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

Abstract

IntroductionCell 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.MethodsIn 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 AβPP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid β-peptides (Aβ) deposition, and microglial function of the mice were investigated.ResultsWe found that transplantation of HUMSC-NCs into AβPP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced Aβ 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-1β (IL-1β) and tumor necrosis factor-α (TNF-α), was significantly reduced. Moreover, the expression of Aβ-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.ConclusionsHUMSC-NC transplantation decreased Aβ deposition and improved memory in AβPP/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.

Brain mesenchymal stem cells: The other stem cells of the brain?

“…Brain implanted marrow stromal cells also differentiate into glial cells [25] . Importantly, grafting MSCs in several brain lesion models reduces neuronal deficits [35][36][37][38][39][40][41][42] . However, current evidence suggests that in the experimental models used, the repair and functional improvements reported are primarily mediated by paracrine or cell-cell interactions rather than by the successful engraftment and the in situ transdifferentiation of implanted MSCs into neural cells [43][44][45][46][47] .…”

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

“…However, most studies indicate that the cell grafts exhibit poor differentiation and survival in mouse models of AD, suggesting that the functional recovery from AD may be mediated by paracrine mechanisms [16,21,22]. Stem cells are known to secrete a broad repertoire of trophic and immunomodulatory factors, which can be harvested in serum-free conditioned media [23] [24].…”

Stem Cells and Neuronal Differentiation

“…hMSC treatment had a protective effect on progressive loss of dopaminergic neurons induced by MG-132 in vivo through differentiation and trophic effect [206]. Human umbilical cord MSC-derived neuron-like cells have shown rescue of memory deficits and reduced amyloid-beta deposition in an A"PP/PS1 transgenic mouse model [207]. In addition, neuroectodermally converted BM-MSCs led to decrease of A" peptides by regulation of two genes F-spondin and neprilysin [208].…”