{"title":"METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m<sup>6</sup>A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis.","authors":"Sa Li, Jiajie Hao, Guangliang Hong, Hongzhi Dong, He Liu, Lingmei Jin, Zhihao Zhang, Haoyu Wu, Mingli Hu, Rujin Huang, Guanzheng Luo, Jiangping He, Jiekai Chen, Kaixin Wu","doi":"10.1186/s13619-025-00241-1","DOIUrl":"https://doi.org/10.1186/s13619-025-00241-1","url":null,"abstract":"<p><p>N6-methyladenosine (m<sup>6</sup>A) plays crucial roles in development and cellular reprogramming. During embryonic development, pluripotency transitions from a naïve to a primed state, and modeling the reverse primed-to-naïve transition (PNT) provides a valuable framework for investigating pluripotency regulation. Here, we show that inhibiting METTL3 significantly promotes PNT in an m<sup>6</sup>A-dependent manner. Mechanistically, we found that suppressing METTL3 and YTHDF2 prolongs the lifetimes of pluripotency-associated mRNAs, such as Nanog and Sox2, during PNT. In addition, Gstp1 was identified as a downstream target of METTL3 inhibition and YTHDF2 knockout. Gstp1 overexpression enhances PNT, whereas its inhibition impedes the transition. Overall, our findings suggest that YTHDF2 facilitates the removal of pluripotency gene transcripts and Gstp1, thereby promoting PNT reprogramming through m<sup>6</sup>A-mediated posttranscriptional control.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"19"},"PeriodicalIF":4.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids.","authors":"Fan Hong, Xiaodan Wang, Nanshan Zhong, Ze Zhang, Shibo Lin, Mengxian Zhang, Haonan Li, Yuan Liu, Yalong Wang, Lianzheng Zhao, Xiao Yang, Hongwen Zhou, Hui Liang, Ye-Guang Chen","doi":"10.1186/s13619-025-00237-x","DOIUrl":"10.1186/s13619-025-00237-x","url":null,"abstract":"<p><p>The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis. Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation, the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood. In this study, by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways, we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids. These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues. Specifically, BMP4 signaling stimulates pit cell and parietal cell differentiation. Furthermore, BMP4 and EGF signaling cooperate to enhance pit cell differentiation, whereas inhibition of TGF-β and BMP4 signaling promotes chief cell differentiation. We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation. In addition, BMP4, together with the small molecule Isoxazole 9, promotes parietal and enteroendocrine cell differentiation. Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human. Together, our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human, laying a foundation for future investigation and potential clinical use of gastric organoids.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"18"},"PeriodicalIF":4.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell RegenerationPub Date : 2025-05-14DOI: 10.1186/s13619-025-00231-3
Huijie Hu, Dongyue Wang, Yanlu Chen, Liang Gao
{"title":"Morphological segmentation with tiling light sheet microscopy to quantitatively analyze the three-dimensional structures of spinal motoneurons.","authors":"Huijie Hu, Dongyue Wang, Yanlu Chen, Liang Gao","doi":"10.1186/s13619-025-00231-3","DOIUrl":"10.1186/s13619-025-00231-3","url":null,"abstract":"<p><p>Spinal motoneurons control muscle fibers contraction and drive all motor behaviors in vertebrates. Although spinal motoneurons share the fundamental role of innervating muscle fibers, they exhibit remarkable diversity that reflects their specific identities. Defining the morphological changes during postnatal development is critical for elucidating this diversity. However, our understanding of the three-dimensional (3D) morphology of spinal motoneurons at these stages remains limited, largely due to the lack of high-throughput imaging tools. Using tiling light sheet microscopy combined with tissue clearing methods, we imaged motoneurons of the lateral and median motor column in the cervical and lumbar cord during postnatal development. By analyzing their soma size, we found that motoneurons innervating the upper limbs differentiate into two subpopulations with distinct soma size by postnatal day 14 (P14), while differentiation of motoneurons innervating the lower limbs is delayed. Furthermore, coupling adenovirus labeling with 3D volumetric reconstruction, we traced and measured the number and lengths of dendrites of flexor and extensor motoneurons in the lumbar cord, finding that the number of dendrites initially increases and subsequently declines as dendritic order rises. Together, these findings provide a quantitative analysis of the 3D morphological changes underlying spinal motoneuron diversity.