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  • REVIEW
    Mohammad Rafi Khezri, Hsiang-Yin Hsueh, Somayeh Mohammadipanah, Javad Khalili Fard, Morteza Ghasemnejad-Berenji
    Cell Proliferation, 2024, 57(7): e13608. https://doi.org/10.1111/cpr.13608
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    The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.

  • ORIGINAL ARTICLE
    Xinyu Liu, Xiaoxiao Xu, Yanting Lai, Xiaodi Zhou, Limei Chen, Qiong Wang, Yili Jin, Delun Luo, Xiaoyan Ding
    Cell Proliferation, 2024, 57(7): e13623. https://doi.org/10.1111/cpr.13623
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    The objective of this study was to investigate the effects and molecular mechanisms of tetrahedral framework nucleic acids-microRNA22 (tFNAs-miR22) on inhibiting pathological retinal neovascularization (RNV) and restoring physiological retinal vessels. A novel DNA nanocomplex (tFNAs-miR22) was synthesised by modifying microRNA-22 (miR22) through attachment onto tetrahedral frame nucleic acids (tFNAs), which possess diverse biological functions. Cell proliferation, wound healing, and tube formation were employed for in vitro assays to investigate the angiogenic function of cells. Oxygen-induced retinopathy (OIR) model was utilised to examine the effects of reducing pathological neovascularization (RNV) and inhibiting vascular occlusion in vivo. In vitro, tFNAs-miR22 demonstrated the ability to penetrate endothelial cells and effectively suppress cell proliferation, tube formation, and migration in a hypoxic environment. In vivo, tFNAs-miR22 exhibited promising results in reducing RNV and promoting the restoration of normal retinal blood vessels in OIR model through modulation of the Wnt pathway. This study provided a theoretical basis for the further understanding of RNV, and highlighted the innovative and potential of tFNAs-miR22 as a therapeutic option for ischemic retinal diseases.

  • ORIGINAL ARTICLE
    Laura González-Llera, Daniel Sobrido-Cameán, Ana Quelle-Regaldie, Laura Sánchez, Antón Barreiro-Iglesias
    Cell Proliferation, 2024, 57(5): e13594. https://doi.org/10.1111/cpr.13594
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    The study of neurogenesis is essential to understanding fundamental developmental processes and for the development of cell replacement therapies for central nervous system disorders. Here, we designed an in vivo drug screening protocol in developing zebrafish to find new molecules and signalling pathways regulating neurogenesis in the ventral spinal cord. This unbiased drug screen revealed that 4 cyclooxygenase (COX) inhibitors reduced the generation of serotonergic interneurons in the developing spinal cord. These results fitted very nicely with available single-cell RNAseq data revealing that floor plate cells show differential expression of 1 of the 2 COX2 zebrafish genes (ptgs2a). Indeed, several selective COX2 inhibitors and two different morpholinos against ptgs2a reduced the number of serotonergic neurons in the ventral spinal cord and led to locomotor deficits. Single-cell RNAseq data and different pharmacological manipulations further revealed that COX2-floor plate-derived prostaglandin D2 promotes neurogenesis in the developing spinal cord by promoting mitotic activity in progenitor cells. Rescue experiments using a phosphodiesterase-4 inhibitor suggest that intracellular changes in cAMP levels underlie the effects of COX inhibitors on neurogenesis and locomotion. Our study provides compelling in vivo evidence showing that prostaglandin signalling promotes neurogenesis in the ventral spinal cord.

  • ORIGINAL ARTICLE
    Yuan Liang, Rui Zhang, Siddhartha Biswas, Qingfa Bu, Zibo Xu, Lei Qiao, Yan Zhou, Jiaqi Tang, Jinren Zhou, Haoming Zhou, Ling Lu
    Cell Proliferation, 2024, 57(4): e13576. https://doi.org/10.1111/cpr.13576
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    Non-alcoholic fatty liver disease (NAFLD) has emerged as the primary risk factor for hepatocellular carcinoma (HCC), owing to improved vaccination rates of Hepatitis B and the increasing prevalence of metabolic syndrome related to obesity. Although the importance of innate and adaptive immune cells has been emphasized, the malignant transformation of hepatocytes and their intricate cellular network with the immune system remain unclear. The study incorporated four single-cell transcriptomic datasets of liver tissues covering healthy and NAFLD-related disease status. To identify the subsets and functions of hepatocytes and macrophages, we employed differential composition analysis, functional enrichment analysis, pseudotime analysis, and scenic analysis. Furthermore, an experimental mouse model for the transformation of nonalcoholic steatohepatitis into hepatocellular carcinoma was established for validation purposes. We defined CYP7A1+ hepatocytes enriched in precancerous lesions as ‘Transitional Cells’ in the progression from NAFLD to HCC. CYP7A1+ hepatocytes upregulated genes associated with stress response, inflammation and cancer-associated pathways and downregulated the normal hepatocyte signature. We observed that hypoxia activation accompanied the entire process of inflammation-cancer transformation. Hepatocyte-derived HIF1A was gradually activated during the progression of NAFLD disease to adapt to the hypoxic microenvironment and hepatocytes under hypoxic environment led to changes in the metabolism, proliferation and angiogenesis, promoting the occurrence of tumours. Meanwhile, hypoxia induced the polarization of RACK1+ macrophages that enriched in the liver tissues of NASH towards immunosuppressed TREM2+ macrophages. Moreover, immunosuppressive TREM2+ macrophages were recruited by tumour cells through the CCL15-CCR1 axis to enhance immunosuppressive microenvironment and promote NAFLD-related HCC progression. The study provides a deep understanding of the development mechanism of NAFLD-related HCC and offers theoretical support and experimental basis for biological targets, drug research, and clinical application.

