284352 20260218110649.0 10.3389/fncel.2025.1677505 doi pmid:41602576 pmid pmc:PMC12832296 pmc DZNE-2026-00123 English 610 Hartung, Theresa P:(DE-HGF)0 0 First author Non-hematopoietic erythropoietin splice variant is produced in the diseased human brain and confers neuroprotection. Lausanne 2026 Frontiers Research Foundation article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1771328993_32560 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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 hS3 is part of the endogenous neuroprotective system in the human brain with significant therapeutic potential. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de alternative splicing Other cell-free glycoprotein synthesis Other erythropoietin Other in situ hybridization Other neuroprotection Other oxygen glucose deprivation Other pluripotent stem cells Other Freyer, Dorette 1 Zemella, Anne 2 Radbruch, Helena 3 Weiner, January 4 El-Din, Jasmin Jamal P:(DE-HGF)0 5 Meisel, Andreas 6 Priller, Josef P:(DE-2719)2811122 7 Last author dzne 10.3389/fncel.2025.1677505 Vol. 19, p. 1677505 PERI:(DE-600)2452963-1 1677505 Frontiers in cellular neuroscience 19 2026 1662-5102 http://pub.dzne.de/record/284352/files/DZNE-2026-00123.pdf OpenAccess http://pub.dzne.de/record/284352/files/DZNE-2026-00123.pdf?subformat=pdfa pdfa OpenAccess oai:pub.dzne.de:284352 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-HGF)0 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-HGF)0 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 7 P:(DE-2719)2811122 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2024-12-14 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2024-12-14 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2024-12-14 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2024-12-14 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record 2024-12-14 JCR StatID:(DE-HGF)0100 StatID FRONT CELL NEUROSCI : 2022 2024-12-14 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2023-12-04T12:35:29Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2023-12-04T12:35:29Z WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2024-12-14 Fees StatID:(DE-HGF)0700 StatID 2024-12-14 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2024-12-14 OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review 2023-12-04T12:35:29Z Article Processing Charges StatID:(DE-HGF)0561 StatID 2024-12-14 IF >= 5 StatID:(DE-HGF)9905 StatID FRONT CELL NEUROSCI : 2022 2024-12-14 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2024-12-14 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2024-12-14 I:(DE-2719)5000007 AG Priller Translational Neuropsychiatry 0 journal VDB I:(DE-2719)5000007 UNRESTRICTED FullTexts