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@ARTICLE{Hartung:284352,
      author       = {Hartung, Theresa and Freyer, Dorette and Zemella, Anne and
                      Radbruch, Helena and Weiner, January and El-Din, Jasmin
                      Jamal and Meisel, Andreas and Priller, Josef},
      title        = {{N}on-hematopoietic erythropoietin splice variant is
                      produced in the diseased human brain and confers
                      neuroprotection.},
      journal      = {Frontiers in cellular neuroscience},
      volume       = {19},
      issn         = {1662-5102},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DZNE-2026-00123},
      pages        = {1677505},
      year         = {2025},
      abstract     = {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.},
      keywords     = {alternative splicing (Other) / cell-free glycoprotein
                      synthesis (Other) / erythropoietin (Other) / in situ
                      hybridization (Other) / neuroprotection (Other) / oxygen
                      glucose deprivation (Other) / pluripotent stem cells
                      (Other)},
      cin          = {AG Priller},
      ddc          = {610},
      cid          = {I:(DE-2719)5000007},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41602576},
      pmc          = {pmc:PMC12832296},
      doi          = {10.3389/fncel.2025.1677505},
      url          = {https://pub.dzne.de/record/284352},
}