Abstract
Neural progenitor cell (NPC) transplantation possesses enormous potential for the treatment of disorders and injuries of the central nervous system, including the replacement of lost cells or the repair of host neural circuity after spinal cord injury (SCI). Importantly, cell-based therapies in this context still require improvements such as increased cell survival and host circuit integration, and we propose the implementation of optogenetics as a solution. Blue-light stimulation of NPCs engineered to ectopically express the excitatory light-sensitive protein channelrhodopsin-2 (ChR2-NPCs) prompted an influx of cations and a subsequent increase in proliferation and differentiation into oligodendrocytes and neurons and the polarization of astrocytes from a pro-inflammatory phenotype to a pro-regenerative/anti-inflammatory phenotype. Moreover, neurons derived from blue-light-stimulated ChR2-NPCs exhibited both increased branching and axon length and improved axon growth in the presence of axonal inhibitory drugs such as lysophosphatidic acid or chondroitin sulfate proteoglycan. Our results highlight the enormous potential of optogenetically stimulated NPCs as a means to increase neuroregeneration and improve cell therapy outcomes for enhancing better engraftments and cell identity upon transplantation in conditions such as SCI.
Highlights
The transplantation of neural progenitor cells (NPCs) as a treatment for central nervous system disorders such as spinal cord injury (SCI) has been widely studied [1]
The quantification of Ki67-positive cells demonstrated a significant increase in the proliferation of blue light (BL)-stimulated ChR2-NPCs (p < 0.05, Figure 1B), thereby suggesting that the influx of cations mediated by ChR2 stimulation enhances ChR2-NPC proliferation
We evaluated the functional relevance of optogenetic stimulation during the differentiation of ChR2-NPCs on axonal growth in two inhibitory models—treatment with lysophosphatidic acid (LPA), a potent mitogen that activates the Rho/ROCK pathway and induces growth cone retraction and neurite collapse [25], or with chondroitin sulfate proteoglycans (CSPGs), which mimic one of the major inhibitory signals mediated by the glial scar [26]
Summary
The transplantation of neural progenitor cells (NPCs) as a treatment for central nervous system disorders such as spinal cord injury (SCI) has been widely studied [1]. NPC-based therapies remain, including poor cell survival, limited differentiation, and reduced functional engraftment, which, in turn, limits functional regeneration, offering many times discrete benefits, attributed more to early neuroprotection rather than progressive neuroregeneration due to the short transplant survival (reviewed in [2]). Many different strategies, used alone or in combination, can foster enhanced structural and functional recovery (extensively reviewed in [5]) and include growth factor cocktails [6], optimized biomaterial carriers/scaffolds [7], and small-molecule drugs that promote cell survival [8,9]. Optogenetic strategies include the ectopic expression of light-sensitive ion channels such as channelrhodopsin-2 (ChR2) which, upon stimulation by blue light, become active and trigger a passive cationic ion flow that impacts specific signaling events and influence proliferation, differentiation, survival, and/or cell death [14,15,16,17]
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