STEM CELLS最新文献

{"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11979747/pdf/","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":"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":"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":"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}

{"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":"The miR-290 and miR-302 clusters are essential for reprogramming of fibroblasts to induced pluripotent stem cells.","authors":"Julia Ye, Ryan M Boileau, Ronald J Parchem, Robert L Judson-Torres, Robert Blelloch","doi":"10.1093/stmcls/sxae080","DOIUrl":"10.1093/stmcls/sxae080","url":null,"abstract":"<p><p>The miR-290 and miR-302 clusters of microRNAs are highly expressed in naïve and primed pluripotent stem cells, respectively. Ectopic expression of the embryonic stem cell (ESC)-specific cell cycle regulating family of microRNAs arising from these two clusters dramatically enhances the reprogramming of both mouse and human somatic cells to induced pluripotency. Here, we used genetic knockouts to dissect the requirement for the miR-290 and miR-302 clusters during the reprogramming of mouse fibroblasts into induced pluripotent stem cells (iPSCs) with retrovirally introduced Oct4, Sox2, and Klf4. Knockout of either cluster alone did not negatively impact the efficiency of reprogramming. Resulting cells appeared identical to their ESC microRNA cluster knockout counterparts. In contrast, the combined loss of both clusters blocked the formation of iPSCs. While rare double knockout clones could be isolated, they showed a dramatically reduced proliferation rate, a persistent inability to fully silence the exogenously introduced pluripotency factors, and a transcriptome distinct from individual miR-290 or miR-302 mutant ESC and iPSCs. Taken together, our data show that miR-290 and miR-302 are essential yet interchangeable in reprogramming to the induced pluripotent state.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"43 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555500","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":"Exosomes released from immature neurons regulate adult neural stem cell differentiation through microRNA-7a-5p.","authors":"Xiujian Sun, Yexiang Chen, Ying Zhang, Tiantian Cheng, Huisheng Peng, Yanting Sun, Jing-Gen Liu, Chi Xu","doi":"10.1093/stmcls/sxae082","DOIUrl":"10.1093/stmcls/sxae082","url":null,"abstract":"<p><p>Exosomes in the hippocampal dentate gyrus are essential for modulating the cell signaling and controlling the neural differentiation of hippocampal neural stem cells (NSCs), which may determine the level of hippocampal adult neurogenesis. In the present study, we found that exosomes secreted by immature neurons may promote the neuronal differentiation of mouse NSCs in vitro. By miRNA sequencing, we discovered that miR-7a-5p was significantly lower in exosomes from differentiated immature neurons than those from undifferentiated NSCs. By modulating the level of miR-7a-5p, the mimic and inhibitor of miR-7a-5p could either inhibit or promote the neuronal differentiation of NSCs, respectively. Moreover, we confirmed that miR-7a-5p affected neurogenesis by directly targeting Tcf12, a transcription factor responsible for the differentiation of NSCs. The siRNA of Tcf12 inhibited neuronal differentiation of NSCs, while overexpression of Tcf12 promoted NSC differentiation. Thus, we conclude that the miR-7a-5p content in neural exosomes is essential to the fate determination of adult hippocampal neurogenesis and that miR-7a-5p directly targets Tcf12 to regulate adult hippocampal neurogenesis.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816793","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":"The chondrogenic potential of the bovine tendon sheath-a novel source of stem cells for cartilage repair.","authors":"Ernst B Hunziker, Naomi Nishii, Nahoko Shintani, Kurt Lippuner, Marius J B Keel, Esther Voegelin","doi":"10.1093/stmcls/sxae071","DOIUrl":"10.1093/stmcls/sxae071","url":null,"abstract":"<p><p>The human hand is traumatized more frequently than any other bodily part. Trauma and pathological processes (eg, rheumatoid arthritis, osteoarthritis) commonly implicate the finger joints and specifically damage also the layer of articular cartilage. Endeavors are now being made to surgically repair such cartilage lesions biologically using tissue-engineering approaches that draw on donor cells and/or donor tissues. The tendon sheaths, particularly their inner layers, that is, the peritendineum, surround the numerous tendons in the hand. The peritendineum is composed of mesenchymal tissue. We hypothesize that this tissue harbors pluripotent mesenchymal stem cells and thus could be used for cartilage repair, irrespective of the donor's age. Using a bovine model (young calves vs adult cows), the pluripotentiality of the peritendineal stem cells, namely, their osteogenicity, chondrogenicity, and adipogenicity, was investigated by implementing conventional techniques. Subsequently, the chondrogenic potential of the peritendineal tissue itself was analyzed. Its differentiation into cartilage was induced by the application of specific growth factors (members of the TGF-β-superfamily). The characteristics of the tissue formed were evaluated structurally (immuno) histochemically, histomorphometrically, and biochemically (gene expression and protein level). Our data confirm that the bovine peritendineum contains stem cells whose pluripotentiality is independent of donor age. This tissue could also be induced to differentiate into cartilage, likewise, irrespective of the donor's age. Preliminary investigations with adult human peritendineal biopsy material derived from the hand's peritendineal flexor tendon sheaths revealed that this tissue can also be induced to differentiate into cartilage.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826585","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":"Notch inhibition enhances morphological reprogramming of microRNA-induced human neurons.","authors":"Kyle F Burbach, Shanyun Wu, Andrew S Yoo","doi":"10.1093/stmcls/sxae079","DOIUrl":"10.1093/stmcls/sxae079","url":null,"abstract":"<p><p>The role of Notch signaling in direct neuronal reprogramming remains unknown despite its importance to brain development in vivo. Here, we use microRNA-induced neurons that are directly reprogrammed from human fibroblasts to determine how Notch signaling contributes to neuronal identity. We found that Notch inhibition during the first week of reprogramming was both necessary and sufficient to enhance neurite outgrowth at a later timepoint, indicating an important role in the erasure of the original cell identity. Accordingly, transcriptomic analysis showed that the effect of Notch inhibition was likely due to improvements in fibroblast fate erasure and silencing of non-neuronal genes. To this effect, we identify MYLIP, whose downregulation in response to Notch inhibition significantly promoted neurite outgrowth. Moreover, Notch inhibition resulted in cells with neuronal transcriptome signatures defined by expressing long genes at a faster rate than the control, demonstrating the effect of accelerated fate erasure on neuronal fate acquisition. Our results demonstrate the antagonistic role of Notch signaling to the pro-neuronal microRNAs 9 and 124 and the benefits of its inhibition to the acquisition of neuronal morphology.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685645","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":"Therapeutic potential of stem cell-derived extracellular vesicles in neurodegenerative diseases associated with cognitive decline.","authors":"Matteo Spinelli, Salvatore Fusco, Claudio Grassi","doi":"10.1093/stmcls/sxae074","DOIUrl":"10.1093/stmcls/sxae074","url":null,"abstract":"<p><p>In the central nervous system, cell-to-cell interaction is essential for brain plassticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration vs SC transplantation in the treatment of neurodegenerative disorders.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613252","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}