Electric Field ApplicationIn VivoRegulates Neural Precursor Cell Behavior in the Adult Mammalian Forebrain

Abstract

Deep brain stimulation (DBS), which uses electrical stimulation, is a well-established neurosurgical technique used to treat neurologic disorders. Despite its broad therapeutic use, the effects of electrical stimulation on brain cells is not fully understood. Here, we examine the effects of electrical stimulation on neural stem and progenitor cells (collectively neural precursor cells; NPCs) from the subventricular zone in the adult forebrain of C57BL/6J mice. Previous work has demonstrated that adult-derived NPCs are electro sensitive and undergo rapid and directed migration in response to application of clinically relevant electric fields (EFs). We examine NPC proliferation kinetics and their differentiation profile following EF application using in vitro and in vivo assays. In vitro direct current electrical stimulation of 250 mV/mm is sufficient to elicit a 2-fold increase in the neural stem cell pool and increases neurogenesis and oligogenesis. In vivo, asymmetric biphasic electrical stimulation similarly increases the size of the NPC pool and alters neurogenesis. These findings provide insight into the effects of electrical stimulation on NPCs and suggest its potential use as a regenerative approach to neural repair.

Novel Electrode Designs for Neurostimulation in Regenerative Medicine: Activation of Stem Cells

“…These NPCs are highly responsive to EF application, expanding in number through proliferation and enhanced cell survival, as well as differentiating into newborn neurons. 19 Most striking, NPCs are activated to migrate in a rapid and directed manner in the presence of an applied EF using well-established in vitro assays and live cell imaging. 15 Together, these NPC behaviors provide promise for the design and implementation of regenerative medicine strategies that aim to replace lost or damaged cells following injury or disease, yet several important questions remain unanswered that are pivotal to understanding how to optimize the NPC response.…”

“…However, promising recent work has demonstrated that biphasic in vivo stimulation can enhance NPC migration and regulate cell behavior. 17 , 19 Transferring the in vitro parameters to in vivo settings will be a challenge as the microenvironment also has profound effects on galvanotaxis. The microenvironment plays an important role in what the cell perceives and as such, the galvanotactic response is highly sensitive, yet malleable, with the outcome dependent on the EF parameters such as strength and frequency and the cell's environment (e.g., extracellular matrix [ECM] and nearest neighbors, discussed next).…”

“…Notably, electrical stimulation can elicit other cellular responses, such as cell proliferation. 19 Interestingly, electrical stimulation has been shown to increase the number of blood vessels in the injured brain, 42 modulate blood–brain barrier permeability, 43 , 44 and modulate numbers of microglia and astrocytes. 45–48 The ability to affect the microenvironment creates the possibility of “side effects” such as modulation of the number of astrocytes and microglia but with more insight into the effects of EFs on tissue responses; these “side effects” could be purposely controlled to create an environment more amenable to tissue repair.…”

“… 15–18 Differentiation and proliferation kinetics can also be modified by electrical stimulation, and this has been demonstrated both in vitro and in vivo . 19–21 Optimization of these EFs to better control NPC behavior is still required, but manipulating NPC behavior affords great promise in the field of regenerative medicine.…”

Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain

“…Together with molecular cues and physical factors, electrical currents appear to be another component of cell guidance. Several studies have shown that the application of an electric field increases neurogenesis (Stone et al, 2011 ; Sefton et al, 2020 ) and drives neuroblasts toward the cathode in cell cultures, SVZ explants, and acute brain slices (Babona-Pilipos et al, 2011 ; Cao et al, 2013 ). Human neuronal progenitor cells (hNPCs) also migrate to the cathode in response to an electric field (Feng et al, 2012 ).…”