Activation by ACA induces pluripotency in human blood progenitor cells.

Reprogramming of human somatic cells by transcription factors to pluripotent state holds great promise for regenerative medicine. However, low efficiencies of current reprogramming methods, immunogenicity and lack of understanding regarding the molecular mechanisms responsible for their generation, limits their utilization and raises questions regarding safety for therapeutic application. Here we report that ACA signaling via PI3K/Akt/mTor induces sustained de-differentiation of human blood progenitor cells leading to generation of ACA pluripotent stem cells. Blood-derived pluripotent stem cells differentiate in vitro into cell types of all three germ layers, exhibiting neuronal, liver, or endothelial characteristics. Our results reveal insight into the molecular events regulating cellular reprogramming and also indicate that pluripotency might be controlled in vivo through binding of a natural ligand(s) to ACA receptor enabling reprogramming through defined pathway(s) and providing a safe and efficient method for generation of pluripotent stem cells which could be a breakthrough in human therapeutics.

Transplant of GABAergic precursors restores hippocampal inhibitory function in a mouse model of seizure susceptibility.

Defects in GABAergic function can cause epilepsy. In the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.