Cell Proliferation最新文献

The developing human foetal brain is sensitive to thermal stimulation during pregnancy. However, the mechanisms by which heat exposure affects human foetal brain development remain unclear, largely due to the lack of appropriate research models for studying thermal stimulation. To address this, we have developed a periodic heating model based on brain organoids derived from human pluripotent stem cells. The model recapitulated neurodevelopmental disruptions under prenatal heat exposure at the early stages, providing a paradigm for studying the altered neurodevelopment under environmental stimulation. Our study found that periodic heat exposure led to decreased size and impaired neural tube development in the brain organoids. Bulk RNA-seq analysis revealed that the abnormal WNT signalling pathway and the reduction of G2/M progenitor cells might be involved in heat stimulation. Further investigation revealed increased neural differentiation and decreased proliferation under heat stimulation, indicating that periodic heat exposure might lead to abnormal brain development by altering key developmental processes. Hence, our model of periodically heating brain organoids provides a platform for modelling the effects of maternal fever on foetal brain development and could be extended to applications in neurodevelopmental disorders intervention.

Human induced pluripotent stem cells (hiPSCs) represent a promising cell source for generating functional cells suitable for clinical therapeutic applications, particularly in the context of autologous cell therapies. However, the production of hiPSCs through genetic manipulation, especially involving oncogenes, may raise safety concerns. Furthermore, the complexity and high costs associated with hiPSCs generation have hindered their broad clinical use. In this study, we utilised a recently developed chemical reprogramming method in conjunction with a guided differentiation protocol, introducing a chemically defined strategy for generating functional human retinal pigment epithelium (RPE) cells from adipose tissue, bypassing conventional hiPSCs generation challenges. By utilising small molecule-based chemical cocktails, we reprogrammed somatic adipose cells into human chemically induced pluripotent stem cells (hCiPSCs) in a safer and more streamlined manner, entirely free from gene manipulation. Subsequent differentiation of hCiPSCs into functional RPE cells demonstrated their capability for secretion and phagocytosis, emphasising their vital role in maintaining retinal homeostasis and underscoring their therapeutic potential. Our findings highlight the transformative potential of hCiPSCs as a safer, more efficient option for personalised cell therapies, with applications extending beyond ocular disease to a wide range of medical conditions.

Currently, there is no specific treatment for diabetes-induced osteoporosis (DOP). Our study identified diabetes-induced cellular senescence, marked by elevated activity of senescence-associated β-galactosidase. Targeting senescent cells holds promise for osteoporosis treatment. We demonstrated that scutellarin (SCU) effectively mitigated bone loss in DOP mice, and co-treatment with SCU significantly reduced diabetes-induced senescence in LepR+MSCs. Furthermore, our research highlighted the role of Nrf2 in SCU's anti-senescence effects on bone. The deletion of Nrf2 impaired SCU's ability to alleviate DOP. Mechanistically, SCU enhances Ezh2 expression and increases H3K27me3 activity at the Keap1 promoter region, leading to Keap1 repression and enhanced Nrf2-ARE signalling. Additionally, SCU notably inhibited cellular senescence and diabetes-related osteoporosis, these effects were significantly reduced in Ezh2^LepRcre conditional knockout models. These findings suggest that the Ezh2-Nrf2 signalling axis is crucial for mediating SCU's beneficial effects in this context. Overall, our discoveries provide insights into the mechanisms underlying DOP and propose a potential preventive strategy for this condition.

The cover image is based on the article Cellular senescence mediates retinal ganglion cell survival regulation post-optic nerve crush injury by Yao Yao et al., https://doi.org/10.1111/cpr.13719.

Growing evidence indicates that the deterioration of egg quality caused by postovulatory ageing significantly hampers embryonic development. However, the molecular mechanisms by which postovulatory ageing leads to a decline in oocyte quality have not been fully characterized. In this study, we observed an accelerated decay of maternal mRNAs through RNA-seq analyses in postovulatory-aged (PostOA) oocytes. We noted that these downregulated mRNAs should be degraded during the 2-cell stage. Proteomic analyses revealed that the degradation of maternal mRNAs is associated with the accumulation of DCP1A. The injection of exogenous Dcp1a mRNA or siRNA into MII stage oocytes proved that DCP1A could accelerate the degradation of maternal mRNAs. Additionally, we also found that SPDL1 is crucial for maintaining spindle/chromosome structure and chromosome euploidy in PostOA oocytes. Spdl1-mRNA injection remarkably recovered the meiotic defects in PostOA oocytes. Collectively, our findings provide valuable insights into the molecular mechanisms underlying postovulatory ageing.

Osteoarthritis (OA) is a chronic, degenerative joint disease primarily characterised by damage to the articular cartilage, synovitis and persistent pain, and has become one of the most common diseases worldwide. In OA cartilage, various forms of cell death have been identified, including apoptosis, necroptosis and autophagic cell death. Ever-growing observations indicate that ferroptosis, a newly-discovered iron-dependent form of regulated cell death, is detrimental to OA occurrence and progression. In this review, we first analyse the pathogenetic mechanisms of OA by which iron overload, inflammatory response and mechanical stress contribute to ferroptosis. We then discuss how ferroptosis exacerbates OA progression, focusing on its impact on chondrocyte viability, synoviocyte populations and extracellular matrix integrity. Finally, we highlight several potential therapeutic strategies targeting ferroptosis that could be explored for the treatment of OA.