  • PRACTICE INSIGHTS
    Ling Wang, Shiyu Liu, Ka Li, Aijin Ma, Chenghu Hu, Changlin Wang, Nan Cao, Yunpeng Zhao, Ruifeng Fu, Wenwen Jia, Peng Xiang, Houqi Liu, Zhongquan Qi, Ningwen Zhu, Lingmin Liang, Lei Wang, Jiani Cao, Peijun Zhai, Jiaxi Zhou, Jun Wei, Tao Na, Jun Wu, Zhiying He, Guangdong Zhou, Weifeng Yu, Jinyan Wu, Wen Zeng, Yong Zhang, Lijun Zhu, Boqiang Fu, Jingzhong Zhang, Shuwei Yang, Chengxiang Dai, Hengmi Cui, Jianzhong Jing, Hexin Yan, Xiaowen He, Yongbo Lu, Cailing Tong, Tongbiao Zhao, Jie Hao, Xialin Liu, Yan Jin, Yue Wang
    Cell Proliferation, 2024, 57(3): e13554. https://doi.org/10.1111/cpr.13554
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    ‘General requirements for the production of extracellular vesicles derived from human stem cells’ is the first guideline for stem cells derived extracellular vesicles in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard specifies the general requirements, process requirements, packaging and labelling requirements and storage requirements for preparing extracellular vesicles derived from human stem cells, which is applicable to the research and production of extracellular vesicles derived from stem cells. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that the publication of this guideline will promote institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardisation of extracellular vesicles derived from human stem cells.

  • ORIGINAL ARTICLE
    Jiafei Sun, Xingyu Chen, Yunfeng Lin, Xiaoxiao Cai
    Cell Proliferation, 2024, 57(7): e13624. https://doi.org/10.1111/cpr.13624
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    Certain miRNAs, notably miR29c, demonstrate a remarkable capacity to regulate cellular osteogenic differentiation. However, their application in tissue regeneration is hampered by their inherent instability and susceptibility to degradation. In this study, we developed a novel miR29c delivery system utilising tetrahedral framework nucleic acids (tFNAs), aiming to enhance its stability and endocytosis capability, augment the efficacy of miR29c, foster osteogenesis in bone marrow mesenchymal stem cells (BMSCs), and significantly improve the repair of critical-sized bone defects (CSBDs). We confirmed the successful synthesis and biocompatibility of sticky ends-modified tFNAs (stFNAs) and miR29c-modified stFNAs (stFNAs-miR29c) through polyacrylamide gel electrophoresis, microscopy scanning, a cell counting kit-8 assay and so on. The mechanism and osteogenesis effects of stFNAs-miR29c were explored using immunofluorescence staining, western blotting, and reserve transcription quantitative real-time polymerase chain reaction. Additionally, the impact of stFNAs-miR29c on CSBD repair was assessed via micro-CT and histological staining. The nano-carrier, stFNAs-miR29c was successfully synthesised and exhibited exemplary biocompatibility. This nano-nucleic acid material significantly upregulated osteogenic differentiation-related markers in BMSCs. After 2 months, stFNAs-miR29c demonstrated significant bone regeneration and reconstruction in CSBDs. Mechanistically, stFNAs-miR29c enhanced osteogenesis of BMSCs by upregulating the Wnt signalling pathway, contributing to improved bone tissue regeneration. The development of this novel nucleic acid nano-carrier, stFNAs-miR29c, presents a potential new avenue for guided bone regeneration and bone tissue engineering research.