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"17"},"PeriodicalIF":4.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dasatinib demonstrates efficacy in organoid derived paclitaxel-resistant Trp53/Cdh1-deficient mouse gastric adenocarcinoma with peritoneal metastasis.","authors":"Wenshuai Liu, Lingmeng Li, Leilei Guo, Haojie Li, Zhaoqing Tang, Xuefei Wang, Liyu Huang, Yihong Sun","doi":"10.1186/s13619-025-00232-2","DOIUrl":"https://doi.org/10.1186/s13619-025-00232-2","url":null,"abstract":"<p><p>Gastric cancer peritoneal metastasis (GCPM) typically indicates a poor clinical prognosis and is frequently observed in diffuse gastric cancer (GC) patients with CDH1 loss of function. GCPM characterized for its aggressiveness and resistance to chemotherapy, most notably paclitaxel (PTX), poses significant treatment challenges. Previously, no mouse gastric adenocarcinoma (MGA) cell lines with Trp53 (encoding mouse p53) and Cdh1 (encoding mouse E-cadherin) mutations and a high potential for peritoneal metastasis in mice have been established. Here, we derived a mouse GC cell line, called MTC, from subcutaneously transplanted mouse Trp53<sup>-/-</sup>Cdh1<sup>-/-</sup> GC organoids. Through matching the short tandem repeat profile of MTC with those in current cell banks, we verified the uniqueness of MTC. Furtherly, we confirmed the features of MTC by detecting the expression of p53, E-cadherin, and pan-CK. After long-term exposure of the original MTC line to PTX, we developed a more aggressive, PTX-resistant cell line, termed MTC-R. Compared with MTC, MTC-R demonstrated enhanced tumorigenicity and high potential for peritoneal metastasis in subcutaneous and intraperitoneal tumour models both in BALB/c nude mice and C57BL/6 J mice. Transcriptome analysis revealed the ECM‒receptor interaction pathway activation during the development of PTX resistance, and dasatinib (DASA) was identified as a potential drug targeting this pathway. DASA showed promise in ameliorating disease progression and improving overall survival in MTC-R GCPM model in C57BL/6 J mice. Overall, we established a novel MGA cell line with Trp53 and Cdh1 mutations and its PTX-resistant variant and demonstrated the efficacy of DASA in treating PTX-resistant GCPM.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"16"},"PeriodicalIF":4.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell RegenerationPub Date : 2025-04-22DOI: 10.1186/s13619-025-00234-0
Xinyu Thomas Tang, Lin Veronica Chen, Bo O Zhou
{"title":"Resolving the spatial organization of fetal liver hematopoiesis by SeekSpace.","authors":"Xinyu Thomas Tang, Lin Veronica Chen, Bo O Zhou","doi":"10.1186/s13619-025-00234-0","DOIUrl":"https://doi.org/10.1186/s13619-025-00234-0","url":null,"abstract":"<p><p>The fetal liver is the primary site for the expansion of hematopoietic stem and progenitor cells (HSPCs) during fetal hematopoiesis. However, the spatial organization of different hematopoietic progenitor populations within the fetal liver remains poorly characterized. In this study, we utilized SeekSpace, a high-resolution single-nucleus spatial transcriptomics platform, to map the spatial distribution of hematopoietic stem cells and multipotent progenitor cells (HSC/MPPs) and downstream restricted progenitors (RPs) in relation to other hematopoietic and stromal cell populations in the fetal liver at embryonic day 13.5. Using SeekSpace, we constructed a detailed single-cell spatial transcriptomic atlas of fetal liver hematopoiesis, revealing that both HSC/MPPs and many RPs undergo active expansion in the fetal liver, a process distinct from their behavior in adult bone marrow. Proximity analysis and in situ imaging demonstrated that HSC/MPPs expansion occurs in close association with macrophages and endothelial cells throughout the fetal liver, supported by signaling pathways involving IGF and collagen. In contrast, RPs exhibited no specific spatial proximity to other cell populations during their expansion. Collectively, this study provides a comprehensive resource for understanding the spatial and molecular mechanisms underlying HSC/MPPs and RP expansion during fetal liver hematopoiesis.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"15"},"PeriodicalIF":4.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell RegenerationPub Date : 2025-04-10DOI: 10.1186/s13619-025-00224-2
