Molecular Neurobiology

, Volume 55, Issue 4, pp 3513–3522 | Cite as

Interleukin-6-Mediated Induced Pluripotent Stem Cell (iPSC)-Derived Neural Differentiation

  • Yanuar Alan Sulistio
  • Han Kyu Lee
  • Sung Jun Jung
  • Klaus HeeseEmail author


In an aging society with an increasing threat to higher brain cognitive functions due to dementia, it becomes imperative to identify new molecular remedies for supporting adult neurogenesis. Interleukin-6 (IL-6) is a promising cytokine that can support neurogenesis under conditions of neurodegeneration, and neuron replacement is eventually possible due to its agonistic acting soluble receptor sIL-6R. Here, we report that activation of the IL-6–signal transducer and activator of transcription 3 (STAT3) axis is neurogenic and has potential therapeutic applications for the treatment of neurodegenerative diseases such as Parkinson’s disease (PD).


BDNF Brain Interleukin-6 Neuron Neurotrophin STAT3 



Alzheimer’s disease


AKT (mouse Ak strain thymoma) serine/threonine kinase, protein kinase B (PKB)


Alkaline phosphatase


α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


Action potential




Brain-derived neurotrophic factor


Basic fibroblast growth factor


Bone morphogenetic protein


Bovine serum albumin


Cluster of differentiation 15, 3-fucosyl-N-acetyl-lactosamine, SSEA-1 (stage-specific embryonic antigen 1)


Cluster of differentiation 24 or heat-stable antigen CD24 (HSA)


Cluster of differentiation 44, HCAM (homing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1)


Cluster of differentiation 184, C-X-C chemokine receptor type 4 (CXCR-4)


Cluster of differentiation 271, LNGFR (low-affinity nerve growth factor receptor) or p75NTR (neurotrophin receptor p75)


Methyl-, methylation


Central nervous system


Ciliary neurotrophic factor


cAMP-responsive element binding protein






Dulbecco’s modified Eagle medium


Ethylenediaminetetraacetic acid


Epidermal growth factor


Extracellular-regulated microtubule-associated protein kinase


Fluorescence-activated cell sorting


Fetal bovine serum


Fluorescein isothiocyanate


Fibroblast media


Finkel-Biskis-Jinkins (FBJ) osteosarcoma (Fos) proto-oncogene, activator protein 1 (AP-1) transcription factor subunit


GRB2-associated-binding protein 1


Gamma-aminobutyric acid


Gamma-aminobutyric acid-A receptor


Growth factor


Glial fibrillary acidic protein


Ionotropic glutamate receptor


Glycoprotein 130


Growth factor receptor bound protein 2


4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid






Interleukin-6 receptor


Interleukin-6 signal transducing receptor subunit (gp130)


Induced pluripotent stem cells


Janus kinase


c-Jun N-terminal kinase


Jun proto-oncogene, activator protein 1 (AP-1) transcription factor subunit


Kruppel-like factor 4


Leukemia inhibitory factor


Lin-28 homolog


v-Myc avian myelocytomatosis viral oncogene lung carcinoma-derived homolog


Microtubule-associated protein 2


Microtubule-associated protein kinase


Microtubule-associated protein tau


Marker of proliferation Ki-67


Myelocytomatosis viral oncogene


Neurobasal media


Neuronal nuclei, RNA binding protein fox-1 homolog 3 (RBFOX3)


Non-essential amino acids


Normal human dermal fibroblast cells




Neural stem cell


POU class 5 homeobox 1 (POU5F1)




Tumor protein 53


Phosphate buffer saline


Parkinson’s disease


Phycoerythrin cyanine


Peridinin chlorophyll protein complex




Phosphatidylinositol 3-kinase, and phosphatidylinositol-4,5-bisphosphate 3-kinase


Podocalyxin-like proteins, also known as TRA-1-60 and TRA-1-81 antigens


Penicillin, streptomycin


Sarcoma virus oncogene (small G-protein)