  • ORIGINAL ARTICLE
    Dianlei Guo, Sikai Liu, Jiao Zhang, Xinyu Gu, Lei Shi, Yingchun Su, Shujuan Xu, Rong Ju, Yanhong Wei, Chunqiao Liu
    Cell Proliferation, 2024, 57(6): e13595. https://doi.org/10.1111/cpr.13595
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    Basement membrane (BM) component deposition is closely linked to the establishment of cell polarity. Previously, we showed that Prickle1 is crucial for BM deposition and cell polarity events in tear duct elongation. To gain a deeper understanding of the intimate relationship between BM formation and cell polarity, we generated induced pluripotent stem cells (iPSCs)-derived embryoid bodies (EBs) with a basement membrane separating the visceral endoderm (VE) and inner EB cell mass. We found that Prickle1 was highly expressed in VE of the normal EBs, and the Prickle1 mutant EBs displayed severely impaired BM. Notably, the formation of the basement membrane appeared to rely on the proper microtubule network of the VE cells, which was disrupted in the Prickle1 mutant EBs. Moreover, disruption of vesicle trafficking in the VE hindered BM secretion. Furthermore, reintroducing Prickle1 in the mutant EBs completely rescued BM formation but not the apicobasal cell polarity of the VE. Our data, in conjunction with studies by others, highlight the conserved role of Prickle1 in directing the secretion of BM components of the VE cells during embryonic germ layer differentiation, even in the absence of established general polarity machinery. Our study introduces a novel system based on iPSCs-derived EBs for investigating cellular and molecular events associated with cell polarity.

  • ORIGINAL ARTICLE
    Qiuhan Sun, Liyan Zhang, Tian Chen, Nianci Li, Fangzhi Tan, Xingliang Gu, Yinyi Zhou, Ziyu Zhang, Yicheng Lu, Jie Lu, Xiaoyun Qian, Bing Guan, Jieyu Qi, Fanglei Ye, Renjie Chai
    Cell Proliferation, 2024, 57(7): e13620. https://doi.org/10.1111/cpr.13620
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    Irreversible damage to hair cells (HCs) in the cochlea leads to hearing loss. Cochlear supporting cells (SCs) in the murine cochlea have the potential to differentiate into HCs. Neuron membrane glycoprotein M6B (Gpm6b) as a four-transmembrane protein is a potential regulator of HC regeneration according to our previous research. In this study, we found that AAV-ie-mediated Gpm6b overexpression promoted SC-derived organoid expansion. Enhanced Gpm6b prevented the normal decrease in SC plasticity as the cochlea develops by supporting cells re-entry cell cycle and facilitating the SC-to-HC transformation. Also, overexpression of Gpm6b in the organ of Corti through the round window membrane injection facilitated the trans-differentiation of Lgr5+ SCs into HCs. In conclusion, our results suggest that Gpm6b overexpression promotes HC regeneration and highlights a promising target for hearing repair using the inner ear stem cells combined with AAV.

  • ORIGINAL ARTICLE
    Zhikai Liu, Hanghang Liu, Shibo Liu, Bolun Li, Yao Liu, En Luo
    Cell Proliferation, 2024, 57(6): e13596. https://doi.org/10.1111/cpr.13596
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    Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

  • ORIGINAL ARTICLE
    Mengmeng Zhang, Na Ying, Jie Chen, Liwen Wu, Huajie Liu, Shihua Luo, Dongdong Zeng
    Cell Proliferation, 2024, 57(6): e13603. https://doi.org/10.1111/cpr.13603
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    Breast cancer has overtaken lung cancer as the number one cancer worldwide. Paclitaxel (PTX) is a widely used first-line anti-cancer drug, but it is not very effective in clinical breast cancer therapy. It has been reported that triptolide (TPL) can enhance the anticancer effect of paclitaxel, and better synergistic therapeutic effects are seen with concomitant administration of PTX and TPL. In this study, we developed pH-responsive polymeric micelles for co-delivery of PTX and TPL, which disassembling in acidic tumour microenvironments to target drug release and effectively kill breast cancer cells. Firstly, we synthesized amphiphilic copolymer mPEG2000-PBAE through Michael addition reaction, confirmed by various characterizations. Polymer micelles loaded with TPL and PTX (TPL/PTX-PMs) were prepared by the thin film dispersion method. The average particle size of TPL/PTX-PMs was 97.29 ± 1.63 nm, with PDI of 0.237 ± 0.003 and Zeta potential of 9.57 ± 0.80 mV, LC% was 6.19 ± 0.21%, EE% was 88.67 ± 3.06%. Carrier material biocompatibility and loaded micelle cytotoxicity were assessed using the CCK-8 method, demonstrating excellent biocompatibility. Under the same drug concentration, TPL/PTX-PMs were the most toxic to tumour cells and had the strongest proliferation inhibitory effect. Cellular uptake assays revealed that TPL/PTX-PMs significantly increased intracellular drug concentration and enhanced antitumor activity. Overall, pH-responsive micellar co-delivery of TPL and PTX is a promising approach for breast cancer therapy.

