Phenotype and Stability of Neural Differentiation of Androgenetic Murine ES Cell-Derived Neural Progenitor Cells

Abstract

Uniparental zygotes with two paternal (androgenetic, AG) or two maternal genomes (gynogenetic, GG) cannot develop into viable offsprings but form blastocysts from which pluripotent embryonic stem (ES) cells can be derived. For most organs, it is unclear whether uniparental ES cells can give rise to stably expandable somatic stem cells that can repair injured tissues. Even if previous reports indicated that the capacity of AG ES cells to differentiate in vitro into pan-neural progenitor cells (pNPCs) and into cells expressing neural markers is similar to biparental [normal fertilized (N)] ES cells, their potential for functional neurogenesis is not known. Here we show that murine AG pNPCs give rise to neuron-like cells, which then generate sodium-driven action potentials while maintaining fidelity of imprinted gene expression. Neural engraftment after intracerebral transplantation was achieved only by late (22 days) AG and N pNPCs with in vitro low colony-forming cell (CFC) capacity. However, persisting CFC formation seen, in particular, in early (13 or 16 days) differentiation cultures of N and AG pNPCs correlated with a high incidence of trigerm layer teratomas. As AG ES cells display functional neurogenesis and in vivo stability similar to N ES cells, they represent a unique model system to study the roles of paternal and maternal genomes on neural development and on the development of imprinting-associated brain diseases.

5. Themenbereich Stammzellen: Aktuelle Entwicklungen der Stammzellforschung in Deutschland

“…In differenzierenden AG-ES-Zellen zeigte sich, dass diese Zellen trotz eines fehlenden mütterlichen Genoms neurale Stammzellen (AG-NSCs) bilden, die sich in ihrer Fähigkeit zur Selbsterneuerung und im Multilinien-Differenzierungspotenzial nicht von normalen neuralen Stammzellen (NSCs) unterscheiden (Dinger et al, 2008). Ferner können AG-ES-Zellen zu dopaminergen Neuronen 25 differenzieren (Choi et al, 2005), die neuronale Aktionspotenziale generieren (Wolber, 2013). Dabei bleibt die rein väterliche Genexpression erhalten (Dinger et al, 2008).…”

Inhibition by miR-410 facilitates direct retinal pigment epithelium differentiation of umbilical cord blood-derived mesenchymal stem cells

“…Those RPE cells survived in a host eye and rescued retinal function after subretinal transplantation in a rat model of retinal degeneration. However, a clinical study using pluripotent stem cell-derived RPE cells suggested a severe risk to patients, such as teratoma formation of the remaining undifferentiated ES cells in the host after transplantation [22]. In studies to improve the safety of cell replacement therapy, such as sorting of undifferentiated cells by using SOX1 or SSEA-5 and long-term culturing for differentiation [2122], somatic stem cells have emerged as a useful source for clinical use.…”

Direct cell fate conversion of human somatic stem cells into cone and rod photoreceptor-like cells by inhibition of microRNA-203

“…For example, ES cell-derived neural progenitor cells could give rise to teratomas in a host because of their unlimited self-renewal ability, while somatic stem cells cannot because of their limited self-renewal ability [30]. However, it is important to note that ES cells can proliferate in vitro and in vivo following transplantation.…”