Resting membrane potential


src-family kinase


Soluble glycoprotein 130


Protein tyrosine phosphatase, non-receptor type 6, -11 (Ptpn6/11)


Short hairpin RNA


Soluble interleukin-6 receptor


Portmanteau of Sma (small) and Mad (mothers against decapentaplegic homolog)


Suppressor of cytokine signaling 3


Sex-determining region Y (SRY)-box 2, -6


Son of sevenless protein


Stage-specific embryonic antigen 3, -4


Signal transducer and activator of transcription 3


Transcription factor


Transforming growth factor beta


Podocalyxin-like proteins (PODXL, TRA-1-60, and TRA-1-81 antigens)


Tropomyosin receptor kinase B, neurotrophic receptor tyrosine kinase 2 (NTRK2)


Truncated TRKB (without kinase domain)




β-Tubulin isotype III (also TUJ1)


Vascular dementia


Yes-associated protein


Phosphorylated tyrosine



This study was supported by Hanyang University by providing a scholarship to Y.A.S. and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2009178).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2017_594_MOESM1_ESM.pdf (3.1 mb)
ESM 1 (PDF 3134 kb)


  1. 1.
    Nishikawa S, Goldstein RA, Nierras CR (2008) The promise of human induced pluripotent stem cells for research and therapy. Nat Rev Mol Cell Biol 9(9):725–729CrossRefPubMedGoogle Scholar
  2. 2.
    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M et al (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8(5):409–412CrossRefPubMedGoogle Scholar
  3. 3.
    Pramanik S, Sulistio YA, Heese K (2017) Neurotrophin signaling and stem cells—implications for neurodegenerative diseases and stem cell therapy. Mol Neurobiol. doi: 10.1007/s12035-016-0214-7 PubMedGoogle Scholar
  4. 4.
    Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-6 family of cytokines and gp130. Blood 86(4):1243–1254PubMedGoogle Scholar
  5. 5.
    Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819CrossRefPubMedGoogle Scholar
  6. 6.
    Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8(9):1254–1266CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Feng Q, Wang YI, Yang Y (2015) Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia. Exp Ther Med 9(5):1695–1701CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang XC, Qiu YH, Peng YP (2007) Interleukin-6 protects cerebellar granule neurons from NMDA-induced neurotoxicity. Sheng Li Xue Bao 59(2):150–156PubMedGoogle Scholar
  9. 9.
    Cafferty WB, Gardiner NJ, Das P, Qiu J, McMahon SB, Thompson SW (2004) Conditioning injury-induced spinal axon regeneration fails in interleukin-6 knock-out mice. J Neurosci 24(18):4432–4443CrossRefPubMedGoogle Scholar
  10. 10.
    Gruol DL (2015) IL-6 regulation of synaptic function in the CNS. Neuropharmacology 96(Pt A):42–54CrossRefPubMedGoogle Scholar
  11. 11.
    Hakkoum D, Stoppini L, Muller D (2007) Interleukin-6 promotes sprouting and functional recovery in lesioned organotypic hippocampal slice cultures. J Neurochem 100(3):747–757CrossRefPubMedGoogle Scholar
  12. 12.
    Gadient RA, Otten U (1994) Identification of interleukin-6 (IL-6)-expressing neurons in the cerebellum and hippocampus of normal adult rats. Neurosci Lett 182(2):243–246CrossRefPubMedGoogle Scholar
  13. 13.
    Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250CrossRefPubMedGoogle Scholar
  14. 14.
    Thier M, Marz P, Otten U, Weis J, Rose-John S (1999) Interleukin-6 (IL-6) and its soluble receptor support survival of sensory neurons. J Neurosci Res 55(4):411–422CrossRefPubMedGoogle Scholar
  15. 15.
    Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183(6):2627–2634CrossRefPubMedGoogle Scholar