  • PRACTICE INSIGHTS
    Yu-Kai Wang, Lin Feng, Ai-Jin Ma, Jie Hao, Ying Zhang, Yue-Jun Chen, Zhi-Guo Chen, Jun-Ying Yu, Yan Liu, Chang-Mei Liu, Yu Zhang, Chang-Lin Wang, Zhao-Qian Teng, Jia-Xi Zhou, Tian-Qing Li, Liu Wang, Bo-Qiang Fu, Yu Vincent Fu, Li-Jun Zhu, Ling-Min Liang, Jia-Ni Cao, Lei Wang, Qi Zhou, Andy Peng Xiang, Bao-Yang Hu, Tong-Biao Zhao
    Cell Proliferation, 2024, 57(4): e13563. https://doi.org/10.1111/cpr.13563
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    Human midbrain dopaminergic progenitors (mDAPs) are one of the most representative cell types in both basic research and clinical applications. However, there are still many challenges for the preparation and quality control of mDAPs, such as the lack of standards. Therefore, the establishment of critical quality attributes and technical specifications for mDAPs is largely needed. “Human midbrain dopaminergic progenitor” jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research, is the first guideline for human mDAPs in China. This standard specifies the technical requirements, test methods, inspection rules, instructions for usage, labelling requirements, packaging requirements, storage requirements, transportation requirements and waste disposal requirements for human mDAPs, which is applicable to the quality control for human mDAPs. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that the publication of this guideline will facilitate the institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of human mDAPs for clinical development and therapeutic applications.

  • REVIEW
    Xixian Li, Dan Zhang, Yang Yu, Liang Wang, Muxin Zhao
    Cell Proliferation, 2024, 57(4): e13586. https://doi.org/10.1111/cpr.13586
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    How to effectively repair cutaneous wounds and promote skin rejuvenation has always been a challenging issue for clinical medicine and medical aesthetics. Current conventional medicines exhibit several drawbacks, including limited therapeutic effects, prolonged treatment periods, and high costs. As a novel cell-free therapy, the umbilical cord-derived mesenchymal stem cell (UCMSC) secretome may offer a promising approach for skin regeneration and rejuvenation. The UCMSC secretome is a collection of all proteins secreted by mesenchymal stem cells, including conditioned media, exosomes, and other substances. The UCMSC secretome has numerous abilities to accelerate acute wound healing, including high fibroblast and keratinocyte proliferative activity, pro-angiogenesis, anti-inflammation, anti-fibrosis, and anti-oxidative stress. Its impact on the four stages of wound healing is manifested by inducing the haemostasis phase, inhibiting the inflammation phase, promoting the proliferation phase, and regulating the remodelling phase. Furthermore, it is highly effective in the treatment of chronic wounds, alopecia, aging, and skin homeostasis disturbance. This review focuses on the clinical therapies and application prospects of the UCMSC secretome, encompassing its source, culture, separation, identification, storage, and pretreatment. Additionally, a discussion on the dosage, administration route, efficacy, and biosafety in the clinical situation is presented. This review aims to provide scientific support for the mechanistic investigation and clinical utilisation of the UCMSC secretome in wound healing and skin rejuvenation.

  • ORIGINAL ARTICLE
    Yunlong Ma, Yijun Zhou, Dingping Jiang, Wei Dai, Jingjing Li, Chunyu Deng, Cheng Chen, Gongwei Zheng, Yaru Zhang, Fei Qiu, Haojun Sun, Shilai Xing, Haijun Han, Jia Qu, Nan Wu, Yinghao Yao, Jianzhong Su
    Cell Proliferation, 2024, 57(3): e13558. https://doi.org/10.1111/cpr.13558
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    Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single-cell RNA sequencing (scRNA-seq) technology and genome-wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait-relevant cell types or states. Here, we constructed a computational framework to integrate atlas-level organoid scRNA-seq data, GWAS summary statistics, expression quantitative trait loci, and gene–drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID-19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID-19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID-19-damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID-19, and this cell subset showed a notable increase in cell-to-cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID-19 in a cell-type-specific manner. Overall, our results showcase that host genetic determinants have cellular-specific contribution to COVID-19 severity, and identification of cell type-specific drug targets may facilitate to develop effective therapeutics for treating severe COVID-19 and its complications.

  • ORIGINAL ARTICLE
    Jun Pan, Fang Ye, Hui Li, Chengxuan Yu, Jiajia Mao, Yanyu Xiao, Haide Chen, Junqing Wu, Jiaqi Li, Lijiang Fei, Yijun Wu, Xiaoming Meng, Guoji Guo, Yingying Wang
    Cell Proliferation, 2024, 57(3): e13555. https://doi.org/10.1111/cpr.13555
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    The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 post-transplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell–cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver).

