yamashita K, Nakashima S, Nomura Y, Yonezawa S, Asano Y, Shinoda J, Hara H et al (2014) Fate of graft cells: what should be clarified for development of mesenchymal stem cell therapy for ischemic stroke? Front Cell Neurosci 8:322. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hwa V, Oh Y, Rosenfeld RG (1999) The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 20(6):761–787PubMedGoogle Scholar
  10. 10.
    Jeon HJ, Park J, Shin JH, Chang MS (2017) Insulin-like growth factor binding protein-6 released from human mesenchymal stem cells confers neuronal protection through IGF-1R-mediated signaling. Int J Mol Med 40(6):1860–1868. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Park HW, Lim MJ, Jung H, Lee SP, Paik KS, Chang MS (2010) Human mesenchymal stem cell-derived Schwann cell-like cells exhibit neurotrophic effects, via distinct growth factor production, in a model of spinal cord injury. Glia 58(9):1118–1132. CrossRefPubMedGoogle Scholar
  12. 12.
    Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida M, Naito AT, Nishi J et al (2008) IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454(7202):345–349. CrossRefPubMedGoogle Scholar
  13. 13.
    Kim YS, Yoo A, Son JW, Kim HY, Lee YJ, Hwang S, Lee KY, Lee YJ et al (2017) Early activation of phosphatidylinositol 3-kinase after ischemic stroke reduces infarct volume and improves long-term behavior. Mol Neurobiol 54(7):5375–5384. CrossRefPubMedGoogle Scholar
  14. 14.
    Park HH, Lee KY, Park DW, Choi NY, Lee YJ, Son JW, Kim S, Moon C et al (2018) Tracking and protection of transplanted stem cells using a ferrocenecarboxylic acid-conjugated peptide that mimics hTERT. Biomaterials 155:80–91. CrossRefPubMedGoogle Scholar
  15. 15.
    Son JW, Choi H, Yoo A, Park HH, Kim YS, Lee KY, Lee YJ, Koh SH (2015) Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine. J Neurochem 135(1):186–193. CrossRefPubMedGoogle Scholar
  16. 16.
    Koh SH, Yoo AR, Chang DI, Hwang SJ, Kim SH (2008) Inhibition of GSK-3 reduces infarct volume and improves neurobehavioral functions. Biochem Biophys Res Commun 371(4):894–899. CrossRefPubMedGoogle Scholar
  17. 17.
    Urakawa S, Hida H, Masuda T, Misumi S, Kim TS, Nishino H (2007) Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats. Neuroscience 144(3):920–933. CrossRefPubMedGoogle Scholar
  18. 18.
    Sughrue ME, Mocco J, Komotar RJ, Mehra A, D'Ambrosio AL, Grobelny BT, Penn DL, Connolly ES, Jr. (2006) An improved test of neurological dysfunction following transient focal cerebral ischemia in rats. J Neurosci Methods 151 (2):83–89. doi: CrossRefGoogle Scholar
  19. 19.
    Oxvig C (2015) The role of PAPP-A in the IGF system: location, location, location. J Cell Commun Signal 9(2):177–187. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Torrente D, Avila MF, Cabezas R, Morales L, Gonzalez J, Samudio I, Barreto GE (2014) Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model. Hum Exp Toxicol 33(7):673–684. CrossRefPubMedGoogle Scholar
  21. 21.
    LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16(2):143–163CrossRefGoogle Scholar
  22. 22.
    Mazerbourg S, Callebaut I, Zapf J, Mohan S, Overgaard M, Monget P (2004) Up date on IGFBP-4: regulation of IGFBP-4 levels and functions, in vitro and in vivo. Growth Hormon IGF Res 14(2):71–84. CrossRefGoogle Scholar
  23. 23.
