技术资料

Bipolar disorder (BD) is a complex psychiatric condition usually requiring long-term treatment. Lithium (Li) remains the most effective mood stabilizer for BD,yet it benefits only a subset of patients,and its precise mechanism of action remains elusive. Exome sequencing has identified AKAP11 (A-kinase anchoring protein 11) as a shared risk gene for BD and schizophrenia (SCZ). Given that both the AKAP11-Protein Kinase A (PKA) complex and Li target and inhibit Glycogen Synthase Kinase-3 beta (GSK3β),we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous AKAP11-knockout (Het-AKAP11-KO) iPSC-derived neurons. In this study,we employed genome-wide approaches to assess the effects of Li on the transcriptome and epigenome of human iPSC-derived Het-AKAP11-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-AKAP11-KO,several of which have also been reported as downregulated in synapses of BD and SCZ post-mortem brain tissues. Moreover,we demonstrated that Li treatment partially rescues certain transcriptomic alterations resulting from Het-AKAP11-KO,bringing them closer to the WT state. We suggest two possible mechanisms underlying these transcriptomic effects: (1) Li modulates histone H3K27ac levels at intergenic and intronic enhancers,influencing enhancer activity and transcription factor binding,and (2) Li enhances GSK3β serine 9 phosphorylation,impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li’s potential as a therapeutic agent for BD and SCZ patients carrying AKAP11 loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-AKAP11-KO models. View Publication

Management of chronic kidney disease (CKD) remains a major challenge due limited therapeutic options to reverse fibrosis,which is a critical feature in CKD. Partial epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) is a key driver of fibrosis,and has become an important focus for kidney protection strategies. Blood platelets,a major source of circulating transforming growth factor beta (TGF-β),are implicated in pathogenesis of CKD,but their involvement in EMT and kidney fibrosis remains uncertain. Methods: We used two mouse models of renal fibrosis—diabetic kidney disease (DKD) and unilateral ureter obstruction (UUO)—to examine the connection between platelets,partial EMT,and fibrosis. Platelet inhibition or depletion was performed to assess EMT,cell cycle arrest,and fibrosis. In vitro,platelets were applied to TECs and kidney organoids. To determine the role of TGF-β signaling,we used TGF-βRI inhibitor. Expression of EMT,and fibrosis markers,as well as TGF-β1 signaling,were analyzed using western blot,reverse transcription quantitative PCR (RT-qPCR),enzyme-linked immunosorbent assay (ELISA),and immunostaining. Results: In both animal models,platelet inhibition or depletion resulted in reduced expression of cell cycle arrest marker p21,partial EMT and fibrosis. In vitro,activated platelets stimulated cell cycle arrest,EMT,and fibrosis in TECs and kidney organoids. Chronically injured TECs experience cell-cycle arrest which promote a paracrine EMT program in TECs,jointly leading to fibrosis. This platelet-mediated effect on cell cycle arrest and EMT was driven by TGF-β1 signaling,as selective inhibition of the TGF-β receptor rescued these dysfunctional phenotypes. Conclusions: Our study demonstrates that platelets activate the TGF-β1 pathway,leading to cell cycle arrest,EMT and renal fibrosis. These findings suggest that antiplatelet therapies may have potential renoprotective effects by protecting tubular homeostasis,attenuating partial EMT and fibrosis. View Publication

Chronic compressive cervical spinal cord injury (cCSCI),a debilitating condition,lacks effective treatment options. Addressing this gap,our study introduces a novel rat model of cCSCI developed through spinal cord compression via synthetic polyether sheet implantation,closely mimicking human pathology. We evaluated the model’s fidelity utilizing a comprehensive series of behavioral,electrophysiological,and histological assessments. Our research also explored the therapeutic potential of oligodendrogenic neural progenitor cells (oNPCs) derived from induced pluripotent stem cells. Transplanted oNPCs successfully integrated into the host spinal cord,differentiated into neurons,astrocytes,and oligodendrocytes,and demonstrated a remarkable capacity for enhancing neuroplasticity. Electrophysiological analyses revealed significant improvements in motor evoked potentials and a rectification of the excitability imbalance posttransplantation,indicating substantial recovery of motor circuits. Histological findings complemented these results,showing enhanced remyelination and a reduction in excitatory transmitter expression in the residual gray matter. Functionally,the transplantation of oNPCs led to marked improvements in grip strength,locomotor abilities,and sensory functions,surpassing those seen with standard treatments. This study not only provides a novel and reliable rat model of cCSCI for further research but also highlights the potential of oNPCs as a transformative approach for spinal cord injury therapy,suggesting their significant role in neural regeneration and repair. View Publication