Stem Cell Research & Therapy最新文献

{"title":"Umbilical cord-derived mesenchymal stem cells preferentially modulate macrophages to alleviate pulmonary fibrosis.","authors":"Meng Li, Jun Li, Ying Wang, Guancheng Jiang, Hanguo Jiang, Mengdi Li, Ziying Zhu, Fangli Ren, Yinyin Wang, Muyang Yan, Zhijie Chang","doi":"10.1186/s13287-024-04091-7","DOIUrl":"10.1186/s13287-024-04091-7","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic Pulmonary Fibrosis (IPF) is a type of interstitial lung disease characterized by chronic inflammation due to persistent lung damage. Mesenchymal stem cells (MSCs), including those derived from the umbilical cord (UCMSCs) and placenta (PLMSCs), have been utilized in clinical trials for IPF treatment. However, the varying therapeutic effectiveness between these two MSC types remains unclear.</p><p><strong>Methods: </strong>In this study, we examined the therapeutic differences between UCMSCs and PLMSCs in treating lung damage using a bleomycin (BLM)-induced pulmonary injury mouse model.</p><p><strong>Results: </strong>We showed that UCMSCs had a superior therapeutic impact on lung damage compared to PLMSCs. Upon cytokine stimulation, UCMSCs expressed higher levels of inflammation-related genes and more effectively directed macrophage polarization towards the M2 phenotype than PLMSCs, both in vitro and in vivo. Furthermore, UCMSCs showed a preference for expressing CC motif ligation 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1) compared to PLMSCs. The expression of secreted phosphoprotein 1 (SPP1), triggering receptor expressed on myeloid cells 2 (Trem2), and CCAAT enhancer binding protein beta (Cebpb) in macrophages from mice with the disease treated with UCMSCs was significantly reduced compared to those treated with PLMSCs.</p><p><strong>Conclusions: </strong>Therefore, UCMSCs demonstrated superior anti-fibrotic abilities in treating lung damage, potentially through inducing a more robust M2 polarization of macrophages than PLMSCs.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"475"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855215","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":"Hypoxic mesenchymal stem cell-derived exosomal circDennd2a regulates granulosa cell glycolysis by interacting with LDHA.","authors":"Wenxin Li, Minjun Lu, Junyu Shang, Jiamin Zhou, Li Lin, Yueqin Liu, Dan Zhao, Xiaolan Zhu","doi":"10.1186/s13287-024-04098-0","DOIUrl":"10.1186/s13287-024-04098-0","url":null,"abstract":"<p><strong>Background: </strong>Premature ovarian insufficiency (POI) is an ovarian dysfunction disorder that significantly impacts female fertility. Ovarian granulosa cells (GCs) are crucial somatic components supporting oocyte development that rely on glycolysis for energy production, which is essential for follicular growth. Hypoxia-induced exosomal circRNAs regulate glycolysis, but their biological functions and molecular mechanisms in POI are largely unexplored. The present comprehensive investigation revealed a substantial reduction in ovarian glycolysis levels in POI rats. Notably, hypoxia-induced exosomes originating from mesenchymal stem cells (HM-Exs) exhibit a remarkable capacity to enhance ovarian glycolysis, mitigate GCs apoptosis, reinstate disrupted estrous cycles, modulate sex hormone levels, and curtail the presence of atretic follicles. These restorative actions collectively contribute to fostering fertility revival in POI-afflicted rats.</p><p><strong>Methods: </strong>Cyclophosphamide was administered for 2 weeks to induce POI rat model, and POI rats were randomly divided into three groups and treated with PBS, NM-Exs and HM-Exs, respectively. Ovarian function and fertility were assessed at the end of the study and ovarian tissues were collected for analysis of energy metabolites. The relationship between circDennd2a and POI was explored in vitro by qRT-PCR, Western blotting, CCK-8 assay, EdU staining, TUNEL staining, extracellular acidification rate (ECAR) measurements, and ATP, lactate and pyruvate level assays.</p><p><strong>Results: </strong>Our findings revealed depletion of circDennd2a in serum samples and GCs from individuals suffering from POI. The introduction of HM-Exs-derived circDennd2a (HM-Exs-circDennd2a) effectively counteracted GCs apoptosis by enhancing glycolytic processes and driving cellular proliferation. CircDennd2a interacted with lactate dehydrogenase A (LDHA), which served as a catalyst to increase LDHA enzymatic activity and facilitate the conversion of NADH to NAD+. This biochemical cascade worked synergistically to sustain glycolytic function within GCs.