Tristan Bouschet, K. John McLaughlin, Sigrid Eckardt, Laurent Journot, Chantal Ripoll, Benoît Girard, Annie Varrault, Anne Le Digarcher, Armen Badalyan, Céline Meusnier, Federica Bertaso, Isabelle Sassetti
One strategy for stem cell-based therapy of the cerebral cortex involves the generation and transplantation of functional, histocompatible cortical-like neurons from embryonic stem cells (ESCs). Diploid parthenogenetic Pg-ESCs have recently emerged as a promising source of histocompatible ESC derivatives for organ regeneration but their utility for cerebral cortex therapy is unknown. A major concern with Pg-ESCs is genomic imprinting. In contrast with biparental Bp-ESCs derived from fertilized oocytes, Pg-ESCs harbor two maternal genomes but no sperm-derived genome. Pg-ESCs are therefore expected to have aberrant expression levels of maternally expressed (MEGs) and paternally expressed (PEGs) imprinted genes. Given the roles of imprinted genes in brain development, tissue homeostasis and cancer, their deregulation in Pg-ESCs might be incompatible with therapy. Here, we report that, unexpectedly, only one gene out of 7 MEGs and 12 PEGs was differentially expressed between Pg-ESCs and Bp-ESCs while 13 were differentially expressed between androgenetic Ag-ESCs and Bp-ESCs, indicating that Pg-ESCs but not Ag-ESCs, have a biparental-like imprinting compatible with therapy. In vitro, Pg-ESCs generated cortical-like progenitors and electrophysiologically active glutamatergic neurons that maintained the biparental-like expression levels for most imprinted genes. In vivo, Pg-ESCs participated to the cortical lineage in fetal chimeras. Finally, transplanted Pg-ESC derivatives integrated into the injured adult cortex and sent axonal projections in the host brain.
In conclusion, mouse Pg-ESCs generate functional cortical-like neurons with biparental-like imprinting and their derivatives properly integrate into both the embryonic cortex and the injured adult cortex. Collectively, our data support the utility of Pg-ESCs for cortical therapy. This article is protected by copyright. All rights reserved.
Parthenogenetic Pg-ESCs can be more easily selected for histocompatibility than normal biparental (Bp) ESC lines. However, the application of Pg-ESCs to cortical therapy is unknown and their parental imprinting might be incompatible with therapy. We report that mouse Pg-ESCs had a biparental-like expression of imprinted genes (while androgenetic Ag-ESCs did not) and that they generated cortical-like progenitors and electrophysiologically active neurons. In vivo, transplanted Pg-ESC derivatives integrated into the injured adult cortex. Collectively, this supports the utility of Pg-ESCs for neocortex repair.