  • ORIGINAL ARTICLE
    Rui Ma, Xuemeng Zhou, Xiaohui Zhai, Chuyue Wang, Rong Hu, You Chen, Liyang Shi, Xing Fang, Yuan Liao, Lifeng Ma, Mengmeng Jiang, Junqing Wu, Renying Wang, Jiao Chen, Taiyuan Cao, Ge Du, Yingying Zhao, Weili Wu, Haide Chen, Shanshan Li, Qizhou Lian, Guoji Guo, Jian Xiao, Andrew P. Hutchins, Ping Yuan
    Cell Proliferation, 2024, 57(5): e13591. https://doi.org/10.1111/cpr.13591
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    Highly aggressive gastric cancer (HAGC) is a gastric cancer characterized by bone marrow metastasis and disseminated intravascular coagulation (DIC). Information about the disease is limited. Here we employed single-cell RNA sequencing to investigate peripheral blood mononuclear cells (PBMCs), aiming to unravel the immune response of patients toward HAGC. PBMCs from seven HAGC patients, six normal advanced gastric cancer (NAGC) patients, and five healthy individuals were analysed by single-cell RNA sequencing. The expression of genes of interest was validated by bulk RNA-sequencing and ELISA. We found a massive expansion of neutrophils in PBMCs of HAGC. These neutrophils are activated, but immature. Besides, mononuclear phagocytes exhibited an M2-like signature and T cells were suppressed and reduced in number. Analysis of cell-cell crosstalk revealed that several signalling pathways involved in neutrophil to T-cell suppression including APP-CD74, MIF-(CD74+CXCR2), and MIF-(CD74+CD44) pathways were increased in HAGC. NETosis-associated genes S100A8 and S100A9 as well as VEGF, PDGF, FGF, and NOTCH signalling that contribute to DIC development were upregulated in HAGC too. This study reveals significant changes in the distribution and interactions of the PBMC subsets and provides valuable insight into the immune response in patients with HAGC. S100A8 and S100A9 are highly expressed in HAGC neutrophils, suggesting their potential to be used as novel diagnostic and therapeutic targets for HAGC.

  • CORRECTION
    Cell Proliferation, 2024, 57(5): e13632. https://doi.org/10.1111/cpr.13632
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  • ORIGINAL ARTICLE
    Xinmei Du, Mengmeng Duan, Shiyi Kan, Yueyi Yang, Siqun Xu, Jieya Wei, Jiazhou Li, Hao Chen, Xuedong Zhou, Jing Xie
    Cell Proliferation, 2024, 57(5): e13579. https://doi.org/10.1111/cpr.13579
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    It is well recognized that mitochondrial dynamics plays a vital role in cartilage physiology. Any perturbation in mitochondrial dynamics could cause disorders in cartilage metabolism and even lead to the occurrence of cartilage diseases such as osteoarthritis (OA). TGF-β3, as an important growth factor that appears in the joints of OA disease, shows its great potential in chondrocyte growth and metabolism. Nevertheless, the role of TGF-β3 on mitochondrial dynamics is still not well understood. Here we aimed to investigate the effect of TGF-β3 on mitochondrial dynamics of chondrocytes and reveal its underlying bio-mechanism. By using transmission electron microscopy (TEM) for the number and morphology of mitochondria, western blotting for the protein expressions, immunofluorescence for the cytoplasmic distributions of proteins, and RNA sequencing for the transcriptome changes related to mitochondrial dynamics. We found that TGF-β3 could increase the number of mitochondria in chondrocytes. TGF-β3-enhanced mitochondrial number was via promoting the mitochondrial fission. The mitochondrial fission induced by TGF-β3 was mediated by AMPK signaling. TGF-β3 activated canonical p-Smad3 signaling and resultantly mediated AMPK-induced mitochondrial fission. Taken together, these results elucidate an understanding of the role of TGF-β3 on mitochondrial dynamics in chondrocytes and provide potential cues for therapeutic strategies in cartilage injury and OA disease in terms of energy metabolism.

  • REVIEW
    Yizhou Jin, Zhipeng Fan
    Cell Proliferation, 2024, 57(4): e13578. https://doi.org/10.1111/cpr.13578
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    Drug resistance is perhaps the greatest obstacle in improving outcomes for cancer patients, leading to recurrence, progression and metastasis of various cancers. Exploring the underlying mechanism worth further study. N6-methyladenosine (m6A) is the most common RNA modification found in eukaryotes, playing a vital role in RNA translation, transportation, stability, degradation, splicing and processing. Long noncoding RNA (lncRNA) refers to a group of transcripts that are longer than 200 nucleotides (nt) and typically lack the ability to code for proteins. LncRNA has been identified to play a significant role in regulating multiple aspects of tumour development and progression, including proliferation, metastasis, metabolism, and resistance to treatment. In recent years, a growing body of evidence has emerged, highlighting the crucial role of the interplay between m6A modification and lncRNA in determining the sensitivity of cancer cells to chemotherapeutic agents. In this review, we focus on the recent advancements in the interaction between m6A modification and lncRNA in the modulation of cancer drug resistance. Additionally, we aim to explore the underlying mechanisms involved in this process. The objective of this review is to provide valuable insights and suggest potential future directions for the reversal of chemoresistance in cancer.

