STEM CELLS最新文献

{"title":"Patterning effects of FGF17 and cAMP on generation of dopaminergic progenitors for cell replacement therapy in Parkinson's disease.","authors":"Amalie Holm Nygaard, Alrik L Schörling, Zehra Abay-Nørgaard, Erno Hänninen, Yuan Li, Adrian Ramón Santonja, Gaurav Singh Rathore, Alison Salvador, Charlotte Rusimbi, Katrine Bech Lauritzen, Yu Zhang, Agnete Kirkeby","doi":"10.1093/stmcls/sxaf004","DOIUrl":"10.1093/stmcls/sxaf004","url":null,"abstract":"<p><p>Cell replacement therapies using human pluripotent stem cell-derived ventral midbrain (VM) dopaminergic (DA) progenitors are currently in clinical trials for treatment of Parkinson's disease (PD). Recapitulating developmental patterning cues, such as fibroblast growth factor 8 (FGF8), secreted at the midbrain-hindbrain boundary (MHB), is critical for the in vitro production of authentic VM DA progenitors. Here, we explored the application of alternative MHB-secreted FGF-family members, FGF17 and FGF18, for VM DA progenitor patterning. We show that while FGF17 and FGF18 both recapitulated VM DA progenitor patterning events, FGF17 induced expression of key VM DA progenitor markers at higher levels than FGF8 and transplanted FGF17-patterned progenitors fully reversed motor deficits in a rat PD model. Early activation of the cAMP pathway mimicked FGF17-induced patterning, although strong cAMP activation came at the expense of EN1 expression. In summary, we identified FGF17 as a promising alternative FGF candidate for robust VM DA progenitor patterning.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient and rapid generation of neural stem cells by direct conversion of fibroblasts with single microRNAs.","authors":"Yuanyuan Li, Jing Sun, Tingting Xu, Bo Dai, Yuesi Wang","doi":"10.1093/stmcls/sxaf003","DOIUrl":"10.1093/stmcls/sxaf003","url":null,"abstract":"<p><p>Neural stem cells (NSCs) hold great potential in neurodegenerative disease therapy, drug screening, and disease modeling. However, current approaches for induced NSCs (iNSCs) generation from somatic cells are still slow and inefficient. Here we report the establishment of a rapid and efficient method of iNSCs generation from human and mouse fibroblasts by using single microRNAs (miR-302a). These iNSCs exhibited morphological, molecular and functional properties resembling those of adult human and mouse NSCs, respectively. Additionally, human iNSCs can be expanded for more than 20 passages in vitro. Furthermore, miR-302a alone was demonstrated to be sufficient to reprogram both human and mouse fibroblasts into iNSCs. Our results showed a method of direct conversion of autologous fibroblasts with miR-302a into iNSCs, providing a rapid and efficient strategy to generate iNSCs for both basic research and clinical applications.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of vascularized human retinal organoids from induced pluripotent stem cells.","authors":"Satoshi Inagaki, Shinsuke Nakamura, Yoshiki Kuse, Kota Aoshima, Michinori Funato, Masamitsu Shimazawa, Hideaki Hara","doi":"10.1093/stmcls/sxae093","DOIUrl":"10.1093/stmcls/sxae093","url":null,"abstract":"<p><p>Pluripotent stem cell-derived retinal organoids (ROs) have been investigated for applications in regenerative medicine, retinal disease models, and compound safety evaluation. Although the development of 3D organoids has provided novel opportunities for innovation, some unresolved limitations continue to exist in organoid research; the passive diffusion of oxygen and nutrients limits the growth and functional gain of organoids. Vascularization may circumvent these problems because it allows oxygen and nutrients to enter the organoid core. In the present study, we generate the vascularized retinal organoids (vROs) from healthy human induced pluripotent stem cells. vROs are created from ROs by co-culturing them with vascular organoid (VO)-derived vascular endothelial cells/pericytes. The expression of mature neuronal markers is markedly higher in the vROs than in the ROs. When vROs are cultured under diabetic conditions, their size and the number of retinal ganglion cells are significantly decreased. In conclusion, the co-culture of ROs with VO-derived cells enables the production of ROs with vascular-like structures, and the vROs respond to severe diabetic retinopathy conditions. In summary, our findings underscore the potential of vROs as invaluable tools for elucidating disease mechanisms and screening therapeutic interventions for retinal vascular disorders, thereby paving the way for personalized medicine approaches in ophthalmology.