</p><p><strong>Conclusion: </strong>This study revealed that HM-Exs-circDennd2a promoted LDHA activity and enhanced GCs glycolytic capacity, both of which support its use as a potential clinical diagnostic and therapeutic target for POI.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"484"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855418","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":"Advances in genetically modified neural stem cell therapy for central nervous system injury and neurological diseases.","authors":"Xiangwen Tang, Peng Deng, Lin Li, Yuqing He, Jinchao Wang, Dingjun Hao, Hao Yang","doi":"10.1186/s13287-024-04089-1","DOIUrl":"10.1186/s13287-024-04089-1","url":null,"abstract":"<p><p>Neural stem cells (NSCs) have increasingly been recognized as the most promising candidates for cell-based therapies for the central nervous system (CNS) injuries, primarily due to their pluripotent differentiation capabilities, as well as their remarkable secretory and homing properties. In recent years, extensive research efforts have been initiated to explore the therapeutic potential of NSC transplantation for CNS injuries, yielding significant advancements. Nevertheless, owing to the formation of adverse microenvironment at post-injury leading to suboptimal survival, differentiation, and integration within the host neural network of transplanted NSCs, NSC-based transplantation therapies often fall short of achieving optimal therapeutic outcomes. To address this challenge, genetic modification has been developed an attractive strategy to improve the outcomes of NSC therapies. This is mainly attributed to its potential to not only enhance the differentiation capacity of NSCs but also to boost a range of biological activities, such as the secretion of bioactive factors, anti-inflammatory effects, anti-apoptotic properties, immunomodulation, antioxidative functions, and angiogenesis. Furthermore, genetic modification empowers NSCs to play a more robust neuroprotective role in the context of nerve injury. In this review, we will provide an overview of recent advances in the roles and mechanisms of NSCs genetically modified with various therapeutic genes in the treatment of neural injuries and neural disorders. Also, an update on current technical parameters suitable for NSC transplantation and functional recovery in clinical studies are summarized.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"482"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855357","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":"Transcriptomic and proteomic sequencing unveils the role of vitamin D and metabolic flux shifts in the induction of human hepatic organoids.","authors":"Shule Zhang, Linghong Liu, Xianyu Li, Tiancheng Zhou, Qing Shi, Dong Li, Xiuli Ju","doi":"10.1186/s13287-024-04101-8","DOIUrl":"10.1186/s13287-024-04101-8","url":null,"abstract":"<p><strong>Background: </strong>Hepatic organoids (HOs), validated through comparative sequencing with human liver tissues, are reliable models for liver research. Comprehensive transcriptomic and proteomic sequencing of HOs throughout their induction period will enhance the platform's utility, aiding in the elucidation of liver development's molecular mechanisms.</p><p><strong>Methods: </strong>We developed hepatic organoids (HOs) from embryonic stem cells (ESCs) through a de novo induction protocol, mimicking the stages of fetal liver development: ESCs to definitive endoderm (DE), then to foregut (FG), hepatoblasts (HB), and finally to HOs stage 1 (HO1), culminating in self-organizing HOs stage 2 (HO2) via dissociation and re-inoculation. The successful establishment of HOs was validated by immunofluorescence staining and RT-qPCR for specific markers. Comprehensive transcriptomic and proteomic sequencing and analysis were conducted on FG, HB, HO1, and HO2.</p><p><strong>Results: </strong>Our data suggest that several transcription factors (TFs) activated during the HB stage share overlapping target genes with the vitamin D receptor (VDR). Calcitriol, a direct activator of VDR, notably facilitated the FG to HB stage transition by activating VDR and enhancing key TFs, thereby promoting hepatic progenitor cell maturation. Furthermore, our findings revealed a significant transition towards glycolytic energy metabolism at the HO2 stage, characterized by increased glycolytic flux and reduced oxidative phosphorylation. Inhibition of glycolysis using 2-deoxy-D-glucose (2-DG) led to suppressed growth and differentiation at the HO2 stage. Analysis of signaling pathways indicated upregulation of the HIF-1 pathway, which is associated with glycolysis activation, as well as the MAPK and PI3K-AKT pathways, which regulate HIF-1α protein translation.