STEM CELLS最新文献

{"title":"How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells.","authors":"Bogi Andersen,&nbsp;Junyan Duan,&nbsp;Satya Swaroop Karri","doi":"10.1093/stmcls/sxad013","DOIUrl":"https://doi.org/10.1093/stmcls/sxad013","url":null,"abstract":"<p><p>First described in the early 20th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal tract, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. More recent work showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize the accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 4","pages":"319-327"},"PeriodicalIF":5.2,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10128966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9397087","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":"Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells.","authors":"Tao Li, Kelsey L Conroy, Amy M Kim, Julian Halmai, Kewa Gao, Emily Moreno, Aijun Wang, Anthony G Passerini, Jan A Nolta, Ping Zhou","doi":"10.1093/stmcls/sxad005","DOIUrl":"10.1093/stmcls/sxad005","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs) not only provide an abundant source of vascular cells for potential therapeutic applications in vascular disease but also constitute an excellent model for understanding the mechanisms that regulate the differentiation and the functionality of vascular cells. Here, we reported that myocyte enhancer factor 2C (MEF2C) transcription factor, but not any other members of the MEF2 family, was robustly upregulated during the differentiation of vascular progenitors and endothelial cells (ECs) from hiPSCs. Vascular endothelial growth factors (VEGF) strongly induced MEF2C expression in endothelial lineage cells. The specific upregulation of MEF2C during the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown of MEF2C with shRNA in hiPSCs did not affect the differentiation of ECs from these hiPSCs, but greatly reduced the migration and tube formation capacity of the hiPSC-derived ECs. Through a chromatin immunoprecipitation-sequencing, genome-wide RNA-sequencing, quantitative RT-PCR, and immunostaining analyses of the hiPSC-derived endothelial lineage cells with MEF2C inhibition or knockdown compared to control hiPSC-derived ECs, we identified TNF-related apoptosis inducing ligand (TRAIL) and transmembrane protein 100 (TMEM100) as novel targets of MEF2C. This study demonstrates an important role for MEF2C in regulating human EC functions and highlights MEF2C and its downstream effectors as potential targets to treat vascular malfunction-associated diseases.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 4","pages":"341-353"},"PeriodicalIF":5.2,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10128960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9396195","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":"FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells.","authors":"Yun-Sheng Yang,&nbsp;Man-Hua Liu,&nbsp;Zhao-Wen Yan,&nbsp;Guo-Qiang Chen,&nbsp;Ying Huang","doi":"10.1093/stmcls/sxad008","DOIUrl":"https://doi.org/10.1093/stmcls/sxad008","url":null,"abstract":"<p><p>Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved housekeeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multifaceted physiological and pathological processes. However, the in vivo function of FAM122A is largely unknown. In this study, we observed that Fam122 deletion resulted in embryonic lethality with severe defects of cardiovascular developments and significantly attenuated cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impaired mesendodermal specification and cardiac differentiation from mouse embryonic stem cells but showed no influence on pluripotent identity. Mechanical investigation revealed that the impaired differentiation potential was caused by the dysregulation of histone modification and Wnt and Hippo signaling pathways through modulation of PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This research not only significantly extends our understanding of the regulatory network of mesendodermal/cardiac differentiation but also proposes the potential significance of FAM122A in cardiac regeneration.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 4","pages":"354-367"},"PeriodicalIF":5.2,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/77/sxad008.PMC10498146.