Engraftment of nonintegrating neural stem cells differentially perturbs cortical activity in a dose-dependent manner

Abstract

Neural stem cell (NSC) therapy represents a potentially powerful approach for gene transfer in the diseased central nervous system. However, transplanted primary, embryonic stem cell- and induced pluripotent stem cell-derived NSCs generate largely undifferentiated progeny. Understanding how physiologically immature cells influence host activity is critical to evaluating the therapeutic utility of NSCs. Earlier inquiries were limited to single-cell recordings and did not address the emergent properties of neuronal ensembles. To interrogate cortical networks post-transplant, we used voltage sensitive dye imaging in mouse neocortical brain slices, which permits high temporal resolution analysis of neural activity. Although moderate NSC engraftment largely preserved host physiology, subtle defects in the activation properties of synaptic inputs were induced. High-density engraftment severely dampened cortical excitability, markedly reducing the amplitude, spatial extent, and velocity of propagating synaptic potentials in layers 2-6. These global effects may be mediated by specific disruptions in excitatory network structure in deep layers. We propose that depletion of endogenous cells in engrafted neocortex contributes to circuit alterations. Our data provide the first evidence that nonintegrating cells cause differential host impairment as a function of engrafted load. Moreover, they emphasize the necessity for efficient differentiation methods and proper controls for engraftment effects that interfere with the benefits of NSC therapy.

Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases

“…Another concern is that high levels of donor NSC engraftment can interfere with neuronal circuits; however, the level required to interfere with function appears to be well above that needed for therapy. 114…”

Interneuron Progenitor Transplantation to Treat CNS Dysfunction

“…In addition transplanted neural cells have been proposed to create homeostatic environments by releasing factors that repair and counter inflammation and scarring ( Park et al, 2002 ; Lee et al, 2007 ). More recently, interrogation of host circuit physiology following engraftment of undifferentiated and non-integrating cells revealed a dose-dependent dampening of cortical excitability and depletion of host cell populations underscoring the importance of engraftment density in designing cell based therapeutic protocols ( Weerakkody et al, 2013 ). Considering the wide-ranging repertoire of transplant-induced effects, discovery of molecular mechanisms underlying these may uncover novel treatment targets in the future.…”

Immature Interneurons Create a Lasting Impression

“…Looking only at the electrophysiology of the hPSC inter-neurons, one might even suspect that they are not inhibitory interneurons at all. Moreover, nonintegrating cells are a worry, as a prior study showed that transplants into the developing cortex of a high number of nonintegrating neural stem cells caused defects in cortical network function (10). These concerns are somewhat alleviated by single-cell reverse transcription-polymerase chain reaction (RT-PCR) experiments, demonstrating expression of genes indicative of GABAergic interneuron fates, as well as the synaptic physiology; fully mature or not, these transplants are well integrated into the host circuitry and can supply robust GABAergic inhibition to their neighbors, as demonstrated by an impressive number of intracellular recordings in the acute slice preparation in a variety of configurations.…”