  16. 16.
    Ihara S, Nakajima K, Fukada T, Hibi M, Nagata S, Hirano T, Fukui Y (1997) Dual control of neurite outgrowth by STAT3 and MAP kinase in PC12 cells stimulated with interleukin-6. EMBO J 16(17):5345–5352CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sterneck E, Kaplan DR, Johnson PF (1996) Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. J Neurochem 67(4):1365–1374CrossRefPubMedGoogle Scholar
  18. 18.
    Wu YY, Bradshaw RA (1996) Induction of neurite outgrowth by interleukin-6 is accompanied by activation of Stat3 signaling pathway in a variant PC12 cell (E2) line. J Biol Chem 271(22):13023–13032CrossRefPubMedGoogle Scholar
  19. 19.
    Marz P, Herget T, Lang E, Otten U, Rose-John S (1997) Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation. Eur J Neurosci 9(12):2765–2773CrossRefPubMedGoogle Scholar
  20. 20.
    Ihara S, Iwamatsu A, Fujiyoshi T, Komi A, Yamori T, Fukui Y (1996) Identification of interleukin-6 as a factor that induces neurite outgrowth by PC12 cells primed with NGF. J Biochem 120(5):865–868CrossRefPubMedGoogle Scholar
  21. 21.
    Abeyama K, Kawano K, Nakajima T, Takasaki I, Kitajima I, Maruyama I (1995) Interleukin 6 mediated differentiation and rescue of cell redox in PC12 cells exposed to ionizing radiation. FEBS Lett 364(3):298–300CrossRefPubMedGoogle Scholar
  22. 22.
    Nakafuku M, Satoh T, Kaziro Y (1992) Differentiation factors, including nerve growth factor, fibroblast growth factor, and interleukin-6, induce an accumulation of an active Ras.GTP complex in rat pheochromocytoma PC12 cells. J Biol Chem 267(27):19448–19454PubMedGoogle Scholar
  23. 23.
    Satoh T, Nakamura S, Taga T, Matsuda T, Hirano T, Kishimoto T, Kaziro Y (1988) Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. Mol Cell Biol 8(8):3546–3549CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Islam O, Gong X, Rose-John S, Heese K (2009) Interleukin-6 and neural stem cells: more than gliogenesis. Mol Biol Cell 20(1):188–199. doi: 10.1091/mbc.E08-05-0463 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bowen KK, Dempsey RJ, Vemuganti R (2011) Adult interleukin-6 knockout mice show compromised neurogenesis. Neuroreport 22(3):126–130CrossRefPubMedGoogle Scholar
  26. 26.
    Marz P, Otten U, Rose-John S (1999) Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. Eur J Neurosci 11(9):2995–3004CrossRefPubMedGoogle Scholar
  27. 27.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872CrossRefPubMedGoogle Scholar
  28. 28.
    Hussein SM, Nagy AA (2012) Progress made in the reprogramming field: new factors, new strategies and a new outlook. Curr Opin Genet Dev 22(5):435–443CrossRefPubMedGoogle Scholar
  29. 29.
    Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275–280CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Morizane A, Doi D, Kikuchi T, Nishimura K, Takahashi J (2011) Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J Neurosci Res 89(2):117–126CrossRefPubMedGoogle Scholar
  31. 31.
    Yuan SH, Martin J, Elia J, Flippin J, Paramban RI, Hefferan MP, Vidal JG, Mu Y et al (2011) Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS One 6(3):e17540CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mishra M, Akatsu H, Heese K (2011) The novel protein MANI modulates neurogenesis and neurite-cone growth. J Cell Mol Med 15(8):1713–1725. doi: 10.1111/j.1582-4934.2010.01134.x CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mishra M, Heese K (2011) P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis. J Cell Mol Med 15(11):2462–2477. doi: 10.1111/j.1582-4934.2010.01248.x CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Guez-Barber D, Fanous S, Harvey BK, Zhang Y, Lehrmann E, Becker KG, Picciotto MR, Hope BT (2012) FACS purification of immunolabeled cell types from adult rat brain. J Neurosci Methods 203(1):10–18CrossRefPubMedGoogle Scholar