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226150","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":"Mesenchymal Stem Cell-Derived Exosomes Ameliorate Diabetic Kidney Disease Through the NLRP3 Signaling Pathway.","authors":"Yinghui Wang,&nbsp;Jiaxi Liu,&nbsp;Honggang Wang,&nbsp;Shasha Lv,&nbsp;Qingzhen Liu,&nbsp;Shan Li,&nbsp;Xue Yang,&nbsp;Gang Liu","doi":"10.1093/stmcls/sxad010","DOIUrl":"https://doi.org/10.1093/stmcls/sxad010","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Exosomes (Exo) derived from human umbilical cord mesenchymal stem cells (HUC-MSCs) have been demonstrated to be an effective therapy for DKD, but the underlying mechanisms of this action remain poorly defined. We investigated the association of DKD with inflammasome activation and the pathophysiological relevance of Exo-mediated inflammation relief as well as damage repair in this progression. We co-cultured podocytes and HUC-MSCs derived Exo (MSCs-Exo) under high glucose (HG) and injected MSCs-Exo into diabetic mice, then we detected the NLRP3 inflammasome both in vitro and in vivo. We found that HG reduced the viability of podocytes, activated the NLRP3 signaling pathway and increased inflammation in podocytes and diabetic mice. MSCs-Exo attenuated the inflammation, including the expression of IL-6, IL-1β, IL-18, TNF-α; depressed the activation of NLRP3 signaling pathway in podocytes under HG and diabetic mice, ameliorated kidney injury. Furthermore, miR-22-3p, which is relatively highly expressed miRNAs in exosomes of MSCs, may be the key point in this progress, by suppressing the expression of its known target, NLRP3. Knocking down miR-22-3p from MSCs-Exo abolished their anti-inflammation activity and beneficial function both in vitro and in vivo. Collectively, our results have demonstrated that exosomes transferring miR-22-3p protected the podocytes and diabetic mice from inflammation by mediating NLRP3 inflammasome, indicating that MSC-derived exosomes may be a promising therapeutic cell-free strategy for DKD.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 4","pages":"368-383"},"PeriodicalIF":5.2,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9453704","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":"HSC Niche Dynamics in Regeneration, Pre-malignancy, and Cancer: Insights From Mathematical Modeling.","authors":"Rasmus Kristoffer Pedersen,&nbsp;Morten Andersen,&nbsp;Vibe Skov,&nbsp;Lasse Kjær,&nbsp;Hans C Hasselbalch,&nbsp;Johnny T Ottesen,&nbsp;Thomas Stiehl","doi":"10.1093/stmcls/sxac079","DOIUrl":"https://doi.org/10.1093/stmcls/sxac079","url":null,"abstract":"<p><p>The hematopoietic stem cell (HSC) niche is a crucial driver of regeneration and malignancy. Its interaction with hematopoietic and malignant stem cells is highly complex and direct experimental observations are challenging. We here develop a mathematical model which helps relate processes in the niche to measurable changes of stem and non-stem cell counts. HSC attached to the niche are assumed to be quiescent. After detachment HSC become activated and divide or differentiate. To maintain their stemness, the progeny originating from division must reattach to the niche. We use mouse data from literature to parametrize the model. By combining mathematical analysis and computer simulations, we systematically investigate the impact of stem cell proliferation, differentiation, niche attachment, and detachment on clinically relevant scenarios. These include bone marrow transplantation, clonal competition, and eradication of malignant cells. According to our model, sampling of blood or bulk marrow provides only limited information about cellular interactions in the niche and the clonal composition of the stem cell population. Furthermore, we investigate how interference with processes in the stem cell niche could help to increase the effect of low-dose chemotherapy or to improve the homing of genetically engineered cells.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"260-270"},"PeriodicalIF":5.2,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9177154","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":"Efficacy of Whole Cancer Stem Cell-Based Vaccines: A Systematic Review of Preclinical and Clinical Studies.","authors":"Farideh Hashemi,&nbsp;Mahdieh Razmi,&nbsp;Fatemeh Tajik,&nbsp;Margot Zöller,&nbsp;Masoumeh Dehghan Manshadi,&nbsp;Forough Mahdavinezhad,&nbsp;Amir Tiyuri,&nbsp;Roya Ghods,&nbsp;Zahra Madjd","doi":"10.1093/stmcls/sxac089","DOIUrl":"https://doi.org/10.1093/stmcls/sxac089","url":null,"abstract":"<p><strong>Background: </strong>Despite the conventional cancer therapeutic, cancer treatment remains a medical challenge due to neoplasm metastasis and cancer recurrence; therefore, new approaches promoting therapeutic strategies are highly desirable. As a new therapy, the use of whole neoplastic stem cells or cancer stem cell (CSC)-based vaccines is one strategy to overcome these obstacles. We investigated the effects of whole CSC-based vaccines on the solid tumor development, metastasis, and survival rate.