MiR-302a reprogrammed fibroblast-derived induced anti-aging neural stem cells improve cognition and prolong lifespan in Alzheimer's disease model

Abstract

Abstract Background: Neural stem cells (NSC) are essential for maintaining tissue homeostasis and promoting longevity in living organisms. As a promising approach to treating neurodegenerative diseases, NSC transplantation has been hampered by crucial issues such as cellular senescence, immune rejection, and low cell viability. Methods: MiR-302a was used to reprogram human and mouse fibroblast cells into induced neural stem cells (iNSCs). In vitro, differentiation experiments were performed to demonstrate that iNSCs have the ability to differentiate into neurons, astrocytes, and oligodendrocytes. INSCs were transplanted into nude mice to evaluate cell survival, differentiation, and tumor formation in vivo. Multi-electrode arrays were used to determine that the differentiated neurons from iNSCs have mature electrophysiological functions. INSCs were treated with oxidative damage to test their antioxidant and anti-aging abilities. The supernatant of iNSCs was used to treat aged cells to determine their antioxidant and anti-aging effects. INSCs were transplanted into SAMP8 rapid aging Alzheimer's disease (AD) mouse model for behavioral tests to evaluate the improvement and therapeutic effects of iNSCs treatment on cognitive function and memory. Tests were also performed to assess lifespan extension, improved glycemic control, promoted motor ability recovery, improved reproductive ability, and improved hearing. Results: We report that a single miR-302 factor alone can effectively reprogram human and mouse fibroblasts directly into iNSCs within 2-3 days, confirmed by cell phenotype, molecular characterization, and functional analysis. The anti-aging factors Nrf2, Sirt6, and Foxo3 are highly expressed in induced neural stem cells reprogrammed by miR-302a (miR-302a-hiNSCs). Compared to other iNSCs, miR-302a-hiNSCs showed delayed aging and increased resilience to oxidative stress. MiR-302a-hiNSCs were implanted into SAMP8 mice to improve cognition, extend longevity by 40.625%, increase fatigue resistance, and enhance blood sugar control, hair regrowth, and reproduction. Conclusion: Our study highlights the potential of iNSCs generated based on miR-302a as a promising therapeutic approach for treating various age-related diseases and conditions. We found the iNSCs treatment to improve lifespan, cognitive abilities in late-stage AD, fatigue resistance, hair regeneration, blood glucose, and fat metabolism, renal function, reproductive function, and hearing loss.