  • ORIGINAL ARTICLE
    Hui Xu, Jin Wang, Murad Al-Nusaif, Huipeng Ma, Weidong Le
    Cell Proliferation, 2024, 57(3): e13560. https://doi.org/10.1111/cpr.13560
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    In non-small cell lung cancer (NSCLC), metastasis is the most common phenotype, and autophagy plays a vital role in its regulation. However, there are limited data on how autophagy-related genes and metastasis-related genes affect NSCLC progression. Our goal was to identify the genes that regulate autophagy and metastasis in NSCLC, and to assess the underlying mechanisms in this current study. RNA sequencing data from public databases were used to screen differentially expressed autophagy- and metastasis-associated genes. Enrichment analyses and immune correlations were conducted to identify hub genes and potential regulating pathways in NSCLC. In this study, we found that CCL2 expression was highly expressed in NSCLC tissues and high CCL2 level was correlated with strong infiltration in lung tissues from NSCLC patients. Overexpression of CCL2 can enhance the metastasis of NSCLC cells in nude mice. Furthermore, CCL2 activated the PI3K/Akt/mTOR signalling pathway axis, promoted epithelial–mesenchymal transition (EMT), and blocked the autophagic flux in NSCLC cells. Therefore, our results indicate that CCL2 promotes metastasis and EMT of NSCLC via PI3K/Akt/mTOR axis and autophagy signalling pathways. We believe that CCL2 could be a probable target for the diagnosis and therapeutics of NSCLC, and this study may expand our understanding of lung cancer.

  • ORIGINAL ARTICLE
    Xiaoru Shao, Zhong Hu, Huiqin Su, Yuzhong Wang, Yunfeng Lin
    Cell Proliferation, 2024, 57(3): e13561. https://doi.org/10.1111/cpr.13561
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    This study aimed to explore the osteogenic ability and mitochondrial autophagy of periodontal ligament stem cells (PDLSCs) under cyclic tensile stress (CTS). Primary PDLSCs were isolated from the periodontal membrane and cultured by passage. Alizarin red staining, alkaline phosphatase detection, reverse transcription polymerase chain reaction (RT-PCR), and Western blotting were used to detect the osteogenic differentiation level of PDLSCs. Mitochondrial autophagy in PDLSCs after CTS was measured using a mitochondrial autophagy detection kit, and the expression levels of autophagy-related proteins LC3B, LAMP1 and Beclin1 were measured using cellular immunofluorescence technology, RT-PCR and Western blot. After applying CTS, the osteogenic differentiation ability of PDLSCs was significantly improved, and the expression of alkaline phosphatase on the surface of the cell membrane and the formation of calcium nodules in PDLSCs were significantly increased respectively. We also studied the relevant mechanism of action and found that applying CTS can promote the osteogenic differentiation of PDLSCs and is related to the activation of mitochondrial autophagy. This study provides new insights into the mechanism of increased osteogenic differentiation on the tension side of orthodontic teeth and provides new experimental evidence for the involvement of mitochondrial autophagy in the regulation of osteogenic differentiation.

  • ORIGINAL ARTICLE
    Xiaokai Li, Sha Zeng, Li Chen, Yu Zhang, Xuemin Li, Biwei Zhang, Duo Su, Qinjiao Du, Jiaman Zhang, Haoming Wang, Zhining Zhong, Jinwei Zhang, Penghao Li, Anan Jiang, Keren Long, Mingzhou Li, Liangpeng Ge
    Cell Proliferation, 2024, 57(3): e13552. https://doi.org/10.1111/cpr.13552
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    Cebpa is a master transcription factor gene for adipogenesis. However, the mechanisms of enhancer–promoter chromatin interactions controlling Cebpa transcriptional regulation during adipogenic differentiation remain largely unknown. To reveal how the three-dimensional structure of Cebpa changes during adipogenesis, we generated high-resolution chromatin interactions of Cebpa in 3T3-L1 preadipocytes and 3T3-L1 adipocytes using circularized chromosome conformation capture sequencing (4C-seq). We revealed dramatic changes in chromatin interactions and chromatin status at interaction sites during adipogenic differentiation. Based on this, we identified five active enhancers of Cebpa in 3T3-L1 adipocytes through epigenomic data and luciferase reporter assays. Next, epigenetic repression of Cebpa-L1-AD-En2 or -En3 by the dCas9-KRAB system significantly down-regulated Cebpa expression and inhibited adipocyte differentiation. Furthermore, experimental depletion of cohesin decreased the interaction intensity between Cebpa-L1-AD-En2 and the Cebpa promoter and down-regulated Cebpa expression, indicating that long-range chromatin loop formation was mediated by cohesin. Two transcription factors, RXRA and PPARG, synergistically regulate the activity of Cebpa-L1-AD-En2. To test whether Cebpa-L1-AD-En2 plays a role in adipose tissue development, we injected dCas9-KRAB-En2 lentivirus into the inguinal white adipose tissue (iWAT) of mice to suppress the activity of Cebpa-L1-AD-En2. Repression of Cebpa-L1-AD-En2 significantly decreased Cebpa expression and adipocyte size, altered iWAT transcriptome, and affected iWAT development. We identified functional enhancers regulating Cebpa expression and clarified the crucial roles of Cebpa-L1-AD-En2 and Cebpa promoter interaction in adipocyte differentiation and adipose tissue development.