</p><p><strong>Methods: </strong>Primary electronic databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) and a major clinical registry were searched. Interventional studies of whole CSC-based vaccines in rodent cancer models (38 studies) and human cancer patients (11 studies) were included; the vaccine preparation methodologies, effects, and overall outcomes were evaluated.</p><p><strong>Results: </strong>Preclinical studies were divided into 4 groups: CSC-lysates/ inactivated-CSC-based vaccines, CSC-lysate-loaded dendritic cell (CSC-DC) vaccines, cytotoxic T-cell (CTL) vaccines generated with CSC-DC (CSC-DC-CTL), and combinatorial treatments carried out in the prophylactic and therapeutic experimental models. The majority of preclinical studies reported a promising effect on tumor growth, survival rate, and metastasis. Moreover, whole CSC-based vaccines induced several antitumor immune responses. A small number of clinical investigations suggested that the whole CSC-based vaccine treatment is beneficial; however, further research is required.</p><p><strong>Conclusions: </strong>This comprehensive review provides an overview of the available methods for assessing the efficacy of whole CSC-based vaccines on tumor development, metastasis, and survival rate. In addition, it presents a set of recommendations for designing high-quality clinical studies that may allow to determine the efficacy of whole CSC-based-vaccines in cancer therapy.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"207-232"},"PeriodicalIF":5.2,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9177723","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":"Wnt/BMP Mediated Metabolic Reprogramming Preserves Multipotency of Neural Crest-Like Stem Cells.","authors":"Pihu Mehrotra, Izuagie Ikhapoh, Pedro Lei, Georgios Tseropoulos, Yali Zhang, Jianmin Wang, Song Liu, Marianne E Bronner, Stelios T Andreadis","doi":"10.1093/stmcls/sxad001","DOIUrl":"10.1093/stmcls/sxad001","url":null,"abstract":"<p><p>Neural crest-like stem cells resembling embryonic neural crest cells (NCs) can be derived from adult human tissues such as the epidermis. However, these cells lose their multipotency rapidly in culture limiting their expansion for clinical use. Here, we show that the multipotency of keratinocyte-derived NCs (KC-NCs) can be preserved by activating the Wnt and BMP signaling axis, promoting expression of key NC-specifier genes and ultimately enhancing their differentiation potential. We also show that transcriptional changes leading to multipotency are linked to metabolic reprogramming of KC-NCs to a highly glycolytic state. Specifically, KC-NCs treated with CHIR and BMP2 rely almost exclusively on glycolysis for their energy needs, as seen by increased lactate production, glucose uptake, and glycolytic enzyme activities. This was accompanied by mitochondrial depolarization and decreased mitochondrial ATP production. Interestingly, the glycolytic end-product lactate stabilized β-catenin and further augmented NC-gene expression. Taken together, our study shows that activation of the Wnt/BMP signaling coordinates the metabolic demands of neural crest-like stem cells governing decisions regarding multipotency and differentiation, with possible implications for regenerative medicine.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"287-305"},"PeriodicalIF":4.0,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9550198","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":"The Telomerase Connection of the Brain and Its Implications for Neurodegenerative Diseases.","authors":"Gabriele Saretzki","doi":"10.1093/stmcls/sxac078","DOIUrl":"https://doi.org/10.1093/stmcls/sxac078","url":null,"abstract":"<p><p>Telomerase, consisting of the protein subunit telomerase reverse transcriptase (TERT) and RNA component TERC, is best known for maintaining and extending human telomeres, the ends of linear chromosomes, in tissues, where it is active, such as stem cells, germline cells, lymphocytes and endothelial cells. This function is considered as canonical. However, various non-canonical functions for the protein part TERT have been discovered. There are multiple such roles which can interfere with several signaling pathways, cancer development and many other processes. One of these non-canonical functions includes shuttling of the TERT protein out of the