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enrichment of spermatogonial stem cells and staging of the testis cycle in a dasyurid marsupial, the fat-tailed dunnart.","authors":"Gerard A Tarulli, Patrick R S Tatt, Rhys Howlett, Sara Ord, Stephen R Frankenberg, Andrew J Pask","doi":"10.1093/stmcls/sxaf007","DOIUrl":"10.1093/stmcls/sxaf007","url":null,"abstract":"<p><p>There is increasing interest in the use of marsupial models in research, for use in next-generation conservation by improving fitness through genetic modification, and in de-extinction efforts. Specifically, this includes dasyurid marsupials such as the Thylacine, Tasmanian devil, quolls, and the small rodent-like dunnarts. Technologies for generating genetically modified Australian marsupials remain to be established. Given the need to advance research in this space, the fat-tailed dunnart (Sminthopsis crassicaudata) is being established as a model for marsupial spermatogonial stem cell isolation, modification, and testicular transplantation. This species is small (60-90 mm body size), polyovulatory (8-12 pups per birth), and can breed in standard rodent facilities when housed in a 12:12 light cycle. To develop the fat-tailed dunnart as a model for next-generation marsupial conservation, this study aimed to enrich dunnart spermatogonial stem cells from whole testis digestions using a fluorescent dye technology and fluorescence-activated cell sorting. This approach is not dependent on antibodies or genetic reporter animals that are limiting factors when performing cell sorting on species separated from humans and mice by large evolutionary timescales. This study also assessed the development of spermatogonia and spermatogenesis in the fat-tailed dunnart, by making the first definition of the cycle of the seminiferous epithelium in any dasyurid. Overall, this is the first detailed study to assess the cycle of dasyurid spermatogenesis and provides a valuable method to enrich marsupial spermatogonial stem cells for cellular, functional, and molecular analysis.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing the diversity and potential of endogenous skeletal stem cells for musculoskeletal tissue regeneration.","authors":"Kelly C Weldon, Michael T Longaker, Thomas H Ambrosi","doi":"10.1093/stmcls/sxaf006","DOIUrl":"10.1093/stmcls/sxaf006","url":null,"abstract":"<p><p>In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)-a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties-in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular microvesicles/exosomes-magic bullets in horizontal transfer between cells of mitochondria and molecules regulating mitochondria activity.","authors":"Mariusz Z Ratajczak, Kannathasan Thetchinamoorthy, Diana Wierzbicka, Adrian Konopko, Janina Ratajczak, Magdalena Kucia","doi":"10.1093/stmcls/sxae086","DOIUrl":"10.1093/stmcls/sxae086","url":null,"abstract":"<p><p>Extracellular microvesicles (ExMVs) were one of the first communication platforms between cells that emerged early in evolution. Evidence indicates that all types of cells secrete these small circular structures surrounded by a lipid membrane that plays an important role in cellular physiology and some pathological processes. ExMVs interact with target cells and may stimulate them by ligands expressed on their surface and/or transfer to the target cells their cargo comprising various RNA species, proteins, bioactive lipids, and signaling nucleotides. These small vesicles can also hijack some organelles from the cells and, in particular, transfer mitochondria, which are currently the focus of scientific interest for their potential application in clinical settings. Different mechanisms exist for transferring mitochondria between cells, including their encapsulation in ExMVs or their uptake in a \"naked\" form. It has also been demonstrated that mitochondria transfer may involve direct cell-cell connections by signaling nanotubules. In addition, evidence accumulated that ExMVs could be enriched for regulatory molecules, including some miRNA species and proteins that regulate the function of mitochondria in the target cells. Recently, a new beneficial effect of mitochondrial transfer has been reported based on inducing the mitophagy process, removing damaged mitochondria in the recipient cells to improve their energetic state. Based on this novel role of ExMVs in powering the energetic state of target cells, we present a current point of view on this topic and review some selected most recent discoveries and recently published most relevant papers.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in iPSC-astrocyte morphology reflect Alzheimer's disease patient clinical markers.","authors":"Helen A Rowland, Georgina Miller, Qiang Liu, Shuhan Li, Nicola R Sharp, Bryan Ng, Tina Wei, Kanisa Arunasalam, Ivan Koychev, Anne Hedegaard, Elena M Ribe, Dennis Chan, Tharani Chessell, Ece Kocagoncu, Jennifer Lawson, Paresh Malhotra, Basil H Ridha, James B Rowe, Alan J Thomas, Giovanna Zamboni, Henrik Zetterberg, M Zameel Cader, Richard Wade-Martins, Simon Lovestone, Alejo Nevado-Holgado, Andrey Kormilitzin, Noel J Buckley","doi":"10.1093/stmcls/sxae085","DOIUrl":"10.1093/stmcls/sxae085","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer's disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous Aβ oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic ablation of p16 mitigates premature osteoporosis induced by PTHrP nuclear localization sequence and C-terminal deletion through inhibition of cellular senescence.","authors":"Yongli Han, Wanxin Qiao, Qi Xue, Dengshun Miao, Zhan Dong","doi":"10.1093/stmcls/sxae088","DOIUrl":"10.1093/stmcls/sxae088","url":null,"abstract":"<p><strong>Background: </strong>Premature osteoporosis caused by parathyroid hormone-related peptide (PTHrP) dysfunction presents significant bone health challenges. The role of p16-mediated cellular senescence in this condition remains unclear.