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Amino Acids

, Volume 48, Issue 8, pp 1913–1927 | Cite as

The effects of creatine supplementation on striatal neural progenitor cells depend on developmental stage

  • Robert H. Andres
  • Angelique D. Ducray
  • Lukas Andereggen
  • Tabea Hohl
  • Uwe Schlattner
  • Theo Wallimann
  • Hans R. WidmerEmail author
Original Article
Part of the following topical collections:
  1. Creatine

Abstract

Transplantation of neural progenitor cells (NPCs) is a promising experimental therapy for Huntington’s disease (HD). The variables responsible for the success of this approach, including selection of the optimal developmental stage of the grafted cells, are however largely unknown. Supporting cellular energy metabolism by creatine (Cr) supplementation is a clinically translatable method for improving cell transplantation strategies. The present study aims at investigating differences between early (E14) and late (E18) developmental stages of rat striatal NPCs in vitro. NPCs were isolated from E14 and E18 embryos and cultured for 7 days with or without Cr [5 mM]. Chronic treatment significantly increased the percentage of GABA-immunoreactive neurons as compared to untreated controls, both in the E14 (170.4 ± 4.7 %) and the E18 groups (129.3 ± 9.3 %). This effect was greater in E14 cultures (p < 0.05). Similarly, short-term treatment for 24 h resulted in increased induction (p < 0.05) of the GABA-ergic phenotype in E14 (163.0 ± 10.4 %), compared to E18 cultures (133.3 ± 9.5 %). Total neuronal cell numbers and general viability were not affected by Cr (p > 0.05). Protective effects of Cr against a metabolic insult were equal in E14 and E18 NPCs (p > 0.05). Cr exposure promoted morphological differentiation of GABA-ergic neurons, including neurite length in both groups (p < 0.05), but the number of branching points was increased only in the E18 group (p < 0.05). Our results demonstrate that the role of Cr as a GABA-ergic differentiation factor depends on the developmental stage of striatal NPCs, while Cr-mediated neuroprotection is not significantly influenced. These findings have potential implications for optimizing future cell replacement strategies in HD.

Keywords

Creatine Creatine kinase GABA Differentiation Neuroprotection Development 

Abbreviations

ATP

Adenosine triphosphate

BB-CK

Brain-type cytosolic isoform of CK

CK

Creatine kinase

CNS

Central nervous system

Cr

Creatine

CRT

Creatine transporter

Cx

Cortex

DAB

3,3′-Diaminobenzidine

DIV

Day in vitro

DMEM

Dulbecco’s modified Eagle medium

FCS

Fetal calf serum

DMSO

Dimethylsulfoxyde

E14

Embryonic day 14

E18

Embryonic day 18

GAA

Guanidinoacetate

GAMT

Guanidinoacetate methyltransferase

GE

Ganglionic eminence

GFAP

Glial fibrillary acidic protein

HBSS

Hank’s balanced salt solution

HD

Huntington’s disease

HS

Horse serum

ir

Immunoreactive

Me

Mesencephalon

MTT

3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NSC

Neural stem cell

NPC

Neural progenitor cell

PCr

Phosphocreatine

Rh

Rhombencephalon

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

SC

Spinal cord

SDS

Sodium dodecyl sulfate

uMt-CK

Ubiquitous mitochondrial isoform of CK

Notes

Acknowledgments

We would like to thank Susanne Wälchli, Sandra Krebs, Daniela Olac-Gaona and Tanja Guzman for excellent technical assistance. Professor Roger Harris is kindly acknowledged for careful reading of the manuscript. Highly purified creatine monohydrate (Creapure™) was a gift from AlzChem Trostberg, Germany. The study was supported by the Swiss National Science Foundation (Grants No. 31-064975.01, 31-050824, 31-102075/1, 3100A0-112529, 31003A-135565, PBBEB-117034 and PASMP3-123221/1), by the Department of Clinical Research at the University of Berne, by the Swiss Society for Research on Muscle Diseases and by the German Parents Organization for Muscle Patients, Benni & Co.

Compliance with ethical standards

Ethical statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals, as well as human embryonic tissues were approved and in accordance with the ethical standards of the institutions (Department of Neurosurgery, Inselspital, University of Berne, Swiss Federal Institute of Technology, Zurich, and Boston Children’s Hospital, Harvard Medical School) at which the studies were conducted.

Conflicts of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Robert H. Andres
    • 1
  • Angelique D. Ducray
    • 1
  • Lukas Andereggen
    • 1
    • 2
  • Tabea Hohl
    • 1
  • Uwe Schlattner
    • 3
    • 4
  • Theo Wallimann
    • 5
  • Hans R. Widmer
    • 1
    Email author
  1. 1.Department of NeurosurgeryUniversity of Berne, InselspitalBerneSwitzerland
  2. 2.Department of Neurosurgery and F.M. Kirby Neurobiology Center, Boston Children’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Laboratory of Fundamental and Applied BioenergeticsUniversité Grenoble Alpes, BP53Grenoble CedexFrance
  4. 4.Inserm, U1055, BP53Grenoble CedexFrance
  5. 5.Professor emeritus, formerly at Institute of Cell BiologySwiss Federal Institute of Technology (ETH)ZurichSwitzerland

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