SSEA3 and CD105 positivity are associated with the treatment potency of human neural crest-derived nasal turbinate stem cells for Alzheimer's disease.

Abstract

Background: Stem cells have the potential to treat Alzheimer's disease (AD), but clinical outcomes are unpredictable due to inter-donor differences in stem cell properties. This study aimed to determine whether the pluripotency marker SSEA3 and the mesenchymal marker CD105 positivity are associated with the therapeutic efficacy of human neural crest-derived nasal turbinate stem cells (NTSCs) for AD.

Methods: The therapeutic effects of NTSCs obtained from different donors, with varying percentages of SSEA3⁺/CD105⁺ cells, were explored in 5 × FAD transgenic AD mice and cerebral organoids derived from induced pluripotent stem cells (iPSC) of three AD patients. Neuropathological changes associated with AD were examined, including expression of beta-amyloid, inflammation, and neuronal survival. Cognitive functions were evaluated by the Morris water maze (MWM) test.

Results: NTSCs from different donors improved cognitive function and AD-related neuropathology to varying degrees, depending on the percentage of SSEA3⁺/CD105⁺ cells. Compared with NTSCs with a lower percentage of SSEA3⁺/CD105⁺ cells (NTSCs-L), NTSCs with a higher percentage of SSEA3⁺/CD105⁺ cells (NTSCs-H) showed greater properties in vitro, including proliferative capacity, multilineage differentiation potency, and secretion of neuroprotective cytokines. These properties were comparable to those of pure SSEA3⁺/CD105⁺ cells isolated from NTSCs (NTSCs-SC). Both NTSCs-H and NTSCs-SC improved cognitive function and reduced cerebral Aβ deposition, inflammation, and neuronal death in AD model mice. Furthermore, NTSCs-H and NTSCs-SC decreased Aβ aggregates, tau hyperphosphorylation, neuronal death, microglial numbers, and inflammatory cytokine levels in AD cerebral organoids. However, there was no significant difference in AD-related pathological changes between NTSCs-H and NTSCs-SC treatment groups.

Conclusions: Our findings suggest that SSEA3/CD105 positivity is a potential marker of NTSC therapeutic efficacy for the treatment of AD. Future studies should focus on enhancing the therapeutic potential of SSEA3⁺/CD105⁺ NTSCs by improving their functional efficacy and consistency, and advancing their use in clinical settings.