  • PRACTICE INSIGHTS
    Shuaishuai Niu, Chengxiang Xia, Dehao Huang, Lei Wang, Hongbo Hu, Shuyang Yu, Ning Wu, Zhongjun Dong, Jiaxi Zhou, Jun Wu, Junying Yu, Ying Zhang, Changlin Wang, Boqiang Fu, Jiani Cao, Lingmin Liang, Lingxue Xu, Ling Chen, Qi Zhou, Aijin Ma, Tongbiao Zhao, Jie Hao, Jinyong Wang
    Cell Proliferation, 2024, 57(5): e13588. https://doi.org/10.1111/cpr.13588
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    ‘Requirements for Human Natural Killer Cells’ is the latest set of guidelines on human NK cells in China, jointly drafted and agreed upon by experts from the Standards Committee of Chinese Society for Cell Biology. This standard specifies requirements for the human natural killer (NK) cells, including the technical requirements, test methods, test regulations, instructions for use, labeling requirements, packaging requirements, storage and transportation requirements, and waste disposal requirements of NK cells. This standard is applicable for the quality control of NK cells, derived from human tissues, or differentiated/transdifferentiated from stem cells. It was originally released by the Chinese Society for Cell Biology on 30 August, 2022. We hope that the publication of these guidelines will promote institutional establishment, acceptance, and execution of proper protocols and accelerate the international standardization of human NK cells for applications.

  • ORIGINAL ARTICLE
    Xiaoling Wang, Wei Zhang, Siqi Zhao, Hao Yan, Zijuan Xin, Tiantian Cui, Ruge Zang, Lingping Zhao, Haiyang Wang, Junnian Zhou, Xuan Li, Wen Yue, Jiafei Xi, Zhaojun Zhang, Xiangdong Fang, Xuetao Pei
    Cell Proliferation, 2024, 57(7): e13614. https://doi.org/10.1111/cpr.13614
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    Ex vivo red blood cell (RBC) production generates unsatisfactory erythroid cells. A deep exploration into terminally differentiated cells is required to understand the impairments for RBC generation and the underlying mechanisms. Here, we mapped an atlas of terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMN) and pluripotent stem cells (PSC) and observed their dynamic regulation of erythropoiesis at single-cell resolution. Interestingly, we detected a few progenitor cells and non-erythroid cells from both origins. In PSC-derived erythropoiesis (PSCE), the expression of haemoglobin switch regulators (BCL11A and ZBTB7A) were significantly absent, which could be the restraint for its adult globin expression. We also found that PSCE were less active in stress erythropoiesis than in UCBMN-derived erythropoiesis (UCBE), and explored an agonist of stress erythropoiesis gene, TRIB3, could enhance the expression of adult globin in PSCE. Compared with UCBE, there was a lower expression of epigenetic-related proteins (e.g., CASPASE 3 and UBE2O) and transcription factors (e.g., FOXO3 and TAL1) in PSCE, which might restrict PSCE's enucleation. Moreover, we characterized a subpopulation with high proliferation capacity marked by CD99high in colony-forming unit-erythroid cells. Inhibition of CD99 reduced the proliferation of PSC-derived cells and facilitated erythroid maturation. Furthermore, CD99–CD99 mediated the interaction between macrophages and erythroid cells, illustrating a mechanism by which macrophages participate in erythropoiesis. This study provided a reference for improving ex vivo RBC generation.

  • RETRACTION
    Cell Proliferation, 2024, 57(7): e13682. https://doi.org/10.1111/cpr.13682
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  • ORIGINAL ARTICLE
    Wenjun Huang, Rui Zhou, Congshan Jiang, Jie Wang, Yafei Zhou, Xiaoyan Xu, Tao Wang, Anmao Li, Yanmin Zhang
    Cell Proliferation, 2024, 57(4): e13573. https://doi.org/10.1111/cpr.13573
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    Pompe disease (PD) is a rare autosomal recessive disorder that presents with progressive hypertrophic cardiomyopathy. However, the detailed mechanism remains clarified. Herein, PD patient-specific induced pluripotent stem cells were differentiated into cardiomyocytes (PD-iCMs) that exhibited cardiomyopathic features of PD, including decreased acid alpha-glucosidase activity, lysosomal glycogen accumulation and hypertrophy. The defective mitochondria were involved in the cardiac pathology as shown by the significantly decreased number of mitochondria and impaired respiratory function and ATP production in PD-iCMs, which was partially due to elevated levels of intracellular reactive oxygen species produced from depolarized mitochondria. Further analysis showed that impaired fusion and autophagy of mitochondria and declined expression of mitochondrial complexes underlies the mechanism of dysfunctional mitochondria. This was alleviated by supplementation with recombinant human acid alpha-glucosidase that improved the mitochondrial function and concomitantly mitigated the cardiac pathology. Therefore, this study suggests that defective mitochondria underlie the pathogenesis of cardiomyopathy in patients with PD.

