No abstract

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here we show that the pseudouridine synthase PUS7 is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in glioblastoma patients. The PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identified PUS7 targets in GSCs through small RNA pseudouridine sequencing, and showed that pseudouridylation of PUS7-regulated tRNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identified chemical inhibitors for PUS7, and showed that these compounds prevented PUS7-mediated pseudouridine modification, suppressed tumorigenesis, and extended lifespan of tumor-bearing mice. Overall, we identified an epitranscriptomic regulatory mechanism in glioblastoma and provided preclinical evidence of a potential therapeutic strategy for glioblastoma.

For scleroderma patients, fewer adipose-derived stem cells, because of a history of corticosteroid therapy and a local inflammatory microenvironment, are more important factors, whereas blood supply showed no significant change. Therefore, cell-assisted lipotransfer not only improves the survival rate of transplanted fat but also improves skin texture in bleomycin-induced skin fibrosis nude mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood-brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (A ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases A and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3 / ) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.