Cell Proliferation最新文献

Acute monocytic leukaemia, a subtype of acute myeloid leukaemia (AML), is a highly aggressive malignancy characterised by a poor prognosis, primarily due to the ability of leukaemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukaemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signalling pathway in monocytic AML. Utilising RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8⁺ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8⁺ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML.

During early brain development, the nervous system evolves as cells connect to form a unique neural network, with communication between cell populations vital for neurological balance. This study investigates how the loss of PD-1 in myeloid cells disrupts nervous system development. Specific ablation of PD-1 affects myeloid cell proliferation and classification. As astrogenesis begins, astrocyte proliferation ceases, continuous astrocyte proliferation is observed. Immunofluorescence staining revealed high expression of astrocyte-related genes in PD-1^{f/f; LysM-Cre} mice, which also exhibited more extroverted behaviour. Additionally, the absence of PD-1 enhances CXCL1 expression through the NF-κB pathway, promoting astrocyte proliferation by interacting with CXCR2. These findings underscore PD-1's regulatory role in myeloid cells and its implications for the myeloid-brain axis.

Micropeptides are endogenous peptides translated from alternative open reading frames (alt-ORFs) within coding or non-coding genes. Emerging evidence suggests that some micropeptides play critical roles in both physiological and pathological processes. Multiple myeloma (MM), a haematological malignancy, remains incurable due to frequent relapses and a limited understanding of its underlying mechanisms. In this study, we sought to investigate the function and molecular mechanism of a novel micropeptide in MM pathogenesis. We identified a novel micropeptide, altH19, encoded by the lncRNA H19, which is highly expressed in patients of MM. Functional assays revealed that altH19 promotes myeloma cell proliferation and colony formation significantly. Furthermore, altH19 induces multipolar mitosis by upregulating the expression of Aurora B, Centrin 2 and phosphorylated histone H3. Flow cytometry analyses confirmed that overexpression of altH19 enhances DNA replication and accelerates the transition from early to mid-late stages of the DNA replication process. Conversely, knockout of altH19 reverses these effects. Mechanistically, altH19 directly interacts with phosphorylated CDK2 at threonine 160, thereby enhancing CDK2 T160 phosphorylation and activating the downstream E2F1 target RB phosphorylation. Notably, altH19 was able to restore phosphorylation levels of CDK2 and RB that were otherwise suppressed by the CDK2-selective inhibitor Seliciclib. In summary, we identify altH19 as a novel lncRNA-derived micropeptide with a pivotal role in myeloma progression, highlighting the therapeutic potential of targeting the altH19-CDK2-RB axis in MM treatment.

Lactate has been widely recognised as an energy source and metabolic by-product, but increasing evidence supports its critical role as a signalling molecule or epigenetic substrate. During early embryogenesis, lactate production increases during the transition from early to late blastocyst, coinciding with the differentiation of inner mass cell (ICM) into epiblast (EPI) and primitive endoderm (PrE), termed the second cell fate decision. However, the role of this hallmark metabolic change in the second cell fate segregation remains unknown. Herein, using in vitro and in vivo models, we found lactate production is preferentially increased in PrE cells and is essential for ICM differentiation into PrE. Mechanically, increased lactate in PrE precursor cells and FGF signalling in EPI precursor cells reciprocally activate each other and synergise to prompt PrE specification, forming an intercellular positive feedback loop essential for this lineage commitment. Additionally, lactate enhanced histone lactylation levels during differentiation into PrE fate. Thus, our findings construct a complex multilayer model in which intracellular metabolite in PrE cooperates with intercellular growth factor signalling from EPI to regulate early embryonic lineage commitment. Highlighting the multifaceted lactate's function, our findings also advance the current knowledge that bridges epigenetic reprogramming and metabolic remodelling during early embryonic development.

The appropriate allocation of nutrients between the mother and the fetus during mammalian pregnancy primarily depends on a healthy placenta. Fetal growth restriction (FGR) is frequently associated with inadequate maternal nutrition supply and impaired placental function. The precise mechanisms linking maternal nutrient deficiency to compromised fetal and placental development remain largely elusive. In this study, we conducted an in-depth analysis by integrating single-cell/single-nucleus RNA sequencing data from human and mouse placentas along with transcriptomic data from FGR placenta, identifying the GAB1 (GRB2-associated binding protein 1) gene as a potential mediator of dysregulated maternal–fetal exchange, thereby affecting fetal growth. Using a mouse model, we demonstrated that food restriction significantly impeded fetal growth and disrupted placental labyrinth development. Through an in vitro trophoblast differentiation model, we revealed that nutritional restriction impaired GAB1 stability via LC3-interacting region (LIR) motif-mediated selective autophagic degradation, thereby hindering GAB1-MAPK signalling-enhanced trophoblast syncytialisation. These findings elucidate the mechanisms by which placental GAB1 links maternal nutrition status with fetal growth and suggest potential therapeutic strategies for managing pregnancy complications such as FGR.

