PT  - JOURNAL ARTICLE
AU  - Shan Ping Yu
AU  - Jack K. Tung
AU  - Zheng Z. Wei
AU  - Dongdong Chen
AU  - Ken Berglund
AU  - Weiwei Zhong
AU  - James Y. Zhang
AU  - Xiaohuan Gu
AU  - Mingke Song
AU  - Robert E. Gross
AU  - Shinn Z Lin
AU  - Ling Wei
TI  - Optochemogenetics Stimulation of Transplanted iPS-NPCs Enhances Neuronal Repair and Functional Recovery after Ischemic Stroke
AID  - 10.1523/JNEUROSCI.2010-18.2019
DP  - 2019 Jul 01
TA  - The Journal of Neuroscience
PG  - 2010-18
4099  - http://www.jneurosci.org/content/early/2019/07/01/JNEUROSCI.2010-18.2019.short
4100  - http://www.jneurosci.org/content/early/2019/07/01/JNEUROSCI.2010-18.2019.full
AB  - Cell transplantation therapy provides a regenerative strategy for neural repair. We tested the hypothesis that selective excitation of transplanted iPS cell-derived neural progenitor cells (iPS-NPCs) could recapitulate an activity-enriched microenvironment that confers regenerative benefits for the treatment of stroke. Mouse iPS-NPCs were transduced with a novel optochemogenetics fusion protein, luminopsin 3 (LMO3), which consisted of a bioluminescent luciferase, Gaussia luciferase (GLuc), and an opsin, Volvox Channelrhodopsin 1 (VChR1). These LMO3-iPS-NPCs can be activated by either photostimulation using light or by the luciferase substrate coelenterazine (CTZ). In vitro stimulations of LMO3-iPS-NPCs increased expressions of synapsin-1, PSD95, BDNF, SDF-1; and promoted neurite outgrowth. After transplantation into the ischemic cortex of mice, LMO3-iPS-NPCs differentiated into mature neurons. Synapse formation between implanted and host neurons was identified using immunogold electron microscopy (EM) and patch-clamp recordings. Stimulation of transplanted cells with daily intranasal administration of CTZ enhanced axonal myelination, synaptic transmission, improved thalamocortical connectivity, and functional recovery. Patch-clamp and multielectrode array (MEA) recordings in brain slices showed that CTZ or light stimulation facilitated synaptic transmission and induced neuroplasticity mimicking the long-term potentiation (LTP) of excitatory post synaptic potentials (EPSPs). Stroke mice received the combined LMO3-iPS-NPC/CTZ treatment, but not cell or CTZ alone, showed enhanced neural network connections in the peri-infarct region, promoted optimal functional recoveries after stroke in male and female, young and aged mice. Thus, excitation of transplanted cells via the non-invasive optochemogenetics treatment provides a novel integrative cell therapy with comprehensive regenerative benefits after stroke.Significant StatementNeural network reconnection is critical for repairing damaged brain, strategies that promote this repair are expected to improve functional outcomes. This study pioneers in the generation and application of an optochemogenetics approach in stem cell transplantation therapy after stroke for optimal neural repair and functional recovery. Using iPS cell-derived neural progenitor cells (iPS-NPCs) expressing the novel optochemogenetic probe luminopsin (LMO3), and intranasally delivered luciferase substrate coelenterazine (CTZ), we show enhanced regenerative properties of LMO3-iPS-NPCs in vitro and after transplantation into the ischemic brain of different genders and ages. The non-invasive repeated CTZ stimulation of transplanted cells is feasible for clinical applications. The synergetic effects of the combinatorial cell therapy may have significant impacts on regenerative approach for treatments of CNS injuries.