  • LETTER TO THE EDITOR
    Songnan Sui, Yun Tian, Xiaofang Wang, Chengwu Zeng, Oscar Junhong Luo, Yangqiu Li
    Cell Proliferation, 2024, 57(3): e13583. https://doi.org/10.1111/cpr.13583
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  • ORIGINAL ARTICLE
    Huan-Huan Deng, Shi-Yuan Tong, Dan Shen, Shu-Qing Zhang, Yinghui Fu
    Cell Proliferation, 2024, 57(5): e13587. https://doi.org/10.1111/cpr.13587
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    The majority of neocortical projection neurons are generated indirectly from radial glial cells (RGCs) mediated by intermediate progenitor cells (IPCs) in mice. IPCs are thought to be a great breakthrough in the evolutionary expansion of the mammalian neocortex. However, the precise ratio of neuron production from IPCs and characteristics of RGC differentiation process are still unclear. Our study revealed that direct neurogenesis was seldom observed and increased slightly at late embryonic stage. Besides, we conducted retrovirus sparse labelling combined carboxyfluorescein diacetate succinimide ester (CFSE) and Tbr2-CreER strain to reconstruct individual lineage tree in situ. The lineage trees simulated the output of RGCs at per round of division in sequence with high temporal, spatial and cellular resolution at P7. We then demonstrated that only 1.90% of neurons emanated from RGCs directly in mouse cerebral neocortex and 79.33% of RGCs contributed to the whole clones through IPCs. The contribution of indirect neurogenesis was underestimated previously because approximately a quarter of IPC-derived neurons underwent apoptosis. Here, we also showed that abundant IPCs from first-generation underwent self-renewing division and generated four neurons ultimately. We confirmed that the intermediate proliferative progenitors expressed higher Cux2 characteristically at early embryonic stage. Finally, we validated that the characteristics of neurogenetic process in lineages and developmental fate of neurons were conserved in Reeler mice. This study contributes to further understanding of neurogenesis in neocortical development.

  • LETTER TO THE EDITOR
    Fan Li, Najmeh Karimi, Siqi Wang, Tianshi Pan, Jingxi Dong, Xin Wang, Sinan Ma, Qingtong Shan, Chao Liu, Ying Zhang, Wei Li, Guihai Feng
    Cell Proliferation, 2024, 57(7): e13655. https://doi.org/10.1111/cpr.13655
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  • ORIGINAL ARTICLE
    Xuan T. T. Dang, Cao Dai Phung, Claudine Ming Hui Lim, Migara Kavishka Jayasinghe, Jorgen Ang, Thai Tran, Herbert Schwarz, Minh T. N. Le
    Cell Proliferation, 2024, 57(7): e13622. https://doi.org/10.1111/cpr.13622
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    Neoantigen delivery using extracellular vesicles (EVs) has gained extensive interest in recent years. EVs derived from tumour cells or immune cells have been used to deliver tumour antigens or antitumor stimulation signals. However, potential DNA contamination from the host cell and the cost of large-scale EV production hinder their therapeutic applications in clinical settings. Here, we develop an antigen delivery platform for cancer vaccines from red blood cell-derived EVs (RBCEVs) targeting splenic DEC-205+ dendritic cells (DCs) to boost the antitumor effect. By loading ovalbumin (OVA) protein onto RBCEVs and delivering the protein to DCs, we were able to stimulate and present antigenic OVA peptide onto major histocompatibility complex (MHC) class I, subsequently priming activated antigen-reactive T cells. Importantly, targeted delivery of OVA using RBCEVs engineered with anti-DEC-205 antibody robustly enhanced antigen presentation of DCs and T cell activation. This platform is potentially useful for producing personalised cancer vaccines in clinical settings.

  • ORIGINAL ARTICLE
    Weitong Cui, Xiao Yang, Yikai Dou, Yue Du, Xiaohong Ma, Lei Hu, Yunfeng Lin
    Cell Proliferation, 2024, 57(7): e13625. https://doi.org/10.1111/cpr.13625
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    Osteoporosis (OP) is a common disease characterized by bone loss and bone tissue microstructure degradation. Drug treatment is a common clinical treatment that aims to increase bone mass and bone density. Tetrahedral DNA nanostructures (TDNs) are three-dimensional tetrahedral frames formed by folding four single-stranded DNA molecules, which have good biological safety and can promote bone regeneration. In this study, a mouse model of OP was established by ovariectomy (OVX) and TDN was injected into the tail vein for 8 weeks. We found that ovariectomized mice could simulate some physiological changes in OP. After treatment with TDNs, some of this destruction in mice was significantly improved, including an increase in the bone volume fraction (BV/TV) and bone trabecular number (Tb. N), decrease in bone separation (Tb. SP), reduction in the damage to the mouse cartilage layer, reduction in osteoclast lacunae in bone trabecula, and reduction in the damage to the bone dense part. We also found that the expression of ALP, β-Catenin, Runx2, Osterix, and bone morphogenetic protein (BMP)2 significantly decreased in OVX mice but increased after TDN treatment. Therefore, this study suggests that TDNs may regulate the Wnt/β-Catenin and BMP signalling pathways to improve the levels of some specific markers of osteogenic differentiation, such as Runx2, ALP, and Osterix, to promote osteogenesis, thus showing a therapeutic effect on OP mice.