Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host
Open Access
- 10 February 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (11), 5184-5189
- https://doi.org/10.1073/pnas.0915134107
Abstract
How grafted neural stem cells (NSCs) and their progeny integrate into recipient brain tissue and functionally interact with host cells is as yet unanswered. We report that, in organotypic slice cultures analyzed by ratiometric time-lapse calcium imaging, current-clamp recordings, and dye-coupling methods, an early and essential way in which grafted murine or human NSCs integrate functionally into host neural circuitry and affect host cells is via gap-junctional coupling, even before electrophysiologically mature neuronal differentiation. The gap junctions, which are established rapidly, permit exogenous NSCs to influence directly host network activity, including synchronized calcium transients with host cells in fluctuating networks. The exogenous NSCs also protect host neurons from death and reduce such signs of secondary injury as reactive astrogliosis. To determine whether gap junctions between NSCs and host cells may also mediate neuroprotection in vivo, we examined NSC transplantation in two murine models characterized by degeneration of the same cell type (Purkinje neurons) from different etiologies, namely, the nervous and SCA1 mutants. In both, gap junctions (containing connexin 43) formed between NSCs and host cells at risk, and were associated with rescue of neurons and behavior (when implantation was performed before overt neuron loss). Both in vitro and in vivo beneficial NSC effects were abrogated when gap junction formation or function was suppressed by pharmacologic and/or RNA-inhibition strategies, supporting the pivotal mediation by gap-junctional coupling of some modulatory, homeostatic, and protective actions on host systems as well as establishing a template for the subsequent development of electrochemical synaptic intercellular communication.Keywords
This publication has 18 references indexed in Scilit:
- Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cellsProceedings of the National Academy of Sciences of the United States of America, 2007
- Synapse formation on neurons born in the adult hippocampusNature Neuroscience, 2007
- Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic diseaseNature Medicine, 2007
- Neural Stem Cells RescuenervousPurkinje Neurons by Restoring Molecular Homeostasis of Tissue Plasminogen Activator and Downstream TargetsJournal of Neuroscience, 2006
- Purkinje neuron degeneration in nervous ( nr ) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activatorProceedings of the National Academy of Sciences of the United States of America, 2006
- Connexin‐specific cell‐to‐cell transfer of short interfering RNA by gap junctionsThe Journal of Physiology, 2005
- Expression profile of an operationally-defined neural stem cell cloneExperimental Neurology, 2005
- Calcium Waves Propagate through Radial Glial Cells and Modulate Proliferation in the Developing NeocortexNeuron, 2004
- Membrane properties of rat embryonic multipotent neural stem cellsJournal of Neurochemistry, 2003
- Organotypic slice cultures: a technique has come of ageTrends in Neurosciences, 1997