</p><p><strong>Methods: </strong>Using a Pthrp knock-in (KI) mouse model lacking the nuclear localization sequence and C-terminus of PTHrP, we generated p16⁻⁄⁻KI mice and compared them with wild-type, p16⁻⁄⁻, and KI mice. We analyzed survival, skeletal phenotypes, bone marrow mesenchymal stem cell (BM-MSC) function, and molecular markers of senescence.</p><p><strong>Results: </strong>Genetic ablation of p16 in KI mice extended their lifespan, increased body size and weight, and improved skeletal growth. Micro-CT analysis revealed significantly increased bone volume, while histological studies showed enhanced chondrocyte proliferation and osteoblast function in p16⁻⁄⁻KI mice compared to KI mice. In vitro experiments demonstrated enhanced differentiation capacity and reduced senescence of BM-MSCs from p16⁻⁄⁻KI mice, as evidenced by increased colony formation and osteogenic marker expression. Molecular analyses indicated that p16 knockout partially reversed oxidative stress, DNA damage, and cellular senescence observed in KI mice, shown by upregulated antioxidant enzymes, reduced DNA damage markers, and decreased senescence markers.</p><p><strong>Conclusions: </strong>p16-mediated cellular senescence plays a crucial role in premature osteoporosis caused by PTHrP dysfunction. Targeting cellular senescence pathways may offer a promising therapeutic strategy for treating premature osteoporosis and age-related bone loss.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes secreted from amniotic mesenchymal stem cells modify trophoblast activities by delivering miR-18a-5p and regulating HRK-p53 interaction.","authors":"Wendi Zhao, Wenting Li, Jianxin Zuo, Huansheng Zhou, Guoqiang Gao, Yuanhua Ye, Yijing Chu","doi":"10.1093/stmcls/sxae087","DOIUrl":"10.1093/stmcls/sxae087","url":null,"abstract":"<p><strong>Background: </strong>Amniotic mesenchymal stem cells (AMSCs) have been demonstrated as effective in tissue repair and regeneration. Trophoblast dysfunction is associated with several types of pregnancy complications. The aim of this study is to investigate the effects of AMSCs on the biological activities of human trophoblasts, as well as their molecular mechanisms.</p><p><strong>Methods: </strong>Exosomes were isolated from AMSC supernatants, and characterized and quantified by transmission electron microscopy, nanoparticle tracking analysis and Western blotting assay. Immunofluorescence assay was performed to detect the uptake of AMSCs-derived exomes (AMSC-Exos) by human trophoblasts. Human trophoblasts were subjected to transcriptome analysis after being cocultured with AMSC-Exos. Lentiviral transfection was performed to construct the human trophoblast cell lines with stable HRK knockdown or overexpression. Immunohistochemistry was used to detect the HRK expression in preeclampsia (PE) patients. CCK8 and Transwell assays were, respectively, used to detect the trophoblast proliferation and migration. TUNEL flow cytometry assay was used to detect the apoptosis in trophoblasts. Quantitative real-time (qRT) PCR and Western blotting assays were used to detect the mRNA and protein levels of the genes. Dual luciferase reporter assays were used to detect the changes in gene-transcript levels.</p><p><strong>Results: </strong>AMSC-Exos could be absorbed by human trophoblasts. Transcriptome analysis showed that HRK was significantly reduced in human trophoblasts cocultured with AMSC-Exos. HRK inhibited cell proliferation and migration in human trophoblasts and promoted their apoptosis via p53 upregulation. miR-18a-5p, present at high levels in AMSC-Exos, improved trophoblast proliferation and migration, and inhibited their apoptosis by inhibiting the HRK expression.</p><p><strong>Conclusion: </strong>miR-18a-5p present in AMSC-Exos could be absorbed by trophoblasts, in turn, improved their proliferation and migration, and inhibited their apoptosis by HRK downregulation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A serum- and feeder-free system to generate CD4 and regulatory T cells from human iPSCs.","authors":"Helen Fong, Matthew Mendel, John Jascur, Laeya Najmi, Ken Kim, Garrett Lew, Swetha Garimalla, Suruchi Schock, Jing Hu, Andres Gordillo Villegas, Anthony Conway, Jason D Fontenot, Simona Zompi","doi":"10.1093/stmcls/sxaf001","DOIUrl":"10.1093/stmcls/sxaf001","url":null,"abstract":"<p><p>iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGFβ and ATRA. Using genetic engineering, we demonstrated high, non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs ± HLA-A2-targeted CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T-cell proliferation in vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}