Enhanced differentiation of human induced pluripotent stem cells toward the midbrain dopaminergic neuron lineage through GLYPICAN-4 downregulation

Serena Corti, Remi Bonjean, Thomas Legier, Diane Rattier, Christophe Melon, Pascal Salin, Erik A. Toso, Michael Kyba, Lydia Kerkerian-Le Goff, Flavio Maina, Rosanna Dono

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Enhancing the differentiation potential of human induced pluripotent stem cells (hiPSC) into disease-relevant cell types is instrumental for their widespread application in medicine. Here, we show that hiPSCs downregulated for the signaling modulator GLYPICAN-4 (GPC4) acquire a new biological state characterized by increased hiPSC differentiation capabilities toward ventral midbrain dopaminergic (VMDA) neuron progenitors. This biological trait emerges both in vitro, upon exposing cells to VMDA neuronal differentiation signals, and in vivo, even when transplanting hiPSCs at the extreme conditions of floor-plate stage in rat brains. Moreover, it is compatible with the overall neuronal maturation process toward acquisition of substantia nigra neuron identity. HiPSCs with downregulated GPC4 also retain self-renewal and pluripotency in stemness conditions, in vitro, while losing tumorigenesis in vivo as assessed by flank xenografts. In conclusion, our results highlight GPC4 downregulation as a powerful approach to enhance generation of VMDA neurons. Outcomes may contribute to establish hiPSC lines suitable for translational applications.

Original languageEnglish (US)
Pages (from-to)725-742
Number of pages18
JournalStem Cells Translational Medicine
Volume10
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press

Keywords

  • GLYPICAN-4
  • hPSC-derived dopaminergic neurons
  • hiPSCs
  • intrastriatal transplantation
  • self-renewal and differentiation

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