</p><p><strong>Conclusions: </strong>We elucidated a pivotal role for calcitriol in facilitating the transition from FG to HB by activating VDR and augmenting the expression of critical transcription factors (TFs). Besides, our research underscores a shift in metabolic pathways toward glycolytic energy metabolism in HO2 organoids. Overall, our multiomics approach reveals the intricate molecular regulation during the development of HOs.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"478"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855279","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":"ZO-1 boosts the in vitro self-renewal of pre-haematopoietic stem cells from OCT4-reprogrammed human hair follicle mesenchymal stem cells through cytoskeleton remodeling.","authors":"Yingchun Ruan, Xingang Huang, Pengpeng Sun, Xiaozhen Yu, Xiaohua Tan, Yaolin Song, Hua Chen, Zhijing Liu","doi":"10.1186/s13287-024-04080-w","DOIUrl":"10.1186/s13287-024-04080-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The challenge of expanding haematopoietic stem/progenitor cells (HSPCs) in vitro has limited their clinical application. Human hair follicle mesenchymal stem cells (hHFMSCs) can be reprogrammed to generate intermediate stem cells by transducing OCT4 (hHFMSCs&lt;sup&gt;OCT4&lt;/sup&gt;) and pre-inducing with FLT3LG/SCF, and differentiated into erythrocytes. These intermediate cells exhibit gene expression patterns similar to pre-HSCs, making them promising for artificial haematopoiesis. However, further investigation is required to elucidate the in vitro proliferation ability and mechanism underlying the self-renewal of pre-HSCs derived from hHFMSCs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;hHFMSCs&lt;sup&gt;OCT4&lt;/sup&gt; were pre-treated with FLT3LG and SCF cytokines, followed by characterization and isolation of the floating cell subsets for erythroid differentiation through stimulation with hematopoietic cytokines and nutritional factors. Cell adhesion was assessed through disassociation and adhesion assays. OCT4 expression levels were measured using immunofluorescence staining, RT-qPCR, and Western blotting. RNA sequencing and Gene Ontology (GO) enrichment analysis were then conducted to identify proliferation-related biological processes. Proliferative capacity was evaluated through CCK-8, colony formation assays, Ki67 index, and cell cycle analysis. Cytoskeleton was observed through Wright‒Giemsa, Coomassie brilliant blue, and phalloidin staining. Expression of adherens junction (AJ) core members was confirmed through RT‒qPCR, Western blotting, and immunofluorescence staining before and after ZO-1 knockdown. A regulatory network was constructed to determine relationships among cytoskeleton, proliferation, and the AJ pathway. Student's t tests (GraphPad Prism 8.0.2) were used for group comparisons. The results were considered significant at P &lt; 0.05.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Pre-treatment of hHFMSCs&lt;sup&gt;OCT4&lt;/sup&gt; with FLT3LG and SCF leads to the emergence of floating cell subsets exhibiting small, globoid morphology, suspended above adherent cells, forming colonies, and displaying minimal expression of CD45. Excessive OCT4 expression weakens adhesion in floating hHFMSCs&lt;sup&gt;OCT4&lt;/sup&gt;. Floating cells moderately enhanced proliferation and undergo cytoskeleton remodelling, with increased contraction and aggregation of F-actin near the nucleus. The upregulation of ZO-1 could impact the expressions of F-actin, E-cadherin, and β-catenin genes, as well as the nuclear positioning of β-catenin, leading to variations in the cytoskeleton and cell cycle. Finally, a regulatory network revealed that the AJ pathway cored with ZO-1 critically bridges cytoskeletal remodelling and haematopoiesis-related proliferation in a β-catenin-dependent manner.