Erythropoietin promotes regeneration of adult CNS neurons via Jak2/Stat3 and PI3K/AKT pathway activation.
The cytokine hormone erythropoietin (EPO) has proved neuroprotective in CNS injury, and clinical trials for ischemic stroke are ongoing. The capability of EPO to restore postmitotic CNS architecture and function by fibre regeneration has not been examined. Here, we compared in vitro outgrowth capacity of adult retinal ganglion cells (RGCs) following optic nerve (ON) lesion in the presence and absence of EPO. Immediate EPO conditioning in vivo, or delayed EPO treatment of cultures with 10--10,000 IU rhEPO significantly increased numbers (2.66-fold) and length (8.31-fold) of newly generated neurites, without evoking rheological complications. EPO induced Stat3 phosphorylation in RGCs, and inhibition of Jak2/Stat3 abolished EPO-induced growth. EPO-facilitated neuritogenesis was paralleled by upregulation of Bcl-X(L), a Bcl-2 homologue capable of promoting RGC regeneration. The PI3K/Akt pathway was also involved in antiapoptotic and regeneration-enhancing EPO actions. In conclusion, EPO treatment may offer a unique dual-function strategy for neuroprotection and regeneration.
Kretz
Alexandra
A
Department of Neurology, Neuroregeneration Laboratory, University of Jena Medical School, Erlanger Allee 101, D-07747 Jena, Germany. alexandra.kretz@med.uni-jena.de
Happold
Caroline J
CJ
Marticke
Julia K
JK
Isenmann
Stefan
S
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D053614:Janus Kinase 2; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2