Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease

Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

Instant trachea reconstruction using 3D-bioprinted C-shape biomimetic trachea based on tissue-specific matrix hydrogels

Currently,3D-bioprinting technique has emerged as a promising strategy to offer native-like tracheal substitutes for segmental trachea reconstruction.However,there has been very limited breakthrough in tracheal repair using 3D-bioprinted biomimetic trachea owing to the lack of ideal bioinks,the requirement for precise structural biomimicking,and the complexity of multi-step surgical procedures by mean of intramuscular pre-implantation.Herein,we propose a one-step surgical technique,namely direct end-to-end anastomosis using C-shape 3D-bioprinted biomimetic trachea,for segmental trachea defect repair.First,two types of tissue-specific matrix hydrogels were exploited to provide mechanical and biological microenvironment conducive to the specific growth ways of cartilage and fibrous tissue respectively.In contrast to our previous O-shape tracheal design,the tubular structure of alternating C-shape cartilage rings and connecting vascularized-fibrous-tissue rings was meticulously designed for rapid 3D-bioprinting of tracheal constructs with optimal printing paths and models.Furthermore,in vivo trachea regeneration in nude mice showed satisfactory mechanical adaptability and efficient physiological regeneration.Finally,in situ segmental trachea reconstruction by direct end-to-end anastomosis in rabbits was successfully achieved using 3D-bioprinted C-shape biomimetic trachea.This study demonstrates the potential of advanced 3D-bioprinting for instant and efficient repair of segmental trachea defects.