Clinical-grade human dental pulp stem cells improve adult hippocampal neural regeneration and cognitive deficits in Alzheimer's disease.

Disrupted hippocampal functions and progressive neuronal loss represent significant challenges in the treatment of Alzheimer's disease (AD). How to achieve the improvement of pathological progression and effective neural regeneration to ameliorate the intracerebral dysfunctional environment and cognitive impairment is the goal of the current AD therapy. We examined the therapeutic potential of clinical-grade human derived dental pulp stem cells (hDPSCs) in cognitive function and neuropathology in AD. Specifically, we investigated the effect of neural crest-specific derived hDPSCs on endogenous neural regeneration and long-term efficacy following a single transplantation in the triple-transgenic mouse model (3xTg-AD). Our research demonstrated that a single administration of clinical-grade hDPSCs yielded dramatic short-term therapeutic benefits (5 weeks) and sustained partial efficacy (6 months) with respect to improving cognitive impairment and delaying typical pathological progression in 3xTg-AD mice. Intriguingly, exogenous hDPSCs were robustly self-differentiated into newborn functional neurons in the hippocampus of 3xTg-AD mice. The foremost evidence is provided that hDPSCs promote endogenic neural regeneration by enhancing the activation of the Wnt/β-catenin pathway, which may contribute to stabilizing the hippocampal neural network to reverse memory deficits. These findings highlight the multifunctional potential of hDPSCs in AD treatment, which enhances cognition through alleviating neuropathology and providing neural regenerative driving force. Understanding these multiplicity effects is critical to advancing the clinical translation of stem cell-based therapies for AD.