    Chang YK, Chen MH, Chiang YH, Chen YF, Ma WH, Tseng CY, Soong BW, Ho JH et al (2011) Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 18:54. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Boido M, Piras A, Valsecchi V, Spigolon G, Mareschi K, Ferrero I, Vizzini A, Temi S et al (2014) Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy 16(8):1059–1072. CrossRefPubMedGoogle Scholar
  25. 25.
    Bang OY, Lee JS, Lee PH, Lee G (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57(6):874–882. CrossRefPubMedGoogle Scholar
  26. 26.
    Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, Testa L, Stecco A et al (2010) Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol 223(1):229–237CrossRefGoogle Scholar
  27. 27.
    Tsuruta F, Masuyama N, Gotoh Y (2002) The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem 277(16):14040–14047. CrossRefGoogle Scholar
  28. 28.
    Kummer JL, Zawada WM, Freed CR, Chernausek SD, Heidenreich KA (1996) Insulin-like growth factor binding proteins in fetal rat mesencephalic cultures: regulation by fibroblast growth factor and insulin-like growth factor I. Endocrinology 137(8):3551–3556CrossRefGoogle Scholar
  29. 29.
    Nordqvist A-CS, Von Holst H, Holmin S, Sara V, Bellander B-M, Schalling M (1996) Increase of insulin-like growth factor (IGF)-1, IGF binding protein-2 and− 4 mRNAs following cerebral contusion. Mol Brain Res 38(2):285–293CrossRefGoogle Scholar
  30. 30.
    Zhou R, Diehl D, Hoeflich A, Lahm H, Wolf E (2003) IGF-binding protein-4: biochemical characteristics and functional consequences. J Endocrinol 178(2):177–193CrossRefGoogle Scholar
  31. 31.
    Conover CA, Durham SK, Zapf J, Masiarz FR, Kiefer MC (1995) Cleavage analysis of insulin-like growth factor (IGF)-dependent IGF-binding protein-4 proteolysis and expression of protease-resistant IGF-binding protein-4 mutants. J Biol Chem 270(9):4395–4400CrossRefGoogle Scholar
  32. 32.
    Ning Y, Schuller AG, Conover CA, Pintar JE (2008) Insulin-like growth factor (IGF) binding protein-4 is both a positive and negative regulator of IGF activity in vivo. Mol Endocrinol 22(5):1213–1225. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cianfarani S (2012) Insulin-like growth factor-II: new roles for an old actor. Front Endocrinol (Lausanne) 3:118. CrossRefGoogle Scholar
  34. 34.
    Martin-Montanez E, Pavia J, Santin LJ, Boraldi F, Estivill-Torrus G, Aguirre JA, Garcia-Fernandez M (2014) Involvement of IGF-II receptors in the antioxidant and neuroprotective effects of IGF-II on adult cortical neuronal cultures. Biochim Biophys Acta 1842(7):1041–1051. CrossRefPubMedGoogle Scholar
  35. 35.
    Guan J, Williams CE, Skinner SJM, Mallard EC, Gluckman PD (1996) The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins. Endocrinology 137(3):893–898CrossRefGoogle Scholar
  36. 36.
    Xue Y, Yan Y, Gong H, Fang B, Zhou Y, Ding Z, Yin P, Zhang G et al (2014) Insulin-like growth factor binding protein 4 enhances cardiomyocytes induction in murine-induced pluripotent stem cells. J Cell Biochem 115(9):1495–1504. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologyHanyang University College of MedicineGuri-SiRepublic of Korea
  2. 2.Laboratory of Stem Cell & Neurobiology, Department of Oral Anatomy, Dental Research Institute and School of DentistrySeoul National UniversitySeoulRepublic of Korea
  3. 3.Department of Translational MedicineHanyang University Graduate School of Biomedical Science & EngineeringGuri-SiRepublic of Korea
  4. 4.Department of RadiologyHanyang University College of MedicineSeoulRepublic of Korea
  5. 5.Neuroscience Research InstituteSeoul National UniversitySeoulRepublic of Korea

Personalised recommendations