  35. 35.
    Park SY, Yoon SN, Kang MJ, Lee Y, Jung SJ, Han JS (2017) Hippocalcin promotes neuronal differentiation and inhibits astrocytic differentiation in neural stem cells. Stem Cell Reports 8(1):95–111CrossRefPubMedGoogle Scholar
  36. 36.
    Hogg RC, Chipperfield H, Whyte KA, Stafford MR, Hansen MA, Cool SM, Nurcombe V, Adams DJ (2004) Functional maturation of isolated neural progenitor cells from the adult rat hippocampus. Eur J Neurosci 19(9):2410–2420CrossRefPubMedGoogle Scholar
  37. 37.
    Johnson MA, Weick JP, Pearce RA, Zhang SC (2007) Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci 27(12):3069–3077CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Toda H, Takahashi J, Mizoguchi A, Koyano K, Hashimoto N (2000) Neurons generated from adult rat hippocampal stem cells form functional glutamatergic and GABAergic synapses in vitro. Exp Neurol 165(1):66–76CrossRefPubMedGoogle Scholar
  39. 39.
    Owens DF, Kriegstein AR (2002) Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 3(9):715–727CrossRefPubMedGoogle Scholar
  40. 40.
    Shen JM, Huguenard JR, Kriegstein AR (1988) Development of GABA responsiveness in embryonic turtle cortical neurons. Neurosci Lett 89(3):335–341CrossRefPubMedGoogle Scholar
  41. 41.
    Hennou S, Khalilov I, Diabira D, Ben-Ari Y, Gozlan H (2002) Early sequential formation of functional GABA(A) and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus. Eur J Neurosci 16(2):197–208CrossRefPubMedGoogle Scholar
  42. 42.
    Lujan R, Shigemoto R, Lopez-Bendito G (2005) Glutamate and GABA receptor signalling in the developing brain. Neuroscience 130(3):567–580CrossRefPubMedGoogle Scholar
  43. 43.
    Herlenius E, Lagercrantz H (2004) Development of neurotransmitter systems during critical periods. Exp Neurol 190(Suppl 1):S8–21CrossRefPubMedGoogle Scholar
  44. 44.
    Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Petri S, Krampfl K, Dengler R, Bufler J, Weindl A, Arzberger T (2002) Human GABA A receptors on dopaminergic neurons in the pars compacta of the substantia nigra. J Comp Neurol 452(4):360–366CrossRefPubMedGoogle Scholar
  46. 46.
    Tepper JM, Lee CR (2007) GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res 160:189–208CrossRefPubMedGoogle Scholar
  47. 47.
    Ling ZD, Potter ED, Lipton JW, Carvey PM (1998) Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 149(2):411–423CrossRefPubMedGoogle Scholar
  48. 48.
    Gomi M, Aoki T, Takagi Y, Nishimura M, Ohsugi Y, Mihara M, Nozaki K, Hashimoto N et al (2011) Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells. J Neurosci Res 89(9):1388–1399CrossRefPubMedGoogle Scholar
  49. 49.
    Oh J, McCloskey MA, Blong CC, Bendickson L, Nilsen-Hamilton M, Sakaguchi DS (2010) Astrocyte-derived interleukin-6 promotes specific neuronal differentiation of neural progenitor cells from adult hippocampus. J Neurosci Res 88(13):2798–2809PubMedPubMedCentralGoogle Scholar
  50. 50.
    Pratt L, Ni L, Ponzio NM, Jonakait GM (2013) Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6. Pediatr Res 74(4):393–401CrossRefPubMedGoogle Scholar
  51. 51.