The progression of periodontitis, a bacteria-driven inflammatory and bone-destructive disease, involves myriad cellular and molecular mechanisms. Protein regulation significantly influences the pathogenesis and management of periodontitis. However, research regarding its regulatory role in periodontitis remains relatively limited. The ubiquitin-proteasome system (UPS), which mainly involves ubiquitination by E3 ubiquitin ligases (E3s) and deubiquitination by deubiquitinating enzymes (DUBs), is the primary intracellular and non-lysosomal mechanism of protein degradation. Recent studies have provided compelling evidence to support the involvement of UPS in periodontitis progression. Increasing evidence indicated that E3s, such as CUL3, Nedd4-2, Synoviolin, FBXL19, PDLIM2, TRIMs and TRAFs, modulate inflammatory responses and bone resorption in periodontitis through multiple classical signalling pathways, including NLRP3, GSDMD, NF-κB, Wnt/β-catenin and Nrf2. Meanwhile, DUBs, including OTUD1, A20, CYLD, UCH-L1 and USPs, also broadly modulate periodontitis progression by regulating signalling pathways such as NF-κB, Wnt/β-catenin, NLRP3, and BMP2. Therefore, the modulation of E3s and DUBs has proven to be an effective therapy against periodontitis. This review provides a comprehensive overview of the regulatory role of ubiquitinating and deubiquitinating enzymes in periodontitis progression and the underlying mechanisms. Finally, we summarise several chemical and genetic methods that regulate UPS enzymes and pave the way for the development of targeted therapies for periodontitis.

Spermatogenesis is a highly unique and intricate process, finely regulated at multiple levels, including post-transcriptional regulation. N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, plays a significant role in transcriptional regulation during spermatogenesis. Previous research indicated extensive m6A modification at each stage of spermatogenesis, but depletion of Mettl3 and/or Mettl14 in spermatogenic cells with Stra8-Cre did not reveal any detectable abnormalities up to the stage of elongating spermatids. This suggests the involvement of other methyltransferases in the regulation of m6A modification during spermatogonial differentiation and meiosis. As a METTL3/14-independent m6A methyltransferase, METTL16 remains insufficiently studied in its roles during spermatogenesis. We report that male mice with Mettl16^vasa-cre exhibited significantly smaller testes, accompanied by a progressive loss of spermatogonia after birth. Additionally, the deletion of Mettl16 in A1 spermatogonia using Stra8-Cre results in a blockade in spermatogonial differentiation. Given YTHDC1's specific recognition for METTL16 target genes, we further investigated the role of YTHDC1 using Ythdc1-sKO mouse model. Our results indicate that Ythdc1^Stra8-cre also impairs spermatogonial differentiation, similar to the effects observed in Mettl16^Stra8-cre mice. RNA-seq and m6A-seq analyses revealed that deletion of either Mettl6 or Ythdc1 disrupted the gene expression related to chromosome organisation and segregation, ultimately leading to male infertility. Collectively, this study underscores the essential roles of the m6A writer METTL16 and its reader YTHDC1 in the differentiation of spermatogonia.

Mucosal healing is critical to maintain and restore intestinal homeostasis in inflammation. Previous data provide evidence that glial cell line-derived neurotrophic factor (GDNF) restores epithelial integrity by largely undefined mechanisms. Here, we assessed the role of GDNF for mucosal healing. In dextran sodium sulphate (DSS)-induced colitis in mice application of GDNF enhanced recovery as revealed by reduced disease activity index and histological inflammation scores. In biopsy-based wounding experiments GDNF application in mice improved healing of the intestinal mucosa. GDNF-induced epithelial recovery was also evident in wound assays from intestinal organoids and Caco2 cells. These observations were accompanied by an increased number of Ki67-positive cells in vivo after GDNF treatment, which were present along elongated proliferative areas within the crypts. In addition, the intestinal stem cell marker and R-spondin receptor LGR5 was significantly upregulated following GDNF treatment in all experimental models. The effects of GDNF on cell proliferation, LGR5 and Ki67 upregulation were blocked using the RET-specific inhibitor BLU-667. Downstream of RET-phosphorylation, activation of Src kinase was involved to mediate GDNF effects. GDNF promotes intestinal wound healing by promoting cell proliferation. This is mediated by RET-dependent activation of Src kinase with consecutive LGR5 upregulation, indicating activation of the stem cell niche.

Periodontal ligament stem cells (PDLSCs) are key cells that suppress periodontal damage during both the progression and recovery stages of periodontitis. Although substantial evidence has demonstrated that incubation under an inflammatory condition may accelerate senescence of PDLSCs, whether cellular senescence in response to inflammatory incubation contributes to cell dysfunction remain unexplored. In this study, we first observed inflammation-caused PDLSC senescence in periodontitis based on comparisons of matched patients, and this cellular senescence was demonstrated in healthy cells that were subjected to inflammatory conditions. We subsequently designed further experiments to investigate the possible mechanism underlying inflammation-induced PDLSC senescence with a particular focus on the role of long noncoding RNAs (lncRNAs). LncRNA microarray analysis and functional gain/loss studies revealed SLC30A4-AS1 as a regulator of inflammation-mediated PDLSC senescence. By full-length transcriptome sequencing, we found that SLC30A4-AS1 interacted with SRSF3 to affect the alternative splicing (AS) of TP53BP1 and alter the expression of TP53BP1-204. Further functional studies showed that decreased expression of TP53BP1-204 reversed PDLSC senescence, and SLC30A4-AS1 overexpression-induced PDLSC senescence was abolished by TP53BP1-204 knockdown. Our data suggest for the first time that SLC30A4-AS1 plays a key role in regulating PDLSC senescence in inflammatory environments by modulating the AS of TP53BP1.