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

Abstract

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).

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Abbreviations

AD:

Alzheimer’s disease

AKT:

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

ALP:

Alkaline phosphatase

AMPA:

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

AP:

Action potential

APC:

Allophycocyanin

BDNF:

Brain-derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

BMP:

Bone morphogenetic protein

BSA:

Bovine serum albumin

CD15:

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

CD24:

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

CD44:

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

CD184:

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

CD271:

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

CH3:

Methyl-, methylation

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

CREB:

cAMP-responsive element binding protein

Cy:

Cyanine

DAPI:

4′,6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s modified Eagle medium

EDTA:

Ethylenediaminetetraacetic acid

EGF:

Epidermal growth factor

ERK:

Extracellular-regulated microtubule-associated protein kinase

FACS:

Fluorescence-activated cell sorting

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

FM:

Fibroblast media

FOS:

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

GAB1:

GRB2-associated-binding protein 1

GABA:

Gamma-aminobutyric acid

GABAA-R:

Gamma-aminobutyric acid-A receptor

GF:

Growth factor

GFAP:

Glial fibrillary acidic protein

i-Glu-R:

Ionotropic glutamate receptor

gp130:

Glycoprotein 130

GRB2:

Growth factor receptor bound protein 2

HEPES:

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

ICC:

Immunocytochemistry

IL-6:

Interleukin-6

IL-6R:

Interleukin-6 receptor

IL6ST:

Interleukin-6 signal transducing receptor subunit (gp130)

iPSCs:

Induced pluripotent stem cells

JAK:

Janus kinase

JNK:

c-Jun N-terminal kinase

JUN:

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

Klf4:

Kruppel-like factor 4

Lif:

Leukemia inhibitory factor

Lin28:

Lin-28 homolog

L-Myc:

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

MAP2:

Microtubule-associated protein 2

MAPK:

Microtubule-associated protein kinase

MAPT:

Microtubule-associated protein tau

MKI67:

Marker of proliferation Ki-67

MYC:

Myelocytomatosis viral oncogene

NB:

Neurobasal media

NEUN:

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

NEAA:

Non-essential amino acids

NHDF:

Normal human dermal fibroblast cells

NMDA:

N-Methyl-d-aspartate

NSC:

Neural stem cell

OCT4:

POU class 5 homeobox 1 (POU5F1)

P:

Passages

p53:

Tumor protein 53

PBS:

Phosphate buffer saline

PD:

Parkinson’s disease

PE:

Phycoerythrin cyanine

PerCP:

Peridinin chlorophyll protein complex

PFA:

Paraformaldehyde

PI3K:

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

PODXL:

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

P/S:

Penicillin, streptomycin

RAS:

Sarcoma virus oncogene (small G-protein)

RMP:

Resting membrane potential

SFK:

src-family kinase

sgp130:

Soluble glycoprotein 130

SHP1/2:

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

shRNA:

Short hairpin RNA

sIL-6R:

Soluble interleukin-6 receptor

SMAD:

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

SOCS3:

Suppressor of cytokine signaling 3

SOX2/6:

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

SOS:

Son of sevenless protein

SSEA3/4:

Stage-specific embryonic antigen 3, -4

STAT3:

Signal transducer and activator of transcription 3

TF:

Transcription factor

TGFβ:

Transforming growth factor beta

TRA-1-60/81:

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

TRKB:

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

TRKB.T1:

Truncated TRKB (without kinase domain)

TTX:

Tetrodotoxin

TUBB3:

β-Tubulin isotype III (also TUJ1)

VD:

Vascular dementia

YAP:

Yes-associated protein

Y-P:

Phosphorylated tyrosine

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Acknowledgements

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).

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Correspondence to Klaus Heese.

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The authors declare that they have no conflicts of interest.

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Sulistio, Y.A., Lee, H.K., Jung, S.J. et al. Interleukin-6-Mediated Induced Pluripotent Stem Cell (iPSC)-Derived Neural Differentiation. Mol Neurobiol 55, 3513–3522 (2018). https://doi.org/10.1007/s12035-017-0594-3

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Keywords

  • BDNF
  • Brain
  • Interleukin-6
  • Neuron
  • Neurotrophin
  • STAT3