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;ZO-1 improved the self-renewal of pre-HSCs from OCT4-overexpressing hHFMSCs by remodeling the cytoskeleton via the ZO-1-regulated AJ pathway, suggesting floating hHFMS","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"480"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855329","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":"Immunomodulatory features of MSC-derived exosomes decorated with DC-specific aptamer for improving sublingual immunotherapy in allergic mouse model.","authors":"Mahvash Sadeghi, Sajad Dehnavi, Ali Khodadadi, Ata A Ghadiri, Ali Ganji, Moosa Sharifat, Ali Asadirad","doi":"10.1186/s13287-024-04099-z","DOIUrl":"10.1186/s13287-024-04099-z","url":null,"abstract":"<p><strong>Introduction: </strong>Sublingual immunotherapy (SLIT) is an effective and injection-free route for allergen-specific immunotherapy (AIT). Mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo) has been identified as a novel delivery platform with immunomodulatory capacities. In addition, targeting agents such as aptamers (Apt) have been extensively used for specific delivery approaches such as direct delivery of allergen formulations to dendritic cells (DC) to improve the efficacy of specific immunotherapy. In this study, we assessed the effects of MSC-derived Exos containing ovalbumin (Ova) which decorated with DC-specific aptamer in allergic rhinitis mice model.</p><p><strong>Materials and methods: </strong>Exos were harvested from adipose tissue-derived MSCs, and Exo-Apt-Ova complex was formulated. Then, Ova-induced allergic asthma model was simulated and sensitized BALB/c mice were treated sublingually with Exo-Apt-Ova complex (5 µg Ova) twice weekly for 8 weeks. Ova-specific IgE levels in serum and concentrations of interferon-gamma (IFN-γ), interleukin (IL)-4, and transforming growth factor-beta (TGF-β) in the supernatant of cultured splenocytes were evaluated using enzyme-linked immunosorbent assay (ELISA). In addition, lung histologic analysis and nasopharyngeal lavage fluid (NALF) cell count were performed.</p><p><strong>Results: </strong>Administration of Ova-incorporated Apt-modified Exos dramatically increased IFN-γ and TGF-β levels, and decreased IL-4 and IgE levels. In addition, inflammatory responses in the lung tissue and the number of eosinophils in NALF decreased.</p><p><strong>Conclusion: </strong>SLIT using Exo-Ova (5 µg) decorated with DC-specific aptamer induced immunomodulatory responses and remarkably attenuated allergic airway inflammation in mice.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"481"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855425","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":"LL-37 regulates odontogenic differentiation of dental pulp stem cells in an inflammatory microenvironment.","authors":"Yunfeng Ma, Xinyuan Liu, Ruoxi Dai, Quanli Li, Chris Ying Cao","doi":"10.1186/s13287-024-04075-7","DOIUrl":"10.1186/s13287-024-04075-7","url":null,"abstract":"<p><strong>Background: </strong>Inflammation often causes irreversible damage to dental pulp tissue. Dental pulp stem cells (DPSCs), which have multidirectional differentiation ability, play critical roles in the repair and regeneration of pulp tissue. However, the presence of proinflammatory factors can affect DPSCs proliferation, differentiation, migration, and other functions. LL-37 is a natural cationic polypeptide that inhibits lipopolysaccharide (LPS) activity, enhances cytokine production, and promotes the migration of stem cells. However, the potential of LL-37 in regenerative endodontics remains unknown. This study aimed to investigate the regulatory role of LL-37 in promoting the migration and odontogenic differentiation of DPSCs within an inflammatory microenvironment. These findings establish an experimental foundation for the regenerative treatment of pulpitis and provide a scientific basis for its clinical application.</p><p><strong>Materials and methods: </strong>DPSCs were isolated via enzyme digestion combined with the tissue block adhesion method and identified via flow cytometry. The impact of LL-37 on the proliferation of DPSCs was evaluated via a CCK-8 assay. The recruitment of DPSCs was assessed through a transwell assay. The mRNA expression levels of inflammatory and aging-related genes were assessed via reverse transcription‒polymerase chain reaction (RT‒PCR), western blotting, and enzyme‒linked immunosorbent assay (ELISA). The odontogenic differentiation of DPSCs was assessed through alkaline phosphatase (ALP) staining, alizarin red staining, and RT‒PCR analysis.</p><p><strong>Results: </strong>LL-37 has the potential to enhance the migration of DPSCs. In an inflammatory microenvironment, LL-37 can suppress the expression of genes associated with inflammation and aging, such as TNF-α, IL-1β, IL-6, P21, P38 and P53. Moreover, it promotes odontogenic differentiation in DPSCs by increasing ALP activity, increasing calcium nodule formation, and increasing the expression of dentin-related genes such as DMP1, DSPP and BSP.