EXOGENOUS PARACRINE EFFECTS OF DENTAL PULP STEM CELLS ON GLIA AND NEURONAL CIRCUITS: A NEW THERAPEUTIC STRATEGY FOR NEUROPROTECTION

Stem cell graft therapy for neuroprotection requires large numbers of cells, minimal host rejection, and proper integration while avoiding uncontrolled cell proliferation. These requirements and associated challenges significantly increase costs and compromise the successful outcome of this therapeutic approach. Consequently, recent strategies have shifted toward the use of subcellular products, such as the stem cell secretome, as stem cell–derived effects have been shown to be mediated mainly through paracrine mechanisms.
In this context, human dental pulp stem cells (hDPSCs) are of particular interest for brain-related therapies, especially for neuroimmunomodulation. hDPSCs, and consequently their secretome, exhibit strong neurotrophic, angiogenic, anti-inflammatory, and anti-apoptotic activities, as well as enhanced migratory capacity, neurite outgrowth, and immunomodulatory effects. However, it remains unclear to what extent the stem cell secretome is capable of regulating synaptic function and inflammatory and immunomodulatory responses, and whether its use could represent a valid therapeutic strategy to improve synaptic function in cognitive disorders, which impose a substantial economic and social burden on affected individuals and their families.
This work demonstrates that the DPSC-derived secretome, particularly its soluble fraction, is able to modulate microglial state in vitro in response to an inflammatory stimulus, shifting microglia from a reactive phenotype toward a more homeostatic one. Moreover, extracellular vesicles (EVs) derived from the secretome modulate synaptic function during inflammatory conditions, as they were shown to prevent synaptic plasticity impairment within the first 24 hours following an inflammatory event. This effect was demonstrated by assessing long-term potentiation (LTP) in the CA1 region ex vivo.