Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Cell. Neurosci.

Sec. Cellular Neurophysiology

Non-hematopoietic erythropoietin splice variant is produced in the diseased human brain and confers neuroprotection

Provisionally accepted
Theresa HartungTheresa Hartung1,2,3*Dorette FreyerDorette Freyer1Anne ZemellaAnne Zemella4Helena RadbruchHelena Radbruch5January WeinerJanuary Weiner6Jasmin Jamal El-DinJasmin Jamal El-Din3Andreas MeiselAndreas Meisel1,7,8Josef PrillerJosef Priller10,11,9
  • 1Department of Neurology with Experimental Neurology, Charite - Universitatsmedizin Berlin, Berlin, Germany
  • 2Berlin Institute of Health at Charite, Berlin, Germany
  • 3Neuropsychiatry and Laboratory of Molecular Psychiatry, Charite - Universitatsmedizin Berlin Klinik fur Psychiatrie und Psychotherapie Campus Charite Mitte, Berlin, Germany
  • 4Fraunhofer-Institut fur Zelltherapie und Immunologie Institutsteil Bioanalytik und Bioprozesse IZI-BB, Potsdam, Germany
  • 5Department of Neuropathology, Charite - Universitatsmedizin Berlin, Berlin, Germany
  • 6Core Unit Bioinformatics, Berlin Institute of Health at Charite, Berlin, Germany
  • 7Charite - Universitatsmedizin Berlin Centrum fur Schlaganfallforschung Berlin, Berlin, Germany
  • 8Charite - Universitatsmedizin Berlin Neurowissenschaftliches Forschungszentrum, Berlin, Germany
  • 9Neuropsychiatry and Laboratory of Molecular Psychiatry, Charite - Universitatsmedizin Berlin, Berlin, Germany
  • 10Department of Psychiatry and Psychotherapy and DZPG, Technische Universitat Munchen, Munich, Germany
  • 11The University of Edinburgh Centre for Clinical Brain Sciences, Edinburgh, United Kingdom

The final, formatted version of the article will be published soon.

Select one of your emails

You have multiple emails registered with Frontiers:

Notify me on publication

Please enter your email address:

If you already have an account, please login

You don't have a Frontiers account ? You can register here

Erythropoietin (EPO) is a pleiotropic cytokine with important functions in neuronal development and neuroprotection, but hematopoietic effects limit the therapeutic application of EPO in neurological diseases. We discovered human endogenous EPO splice variants that are non-hematopoietic but cytoprotective. Here, we demonstrate at the single-cell level that an alternative splice variant lacking exon 3 (hS3) is expressed in the human brain and is upregulated above EPO mRNA levels in ischemic and inflammatory neurological diseases. Conversely, hS3 mRNA expression is reduced below EPO levels in neurodegenerative disease. In an oxygen-glucose deprivation (OGD) model of ischemia, a single dose of cell-free synthesized constant glycosylated active hS3 protects neuronal cultures derived from human induced pluripotent stem cells (hiPSC) and human embryonic stem cells (hESC) more effectively than EPO. We identify the D-helix as a key functional domain of hS3 and demonstrate that the neuroprotective effect is enhanced by PD29, a novel small peptide derived from the D-helix of hS3. Long-term hS3 administration increases the neuroprotective effects in the OGD model by dose-dependent differential expression of apoptosis-related protein-coding genes and long non-coding RNAs (lncRNAs). In addition, our results suggest that hS3 induces early cell cycle inhibition without impairing differentiation of hiPSC and hESC into neuronal subtypes. In conclusion, EPO splice variant hS3s are is part of the endogenous neuroprotective system in the human brain with significant therapeutic potential.

Keywords: Alternative Splicing, cell-free glycoprotein synthesis, Erythropoietin, In Situ Hybridization, Neuroprotection, oxygenglucose deprivation, Pluripotent Stem Cells

Received: 31 Jul 2025; Accepted: 08 Dec 2025.

Copyright: © 2025 Hartung, Freyer, Zemella, Radbruch, Weiner, El-Din, Meisel and Priller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Theresa Hartung

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material