</p><p><strong>Conclusion: </strong>These findings suggest that the polypeptide LL-37 facilitates the migration of DPSCs and plays a crucial role in resolving inflammation and promoting cell differentiation within an inflammatory microenvironment. Consequently, LL-37 has promising potential as an innovative therapeutic approach for managing inflammatory dental pulp conditions.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"469"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855438","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 vesicles from mesenchymal stem cells improve neuroinflammation and neurotransmission in hippocampus and cognitive impairment in rats with mild liver damage and minimal hepatic encephalopathy.","authors":"Gergana Mincheva, Victoria Moreno-Manzano, Vicente Felipo, Marta Llansola","doi":"10.1186/s13287-024-04076-6","DOIUrl":"10.1186/s13287-024-04076-6","url":null,"abstract":"<p><strong>Background: </strong>Patients with steatotic liver disease may show mild cognitive impairment. Rats with mild liver damage reproduce this cognitive impairment, which is mediated by neuroinflammation that alters glutamate neurotransmission in the hippocampus. Treatment with extracellular vesicles (EV) from mesenchymal stem cells (MSC) reduces neuroinflammation and improves cognitive impairment in different animal models of neurological diseases. TGFβ in these EVs seems to be involved in its beneficial effects. The aim of this work was to assess if MSCs-EVs may improve cognitive impairment in rats with mild liver damage and to analyze the underlying mechanisms, assessing the effects on hippocampal neuroinflammation and neurotransmission. We also aimed to analyze the role of TGFβ in the in vivo effects of MSCs-EVs.</p><p><strong>Methods: </strong>Male Wistar rats with CCl₄-induced mild liver damage were treated with EVs from unmodified MSC or with EVs derived from TGFβ-silenced MSCs and its effects on cognitive function and on neuroinflammation and altered neurotransmission in the hippocampus were analysed.</p><p><strong>Results: </strong>Unmodified MSC-EVs reversed microglia activation and TNFα content, restoring membrane expression of NR2 subunit of NMDA receptor and improved object location memory. In contrast, EVs derived from TGFβ-silenced MSCs did not induce these effects but reversed astrocyte activation, IL-1β content and altered GluA2 AMPA receptor subunit membrane expression leading to improvement of learning and working memory in the radial maze.</p><p><strong>Conclusions: </strong>EVs from MSCs with TGFβ silenced induce different effects on behavior, neuroinflammation and neurotransmitter receptors alterations than unmodified MSC-EVs, indicating that the modification of TGFβ in the MSC-EVs has a notable effect on the consequences of the treatment. This work shows that treatment with MSC-EVs improves learning and memory in a model of mild liver damage and MHE in rats, suggesting that MSC-EVs may be a good therapeutic option to reverse cognitive impairment in patients with steatotic liver disease.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"472"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855310","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":"Using magnetic resonance relaxometry to evaluate the safety and quality of induced pluripotent stem cell-derived spinal cord progenitor cells.","authors":"Jerome Tan, Jiahui Chen, Daniel Roxby, Wai Hon Chooi, Tan Dai Nguyen, Shi Yan Ng, Jongyoon Han, Sing Yian Chew","doi":"10.1186/s13287-024-04070-y","DOIUrl":"10.1186/s13287-024-04070-y","url":null,"abstract":"<p><strong>Background: </strong>The emergence of induced pluripotent stem cells (iPSCs) offers a promising approach for replacing damaged neurons and glial cells, particularly in spinal cord injuries (SCI). Despite its merits, iPSC differentiation into spinal cord progenitor cells (SCPCs) is variable, necessitating reliable assessment of differentiation and validation of cell quality and safety. Phenotyping is often performed via label-based methods including immunofluorescent staining or flow cytometry analysis. These approaches are often expensive, laborious, time-consuming, destructive, and severely limits their use in large scale cell therapy manufacturing settings. On the other hand, cellular biophysical properties have demonstrated a strong correlation to cell state, quality and functionality and can be measured with ingenious label-free technologies in a rapid and non-destructive manner.