Ke Zhao, Indigo T C Chan, Erin H Y Tse, Zhiyao Xie, Tom H Cheung, Yi Arial Zeng
{"title":"Autophagy in adult stem cell homeostasis, aging, and disease therapy.","authors":"Ke Zhao, Indigo T C Chan, Erin H Y Tse, Zhiyao Xie, Tom H Cheung, Yi Arial Zeng","doi":"10.1186/s13619-025-00224-2","DOIUrl":"https://doi.org/10.1186/s13619-025-00224-2","url":null,"abstract":"<p><p>Autophagy is a crucial cellular process that facilitates the degradation of damaged organelles and protein aggregates, and the recycling of cellular components for the energy production and macromolecule synthesis. It plays an indispensable role in maintaining cellular homeostasis. Over recent decades, research has increasingly focused on the role of autophagy in regulating adult stem cells (SCs). Studies suggest that autophagy modulates various cellular processes and states of adult SCs, including quiescence, proliferation, self-renewal, and differentiation. The primary role of autophagy in these contexts is to sustain homeostasis, withstand stressors, and supply energy. Notably, the dysfunction of adult SCs during aging is correlated with a decline in autophagic activity, suggesting that autophagy is also involved in SC- and aging-associated disorders. Given the diverse cellular processes mediated by autophagy and the intricate mechanisms governing adult SCs, further research is essential to elucidate both universal and cell type-specific regulatory pathways of autophagy. This review discusses the role of autophagy in regulating adult SCs during quiescence, proliferation, self-renewal, and differentiation. Additionally, it summarizes the relationship between SC aging and autophagy, providing therapeutical insights into treating and ameliorating aging-associated diseases and cancers, and ultimately promoting longevity.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"14"},"PeriodicalIF":4.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Preserving blood-retinal barrier integrity: a path to retinal ganglion cell protection in glaucoma and traumatic optic neuropathy.","authors":"Lai-Yang Zhou, Zhen-Gang Liu, Yong-Quan Sun, Yan-Zhong Li, Zhao-Qian Teng, Chang-Mei Liu","doi":"10.1186/s13619-025-00228-y","DOIUrl":"10.1186/s13619-025-00228-y","url":null,"abstract":"<p><p>Retinal ganglion cells (RGCs) are the visual gateway of the brain, with their axons converging to form the optic nerve, making them the most vulnerable target in diseases such as glaucoma and traumatic optic neuropathy (TON). In both diseases, the disruption of the blood-retinal barrier(BRB) is considered an important mechanism that accelerates RGC degeneration and hinders axon regeneration. The BRB consists of the inner blood-retinal barrier (iBRB) and the outer blood-retinal barrier (oBRB), which are maintained by endothelial cells(ECs), pericytes(PCs), and retinal pigment epithelial (RPE), respectively. Their functions include regulating nutrient exchange, oxidative stress, and the immune microenvironment. However, in glaucoma and TON, the structural and functional integrity of the BRB is severely damaged due to mechanical stress, inflammatory reactions, and metabolic disorders. Emerging evidence highlights that BRB disruption leads to heightened vascular permeability, immune cell infiltration, and sustained chronic inflammation, creating a hostile microenvironment for RGC survival. Furthermore, the dynamic interplay and imbalance among ECs, PCs, and glial cells within the neurovascular unit (NVU) are pivotal drivers of BRB destruction, exacerbating RGC apoptosis and limiting optic nerve regeneration. The intricate molecular and cellular mechanisms underlying these processes underscore the BRB's critical role in glaucoma and TON pathophysiology while offering a compelling foundation for therapeutic strategies targeting BRB repair and stabilization. This review provides crucial insights and lays a robust groundwork for advancing research on neural regeneration and innovative optic nerve protective strategies.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"13"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell RegenerationPub Date : 2025-03-27DOI: 10.1186/s13619-025-00229-x
Fei Zhu, Guangjun Nie