Y. Shen, Q. Tang, J. Wang, et al., “Targeting RORα in Macrophages to Boost Diabetic Bone Regeneration,” Cell Proliferation 56 (2023): e13474.

Figure 6H was published with incorrect images for the Vehicle and BX471 groups. The correction does not alter any findings and conclusions reported in this article.

We apologise for this error.

Aging is characterised by progressive structural and functional changes in the liver, with the extracellular matrix (ECM) playing a key role in modulating these changes. Our study presents a comprehensive proteomic analysis of the liver ECM across different age stages, uncovering significant age-related changes. Through the identification of 158 ECM proteins in decellularised rat liver scaffolds, we reveal the intricate relationship between ECM composition and liver maturation, as well as the decrease in regenerative capacity. Lumican was identified as a critical regulator with heightened expression in neonatal livers, which is associated with enhanced hepatocyte proliferation and maintenance of stem cell characteristics. Temporal expression analysis distinguished four distinct clusters of ECM proteins, each reflecting the liver's functional evolution from early development to old age. Early developmental stages were marked by proteins essential for liver growth, while adulthood was characterised by a robust ECM supporting metabolic functions. Middle age showed a regulatory shift towards protease balance, and later life was associated with haemostasis-related processes. Our findings underscore the multifaceted role of the ECM in liver health and aging, offering potential opportunities for therapeutic intervention to counteract age-induced liver dysfunction. This study provides a foundational understanding of ECM dynamics in liver aging and sets the stage for the development of innovative strategies to mitigate the effects of age-related liver decline.

RETRACTION: B. H. Choi, T. M. Colon, E. Lee, Z. Kou, W. Dai, “ CBX8 Interacts with Chromatin PTEN and Is Involved in Regulating Mitotic Progression,” Cell Proliferation 54, no. 11 (2021): e13110. https://doi.org/10.1111/cpr.13110.

The above article, published online on 15 December 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Deputy Editor, Yunfeng Lin; and John Wiley & Sons Ltd. A third party reported that the PTEN control bands in Figure 1A had previously been published in another article by some of the same authors (Choi et al. 2017 [https://doi.org/10.1186/s40164-017-0079-0]). Author W. Dai responded to an inquiry by the publisher, but the authors were not able to locate the original data for further analysis. The publisher has confirmed that both articles report on different experimental conditions and time points for both sets of PTEN controls. The retraction has been agreed to because the duplication of the PTEN control data from an earlier publication fundamentally compromises the reliability of the reported results. The authors did not respond to our notice regarding the retraction.

While the core conclusions of our study remain fully supported by validated data, we acknowledge that this misrepresentation compromises methodological transparency. We deeply regret any confusion this may have caused readers and the scientific community. Our reanalysed results from the revised images demonstrate that MNU-induced colony formation in GES-1 cells showed no significant difference compared to the control group at the 3-month time point, whereas statistically significant differences were observed at the 6-month time point. While this temporal distinction does not impact the core conclusions of our study, we believe it is imperative to present the authentic experimental findings to our readers.

We apologise for this error.

SNARE proteins are required for membrane fusion events throughout the endomembrane system, and are therefore associated with vesicular transport. Here, we found that the SNARE family member, YKT6, is indispensable for male fertility in mice. Conditional Ykt6 knockout in pre-meiotic and meiotic germ cells leads to complete sterility and meiotic arrest in male mice, which exhibit loss of spermatocytes in seminiferous tubules, but without obvious disruption of chromosomal behaviours during meiosis. We observed that the abundance of syncytia increases along with abnormal morphology of the Golgi apparatus, while lysosomes decrease in Ykt6-cKO testes. Quantitative proteomics and immunofluorescent staining both showed dysregulation of vesicular transport in YKT6-deficient spermatocytes. Additionally, the recombinant mouse proteins, HA::YKT6 and MYC::STX1A, could interact in vitro, further supporting a likely role in mediating transport vesicle fusion with the plasma membrane. Finally, the absence of TEX14 signal within syncytia and enlarged TEX14 rings between spermatocytes together suggest a failure to stabilise intercellular bridges in Ykt6-cKO testes. These results demonstrate that YKT6 is required for male fertility by promoting meiosis progression through vesicular transport regulation during spermatogenesis in mice, expanding our understanding of YKT6 functions, and suggesting a possible strategy for future interventions for male infertility in humans.