Delayed transplantation of human iPSC-derived neural progenitor cells (NPCs) enhances graft survival, proliferation, and axonal sprouting after stroke. Using bioluminescence imaging and histology in a mouse model of stroke, it is shown that NPC delivery at 7 days post-stroke is more effective than acute transplantation, highlighting the importance of timing for maximizing therapeutic efficacy in cell-based stroke therapies.
Abstract
Neural stem cell therapies hold great promise for improving stroke recovery, but the hostile stroke microenvironment can hinder the initial graft survival. It has long been well documented that the microenvironment evolves over time, making it crucial to identify the optimal transplantation window to maximize therapeutic efficacy. However, it remains uncertain whether acute or delayed local cell transplantations better supports graft viability after stroke. Here, it is shown that delayed intracerebral transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent cells (iPSCs) at 7 days post stroke significantly enhances graft proliferation and survival, and promotes axonal sprouting, compared to acute transplantation at 1 day post stroke, in a mouse model of large cortical stroke. Using in vivo bioluminescence imaging over a 6-week period post-transplantation, a more than fivefold increase is observed in bioluminescence signal in mice that received delayed NPC therapy, compared to those that underwent acute NPC transplantation. The increased number of cell grafts in mice receiving delayed NPC transplantation is driven by increased proliferation rates early after transplantation, which subsequently declines to similarly low levels in both groups. Notably, it is found that the majority of transplanted NPCs differentiate into neurons after 6 weeks, with no significant differences in the neuron-to-glia ratio between acute and delayed transplantation groups. These findings suggest that delayed NPC transplantation improves early graft survival and proliferation, which could help identify the optimal therapeutic window for maximizing the effectiveness of NPC-based therapies in stroke.
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