Abstract
Protection of neurons against oxidative stress is crucial during neuronal development, maintenance and for treating neurodegenerative diseases. However, little is known about the molecular mechanisms underlying sex-specific maturation and survival of neurons. In the present study, we demonstrate NF-κB-p65 mediated neuroprotection in human glutamatergic neurons differentiated from inferior turbinate stem cells (ITSCs) in a sex-dependent manner. We successfully differentiated ITSCs into MAP-2+/NF200+/Synaptophysin+/vGlut2+-glutamatergic neurons in vitro and ex vivo and validated their functionality. TNF-α-dependent NF-κB-p65 activation was accompanied by significant neuroprotection against oxidative stress-induced neuronal death, which was surprisingly higher in neurons from female donors. Accordingly, sex-specific neuroprotection of female neurons was followed by an increased expression of special NF-κB target genes SOD2 and IGF2. Among these, SOD2 is a well known gene protecting cells against oxidative stress resulting in longevity. In addition, IGF2 is known to promote synapse formation and spine maturation, and it has antioxidant and neuroprotective effects against oxidative damage. In conclusion, we show that NF-κB-p65 is a key player in neuroprotection of human neurons, however the protective gene expression program beneath it differs between sexes. Our findings are in accordance with the increasing evidences pointing towards sex-specific differences in risk and severity of neurodegenerative diseases.
Highlights
Acute and chronic nervous system damage in response to an insult such as oxidative stress is directly associated to neuronal death and degeneration[1]
Exposure of Inferior turbinate stem cells (ITSCs) to a neuronal induction medium for 28 days resulted in a neuronal-like morphology indicated by retraction of the cytoplasm towards the nucleus, and extended cellular processes resulting in neurite outgrowth (Fig. 1b–d)
We observed a significant increase in cell death of neurons differentiated from female ITSC-donors compared to their male counterparts, indicating an elevated sensitivity of human female glutamatergic neurons to oxidative stress (Fig. 5d)
Summary
Acute and chronic nervous system damage in response to an insult such as oxidative stress is directly associated to neuronal death and degeneration[1]. NF-κB signalling is directly linked to proliferation of rat NSCs28 and early neuronal differentiation of mouse NSCs29, its direct role in protection of human stem cell-derived neurons against oxidative stress still remains unclear. We demonstrate a neuroprotective role of NF-κB-p65 through maturation of human glutamatergic neurons derived from neural crest-derived stem cells (NCSCs) after oxidative stress insult. Inferior turbinate stem cells (ITSCs) are able to differentiate into a wide variety of cell types from mesodermal and neuro-ectodermal lineages, such as chondrocytes, osteocytes, adipocytes, and glutamatergic as well as dopaminergic neurons[36,37,38] Due to their capability to efficiently give rise to neuronal cell types, ITSCs harbor great potential for the treatment of neurodegenerative diseases[38]. Our findings reveal NF-κB-p65 as a key player in neuroprotection of NCSC-derived neurons in a sex-dependent manner, indicating the pivotal role of NF-κB-signalling during stem cell-based neuronal differentiation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