</p><p><strong>Method: </strong>In this study, we report the use of Magnetic Resonance Relaxometry (MRR), a rapid and label-free method that indicates iron levels based on its readout (T₂). Briefly, we differentiated human iPSCs into SCPCs and compared key iPSC and SCPC cellular markers to their intracellular iron content (Fe³⁺) at different stages of the differentiation process.</p><p><strong>Results: </strong>With MRR, we found that intracellular iron of iPSCs and SCPCs were distinctively different allowing us to accurately reflect varying levels of residual undifferentiated iPSCs (i.e., OCT4⁺ cells) in any given population of SCPCs. MRR was also able to predict Day 10 SCPC OCT4 levels from Day 1 undifferentiated iPSC T₂ values and identified poorly differentiated SCPCs with lower T₂, indicative of lower neural progenitor (SOX1) and stem cell (Nestin) marker expression levels. Lastly, MRR was able to provide predictive indications for the extent of differentiation to Day 28 spinal cord motor neurons (ISL-1/SMI-32) based on the T₂ values of Day 10 SCPCs.</p><p><strong>Conclusion: </strong>MRR measurements of iPSCs and SCPCs has clearly indicated its capabilities to identify and quantify key phenotypes of iPSCs and SCPCs for end-point validation of safety and quality parameters. Thus, our technology provides a rapid label-free method to determine critical quality attributes in iPSC-derived progenies and is ideally suited as a quality control tool in cell therapy manufacturing.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"465"},"PeriodicalIF":7.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786357","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":"Trehalose extricates impaired mitochondrial and autophagy dysregulation in patient iPSC-derived macular corneal dystrophy disease model.","authors":"Divyani Nayak, Shivapriya Shivakumar, Rohit Shetty, K N Prashanthi, Arkasubhra Ghosh, Nallathambi Jeyabalan, Koushik Chakrabarty","doi":"10.1186/s13287-024-04016-4","DOIUrl":"10.1186/s13287-024-04016-4","url":null,"abstract":"<p><strong>Background: </strong>Patient-derived induced pluripotent stem cell (iPSCs) represents a powerful tool for elucidating the underlying disease mechanisms. Macular corneal dystrophy (MCD) is an intractable and progressive bilateral corneal disease affecting the corneal stroma due to mutation/s in carbohydrate sulfotransferase 6 (CHST6) gene. The underlying molecular mechanisms leading to MCD are unclear due to a lack of human contextual model and limited access to affected corneal stromal keratocytes (CSKs) from MCD patients. This has restricted the current treatment option for MCD to restorative corneal transplantation thereby lending itself to the use of iPSCs.</p><p><strong>Methods: </strong>induced pluripotent stem cells (iPSCs) were generated from two MCD patients and a healthy participant by senai virus based reprogramming of the peripheral mononuclear blood cells (PBMCs). The iPSCs were characterized based on the expression of pluripotent markers and formation of embryoid bodies possessing tri-lineage potential. Directed differentiation of the iPSCs to corneal stromal keratocytes (CSKs) was done via intermediate induction of neural crest cells. The iCSKs were characterized by immunocytochemistry and qPCR. Proteostat staining of the iCSKs was done to validate the disease phenotype invitro. Expression of autophagy markers in the iCSKs and JC staining were visualized by immunochemistry and live-cell imaging in trehalose treated iCSKs.</p><p><strong>Results: </strong>We show that the MCD iPSC-derived CSKs (MCDiCSKs) exhibits impaired autophagy assessed by the profiles of autophagy-associated proteins (LAMP1, LC3II/I, p62 and Beclin-1) and mitochondrial membrane potential. Significantly higher protein aggregates in MCDiCSKs was seen compared with the control, which could be rescued upon autophagy modulation. Hence, we treated MCD-iCSKs with trehalose (autophagy inducer) and showed that it protects MCD-iCSKs from mitochondrial dysfunction and maintains autophagic degradation.</p><p><strong>Conclusion: </strong>Our study highlights the possible pathological mechanisms involved in MCD. We found trehalose ameliorate the impaired mitochondrial and autophagy dysregulation in patient iPSC-derived macular corneal dystrophy disease model, which could be a potential alternative for MCD management.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"464"},"PeriodicalIF":7.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786074","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}