{"title":"Cell reprogramming: methods, mechanisms and applications.","authors":"Fei Zhu, Guangjun Nie","doi":"10.1186/s13619-025-00229-x","DOIUrl":"10.1186/s13619-025-00229-x","url":null,"abstract":"<p><p>Cell reprogramming represents a powerful approach to achieve the conversion cells of one type into cells of another type of interest, which has substantially changed the landscape in the field of developmental biology, regenerative medicine, disease modeling, drug discovery and cancer immunotherapy. Cell reprogramming is a complex and ordered process that involves the coordination of transcriptional, epigenetic, translational and metabolic changes. Over the past two decades, a range of questions regarding the facilitators/barriers, the trajectories, and the mechanisms of cell reprogramming have been extensively investigated. This review summarizes the recent advances in cell reprogramming mediated by transcription factors or chemical molecules, followed by elaborating on the important roles of biophysical cues in cell reprogramming. Additionally, this review will detail our current understanding of the mechanisms that govern cell reprogramming, including the involvement of the recently discovered biomolecular condensates. Finally, the review discusses the broad applications and future directions of cell reprogramming in developmental biology, disease modeling, drug development, regenerative/rejuvenation therapy, and cancer immunotherapy.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"12"},"PeriodicalIF":4.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell RegenerationPub Date : 2025-03-26DOI: 10.1186/s13619-025-00230-4
Jie Yang, Donghui Zhang, Wei Jiang
{"title":"Long noncoding RNA as an emerging regulator of endoderm differentiation: progress and perspectives.","authors":"Jie Yang, Donghui Zhang, Wei Jiang","doi":"10.1186/s13619-025-00230-4","DOIUrl":"10.1186/s13619-025-00230-4","url":null,"abstract":"<p><p>Accumulated studies have demonstrated that long noncoding RNAs (lncRNAs) play crucial regulatory roles in diverse biological processes, such as embryonic development and cell differentiation. Comprehensive transcriptome analysis identifies extensive lncRNAs, gradually elucidating their functions across various contexts. Recent studies have highlighted the essential role of lncRNAs in definitive endoderm differentiation, underscoring their importance in early development. In this review, we have analyzed the features of overlapping, proximal, and desert lncRNAs, classified by genomic location, in pluripotent stem cells (PSCs) and the differentiation derivatives. Furthermore, we focus on the endoderm lineage and review the latest advancements in lncRNA identification and their distinct regulatory mechanisms. By consolidating current knowledge, we aim to provide a clearer perspective on how lncRNAs contribute to endoderm differentiation in different manners.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"11"},"PeriodicalIF":4.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Standard: human liver-on-a-chip.","authors":"Haitao Liu, Xu Zhang, Yaqing Wang, Min Zhang, Peng Wang, Jing Shang, Zhongqiang Li, Likun Gong, Xin Xie, Dongyang Liu, Jingbo Pi, Xinghua Gao, Xianliang Li, Wei Ding, Dianbing Wang, Yun Long, Lan Wang, Song Li, Xingchao Geng, Pingkun Zhou, Wanjin Tang, Xian'en Zhang, Chunying Chen, Shengli Yang, Jianhua Qin","doi":"10.1186/s13619-025-00226-0","DOIUrl":"10.1186/s13619-025-00226-0","url":null,"abstract":"<p><p>Organs-on-chips are microphysiological systems designed to replicate key functions of human organs, thereby accelerating innovation in life sciences, such as disease modeling, drug development, and precision medicine. However, the lack of standardized definitions, structural designs, cell sources, model constructions, and functional validations has posed challenges to their widespread translational applications. On April 29, 2024, the Chinese Society of Biotechnology introduced \"Organs-on-chips: Liver\", China's first group standard for human liver-on-a-chip technology. This pioneering standard provides comprehensive guidelines, including scope, terminology, definitions, technical requirements, detection methods, and quality control measures for developing liver models on chips. The introduction of this standard is set to facilitate the establishment of institutional protocols, promote widespread adoption, and drive the international standardization of liver-on-a-chip technologies.</p>","PeriodicalId":9811,"journal":{"name":"Cell Regeneration","volume":"14 1","pages":"9"},"PeriodicalIF":4.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}