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

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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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Authors and Affiliations

  1. Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 133-791, Republic of Korea

    Yanuar Alan Sulistio, Han Kyu Lee, Sung Jun Jung & Klaus Heese

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  1. Yanuar Alan Sulistio
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  2. Han Kyu Lee
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Correspondence to Klaus Heese.

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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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