nucleus upon increased oxidative stress into the cytoplasm and organelles such as mitochondria. Mitochondrial TERT is able to protect cells from oxidative stress, DNA damage and apoptosis although the exact mechanisms are incompletely understood. Recently, a protective role for TERT was described in brain neurons. Here TERT is able to counteract effects of toxic neurodegenerative proteins via changes in gene expression, activation of neurotrophic factors as well as activation of protein degrading pathways such as autophagy. Protein degradation processes are prominently involved in degrading toxic proteins in the brain like amyloid-β, pathological tau and α-synuclein that are responsible for various neurodegenerative diseases. These new findings can have implications for the development of novel treatment strategies for neurodegenerative diseases. The current review summarizes our knowledge on the role of the telomerase protein TERT in brain function, in particular, under the aspect of age-related neurodegenerative diseases. It also describes various strategies to increase TERT levels in the brain.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"233-241"},"PeriodicalIF":5.2,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9182907","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":"IL-22 Promotes Neural Stem Cell Self-Renewal in the Adult Brain.","authors":"Valérie Coronas, Patricia Arnault, Jean-François Jégou, Laetitia Cousin, Hanitriniaina Rabeony, Sandrine Clarhaut, Thomas Harnois, Jean-Claude Lecron, Franck Morel","doi":"10.1093/stmcls/sxad003","DOIUrl":"10.1093/stmcls/sxad003","url":null,"abstract":"<p><p>Mainly known for its role in immune defense and inflammation, interleukin 22 (IL-22) has emerged over the past decade as a cytokine involved in the adaptation of stem/progenitor cell activity for tissue homeostasis and repair. IL-22 is present in the brain, which harbors neural stem cells (NSC) in specific niches of which the ventricular-subventricular zone (V-SVZ) is the most important. In this study, we examined a possible effect of IL-22 on NSC in the adult mouse brain. We demonstrate that the IL-22 receptor is expressed in the V-SVZ, mainly in NSC characterized by their SOX2 expression. Addition of IL-22 to V-VSZ cell cultures resulted in an increase in NSC self-renewal, associated with a shift in NSC division mode towards symmetric proliferative divisions at the expense of differentiative divisions. Conversely, loss of IL-22 in knockout mice led to a decrease in neurosphere yield, suggesting a reduction in the NSC population, which was confirmed by the decrease in cells retaining BrdU labeling in IL-22 knockout mice. Our study supports that IL-22 is involved in the development and/or maintenance of V-VSZ NSC and opens new avenues to further investigate the role of IL-22 in NSC biology in health and disease.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"252-259"},"PeriodicalIF":5.2,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9184527","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":"Chd5 Regulates the Transcription Factor Six3 to Promote Neuronal Differentiation.","authors":"Padmina Shrestha, Anbalagan Jaganathan, Dhananjay Huilgol, Carlos Ballon, Yon Hwangbo, Alea A Mills","doi":"10.1093/stmcls/sxad002","DOIUrl":"10.1093/stmcls/sxad002","url":null,"abstract":"<p><p>Chromodomain helicase DNA-binding protein 5 (Chd5) is an ATP-dependent chromatin remodeler that promotes neuronal differentiation. However, the mechanism behind the action of Chd5 during neurogenesis is not clearly understood. Here we use transcriptional profiling of cells obtained from Chd5 deficient mice at early and late stages of neuronal differentiation to show that Chd5 regulates neurogenesis by directing stepwise transcriptional changes. During early stages of neurogenesis, Chd5 promotes expression of the proneural transcription factor Six3 to repress Wnt5a, a non-canonical Wnt ligand essential for the maturation of neurons. This previously unappreciated ability of Chd5 to transcriptionally repress neuronal maturation factors is critical for both lineage specification and maturation. Thus, Chd5 facilitates early transcriptional changes in neural stem cells, thereby initiating transcriptional programs essential for neuronal fate specification.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":"41 3","pages":"242-251"},"PeriodicalIF":4.0,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10020979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9450423","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}