Using Electrical Stimulation to Enhance the Efficacy of Cell Transplantation Therapies for Neurodegenerative Retinal Diseases: Concepts, Challenges, and Future Perspectives

Abstract

Disease or trauma-induced loss or dysfunction of neurons in any central nervous system (CNS) tissue will have a significant impact on the health of the affected patient. The retina is a multilayered tissue that originates from the neuroectoderm, much like the brain and spinal cord. While sight is not required for life, neurodegenerationrelated loss of vision not only affects the quality of life for the patient but also has societal implications in terms of health care expenditure. Thus, it is essential to develop effective strategies to repair the retina and prevent disease symptoms. To address this need, multiple techniques have been investigated for their efficacy in treating retinal degeneration. Recent advances in cell transplantation (CT) techniques in preclinical, animal, and in vitro culture studies, including further evaluation of endogenous retinal stem cells and the differentiation of exogenous adult stem cells into various retinal cell types, suggest that this may be the most appropriate option to replace lost retinal neurons. Unfortunately, the various limitations of CT, such as immune rejection or aberrant cell behavior, have largely prevented this technique from becoming a widely used clinical treatment option. In parallel with the advances in CT methodology, the use of electrical stimulation (ES) to treat retinal degeneration has also been recently evaluated with promising results. In this review, we propose that ES could be used to enhance CT therapy, whereby electrical impulses can be applied to the retina to control both native and transplanted stem cell behavior/survival in order to circumvent the limitations associated with retinal CT. To highlight the benefits of this dual treatment, we have briefly outlined the recent developments and limitations of CT with regard to its use in the ocular environment, followed by a brief description of retinal ES, as well as described their combined use in other CNS tissues.

Mesenchymal stem cell surgery, rescue and regeneration in retinitis pigmentosa: clinical and rehabilitative prognostic aspects

“…In recent years, the synergy between cellular therapies and electrical stimulation has begun to be considered as a possible treatment for degenerative pathologies. This synergy addresses four main aspects: native cell survival, transplanted cell survival, transplanted cell integration, and functional synapse formation/axon regeneration (Manthey et al, 2017). While the methods of Electrical Stimulation (ES) administration are different, their influence on the preservation of retinal structure and function is similar and based on studies in animal models.…”

“…While the methods of Electrical Stimulation (ES) administration are different, their influence on the preservation of retinal structure and function is similar and based on studies in animal models. In the rat model of retinitis pigmentosa (RP), it has been shown that ES preserved outer nuclear layer (ONL) thickness and delayed inner retinal degeneration (Manthey et al, 2017;Hanif et al, 2016).…”

“…In recent years, the synergy between cellular therapies and electrical stimulation has begun to be considered as a possible treatment for degenerative pathologies. This synergy addresses four main aspects: native cell survival, transplanted cell survival, transplanted cell integration, and functional synapse formation/axon regeneration ( Manthey et al., 2017 ).…”

Target-Derived Neurotrophic Factor Deprivation Puts Retinal Ganglion Cells on Death Row: Cold Hard Evidence and Caveats

“…The stimulation of neuronal activity might induce a more endogenous-like, and thus more physiologically relevant stimulation of NTF expression as compared to artificial supplementation. Ocular electrical stimulation (ES) has shown promising results for neuroprotective therapy in retinal and optic nerve diseases as reviewed by Sehic et al [141] and Manthey et al [142]. Here, we provide a brief overview of studies investigating ES and NTF involvement in the visual system.…”

Regenerative Medicine and Eye Diseases

“…BFGF is known to directly promote the survival of photoreceptors [42]. Synergy with electrical stimulation (ES) addresses four main aspects: survival of native cells, survival of transplanted cells, integration of transplanted cells, and functional formation of synapses/axon regeneration [43]. In recent years, the synergy between cell therapies and electrical stimulation has started to be considered as a possible treatment for degenerative diseases.…”