    Chucair-Elliott AJ, Conrady C, Zheng M, Kroll CM, Lane TE, Carr DJ (2014) Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia 62(9):1418–1434CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cao F, Hata R, Zhu P, Nakashiro K, Sakanaka M (2010) Conditional deletion of Stat3 promotes neurogenesis and inhibits astrogliogenesis in neural stem cells. Biochem Biophys Res Commun 394(3):843–847CrossRefPubMedGoogle Scholar
  53. 53.
    Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H (2007) Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci 25(3):649–658CrossRefPubMedGoogle Scholar
  54. 54.
    Taga T, Fukuda S (2005) Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 28(3):249–256CrossRefPubMedGoogle Scholar
  55. 55.
    Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486–492PubMedGoogle Scholar
  56. 56.
    Takizawa T, Yanagisawa M, Ochiai W, Yasukawa K, Ishiguro T, Nakashima K, Taga T (2001) Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3. Cytokine 13(5):272–279CrossRefPubMedGoogle Scholar
  57. 57.
    Galli R, Pagano SF, Gritti A, Vescovi AL (2000) Regulation of neuronal differentiation in human CNS stem cell progeny by leukemia inhibitory factor. Dev Neurosci 22(1–2):86–95CrossRefPubMedGoogle Scholar
  58. 58.
    Foshay KM, Gallicano GI (2008) Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. Stem Cells Dev 17(2):269–278CrossRefPubMedGoogle Scholar
  59. 59.
    Snyder M, Huang XY, Zhang JJ (2011) Stat3 is essential for neuronal differentiation through direct transcriptional regulation of the Sox6 gene. FEBS Lett 585(1):148–152CrossRefPubMedGoogle Scholar
  60. 60.
    Cheng X, Jin G, Zhang X, Tian M, Zou L (2011) Stage-dependent STAT3 activation is involved in the differentiation of rat hippocampus neural stem cells. Neurosci Lett 493(1–2):18–23CrossRefPubMedGoogle Scholar
  61. 61.
    Ng YP, Cheung ZH, Ip NY (2006) STAT3 as a downstream mediator of Trk signaling and functions. J Biol Chem 281(23):15636–15644CrossRefPubMedGoogle Scholar
  62. 62.
    Yang P, Wen H, Ou S, Cui J, Fan D (2012) IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation. Exp Neurol 236(1):19–27CrossRefPubMedGoogle Scholar
  63. 63.
    Ng DC, Lin BH, Lim CP, Huang G, Zhang T, Poli V, Cao X (2006) Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol 172(2):245–257CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Galun E, Rose-John S (2013) The regenerative activity of interleukin-6. Methods Mol Biol 982:59–77CrossRefPubMedGoogle Scholar
  65. 65.
    Schafer KH, Mestres P, Marz P, Rose-John S (1999) The IL-6/sIL-6R fusion protein hyper-IL-6 promotes neurite outgrowth and neuron survival in cultured enteric neurons. J Interf Cytokine Res 19(5):527–532CrossRefGoogle Scholar
  66. 66.
    Kikuchi T, Morizane A, Doi D, Okita K, Nakagawa M, Yamakado H, Inoue H, Takahashi R et al (2017) Idiopathic Parkinson’s disease patient-derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains. J Neurosci Res. doi: 10.1002/jnr.24014 PubMedGoogle Scholar
  67. 67.
    Xiao B, Ng HH, Takahashi R, Tan EK (2016) Induced pluripotent stem cells in Parkinson’s disease: scientific and clinical challenges. J Neurol Neurosurg Psychiatry 87(7):697–702CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Stoker TB, Barker RA (2016) Cell therapies for Parkinson’s disease: how far have we come? Regen Med 11(8):777–786CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Pen AE, Jensen UB (2017) Current status of treating neurodegenerative disease with induced pluripotent stem cells. Acta Neurol Scand 135(1):57–72CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Graduate School of Biomedical Science and EngineeringHanyang UniversitySeongdong-guRepublic of Korea

Personalised recommendations