Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model

Introduction: Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined. Methods: In this study, we used tricyclodecan 9 yl xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an A beta PP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid beta-peptides (A beta) deposition, and microglial function of the mice were investigated. Results: We found that transplantation of HUMSC-NCs into A beta PP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced A beta deposition in the mice. The beneficial effects were associated with alternatively activated microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), was significantly reduced. Moreover, the expression of A beta-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs. Conclusions: HUMSC-NC transplantation decreased A beta deposition and improved memory in A beta PP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.