Wnts Enhance Neurotrophin-Induced Neuronal Differentiation in Adult Bone-Marrow-Derived Mesenchymal Stem Cells via Canonical and Noncanonical Signaling Pathways

Abstract

Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here, we explored the underlying molecular mechanisms through which Wnt signaling regulates neurotrophins (NTs) in the NT-induced neuronal differentiation of human mesenchymal stem cells (hMSCs). NTs can increase the expression of Wnt1 and Wnt7a in hMSCs. However, only Wnt7a enables the expression of synapsin-1, a synaptic marker in mature neurons, to be induced and triggers the formation of cholinergic and dopaminergic neurons. Human recombinant (hr)Wnt7a and general neuron makers were positively correlated in a dose- and time-dependent manner. In addition, the expression of synaptic markers and neurites was induced by Wnt7a and lithium, a glycogen synthase kinase-3β inhibitor, in the NT-induced hMSCs via the canonical/β-catenin pathway, but was inhibited by Wnt inhibitors and frizzled-5 (Frz5) blocking antibodies. In addition, hrWnt7a triggered the formation of cholinergic and dopaminergic neurons via the non-canonical/c-jun N-terminal kinase (JNK) pathway, and the formation of these neurons was inhibited by a JNK inhibitor and Frz9 blocking antibodies. In conclusion, hrWnt7a enhances the synthesis of synapse and facilitates neuronal differentiation in hMSCS through various Frz receptors. These mechanisms may be employed widely in the transdifferentiation of other adult stem cells.

Multi-lineage differentiation of mesenchymal stem cells – To Wnt, or not Wnt

“…These markers were up-regulated when Wnt signalling was activated using Wnt3a and down-regulated when Wnt signalling was blocked by siRNA for β-catenin [86]. It was also found that Wnt7a enhanced neuronal differentiation in human MSCs via both canonical and non-canonical signalling pathways [87]. Further, the Wnt antagonists Dkk1 and sFRP4 reversed Wnt7a's promoting effect [87].…”

“…It was also found that Wnt7a enhanced neuronal differentiation in human MSCs via both canonical and non-canonical signalling pathways [87]. Further, the Wnt antagonists Dkk1 and sFRP4 reversed Wnt7a's promoting effect [87]. Re-activation of the Wnt signalling pathway reversed the age-related decline in neurogenic differentiation in MSCs derived from dental pulp [88].…”

Roles of Mesenchymal Stem Cells in Spinal Cord Injury

“…Wnt-7a enhanced neuronal differentiation in MSCs via both canonical and noncanonical signaling pathways [131]. Contusion spinal cord injury induced a time-dependent increase in Wnt expression from 6 hours until 28 days postinjury.…”

MicroRNA‐132 directs human periodontal ligament‐derived neural crest stem cell neural differentiation

“…In human body, adult stem cells, including haematopoietic stem cells and mesenchymal stem cells (MSCs), acquire stem cell properties without reprogramming and showed neuroprotective effects on CNS disorders by modulating the plasticity of damaged host tissues, secreting neurotrophic and survival‐promoting growth factors, restoring synaptic transmitter release, integrating into existing neural and synaptic networks, and re‐establishing functional afferent and efferent connections (Wang, Brelén, & Ng, ). Although the differentiation abilities of adult stem cells have long believed to be oligo or unipotent, transdifferentiation of human adult stem cells into neural cells has also been reported using different strategies, including coculture with neuronal cells (Park, Park, Yang, et al, ), exosomes derived from neuronal cells (Takeda & Xu, ), electrical stimulation (Park, Yang, Woo, et al, ), and neurotrophic factor‐based treatment (Tsai, Deng, Lai, et al, ). We previously showed that the neural crest‐originated human periodontal ligament‐derived stem cells (PDLSCs) can be directed into neuronal and retinal lineages with the expression of neuronal markers, synapse formation, and exhibiting glutamate‐induced calcium responses as well as electrical activities (Fortino, Chen, Pelaez, & Cheung, ; Huang, Liang, Geng, et al, ; Ng, Yung, Choy, et al, ).…”