Recently, scientists from the University of California and other institutions have successfully maintained embryonic stem cells in eggs and elucidated the fate of embryonic stem cells. This research may provide scientists with biological characteristics of stem cell pluripotency and evolutionary development new insights. So what important research results have scientists recently made in the field of stem cell research? In this article, the editor has compiled relevant research and shared it with you!
iPSC Vaccine injection control therapy, the difference between CD8+ T cell activation status and T cell subset frequency in tumor-draining lymph nodes.
Image source: Xiaoming Ouyang, et al. Stem Cell Reports (2021). doi: 10.1016/j.stemcr.2021.04.004
[1] Stem Cell Rep: Vaccine strategy based on inducing pluripotent stem cells may be expected to produce powerful Anti-pancreatic cancer potential
doi:10.1016/j.stemcr.2021.04.004
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in the United States,5-year survival rates for patients with PDAC over the past few decades has been in the single digits; surgery remains by far the most effective treatment for this disease; however, only about 10% of patients are diagnosed at an early stage, allowing surgery to remove the tumor in time. Despite the success of scientists in the field of immune checkpoint inhibitor research, PDAC remains somewhat resistant to these drug agents, which makes this type of cancer a cancer because of its interstitial desmoplastic proliferation and lack of effector T cells. The and lower mutant burden becomes a refractory cancer.
Induced pluripotent stem cells (ipsCs) and cancer share cellular similarities and transcriptomic properties; recently, a research report entitled "Antitumor effects of ipsC-based cancer vaccine in pancreatic cancer" was published in the international journal Stem Cell Reports In , scientists from Stanford University and other institutions have delved into the possibility of using non-mutated tumor-associated proteins in induced pluripotent stem cells as the basis for developing PDAC vaccines. We all know that the adaptive immune system recognizes and responds to non-mutated tumor-associated antigens (TAAs), and the FDA-approved therapeutic cancer vaccine called Provenge is a TAA-based vaccine; the researchers noted , induced pluripotent stem cells and cancer cells share the gene expression profile . After clustering analysis of the RNA sequencing data of iPSC cell lines and cancer cell lines, the researchers found that the two share up-regulated genes. A specific gene called ipsC-cancer signature gene is highly expressed by the pluripotent cell population, but only slightly or not at all is expressed in the somatic tissue.
Taken together, our findings support further studies of iPSC vaccination in preclinical and clinical models of PDAC, and the ipsC vaccine is also suitable for studies in other cancer types with lower mutational burdens; of course, later investigators It is also hoped that further research will reveal whether the ipsC cancer vaccine is safe and effective in patients, while also effectively inhibiting tumor growth and re-growth, and helping to clear established tumors.
[2] Nat Commun: Scientists discover key elements affecting specific gene expression in blood stem cells Different transcription factors (TFs, transcription factors) can bind to these regulatory elements and regulate promoter-enhancers in a cell type -specific manner ring. Despite its important role in controlling gene expression, how transcription factors promote promoter-enhancer loops is currently unclear.
CCCTC-binding factor (CTCF) is an important factor to maintain the interaction between chromatin, however, researchers do not know the mechanism of molecule that regulates its binding to chromatin. Organisms maintain vitality and health through an intricate web of biochemical processes that are often remarkably plastic in response to environmental changes, but sometimes go wrong. Treat diseases more effectively. A few days ago, in a research report titled "ZNF143 mediates CTCF-bound promoter–enhancer loops required for murine hematopoietic stem and progenitor cell function" published in the international journal Nature Communications, scientists from the National University of Singapore and other institutions found through research A special molecular switch, , may control the process by which cells turn genes on and off, ensuring that cells perform their designated tasks correctly and adequately in the body.
The research presented here may help improve scientists' understanding of how normal stem cells function, as well as shed light on the pathogenesis of certain diseases. Professor Tenen said, based on the results of this paper, we will be expected to understand the regulatory mechanism of CTCF-DNA binding and gene expression in the later stage, which is of great significance for investigating the developmental disorders and cancer occurrence of and human ; later researchers will continue to In-depth study of the molecular structure of related proteins to further elucidate the pathogenesis of various human diseases. Taken together, ZNF143-CTCF binds to the promoter-enhancer loop or modulates the pattern of gene expression, which is essential for maintaining the function and integrity of mouse hematopoietic stem and progenitor cells , in addition, the researchers also discovered A common feature of gene regulation , namely ZNF143, is a key factor for CTCF binding to promoter enhancer loops.
[3] Stem Cells: Aging niche can "rejuvenate" hematopoietic stem cells?
doi: 10.1002/stem.3372
Senescence of hematopoietic stem cells causes senescence-related leukemia and associated immune remodeling. Senescent hematopoietic stem cells remain viable after transplantation into young recipients after in vitro treatment with a specific inhibitor of Cdc42 activity, which causes hematopoietic stem cell senescence. In this study, Professor Novella Guidi's team determined the effect of the aging niche on the function of -regenerated senescent stellate cells in vitro. The results showed that the senescent niche inhibited the function of regenerated hematopoietic stem cells in vitro, which was at least partly related to aging The low-level cytokines and osteopontin found in the niche are related to , which provides us with ideas to address the effect of the aging niche on the sustained recovery of senescent hematopoietic stem cells in vivo.
The aim of this study was to determine whether the aging niche might affect the youth-like functions of metabolic hematopoietic stem cells. The researchers treated 200 hematopoietic stem cells from aged donors (Ly5.1+) for 16 hours in vitro with +/ casein and then transplanted into young (Y), aged (A) or young osteopontin (OPN). ) in knockout (KO) receptor (Ly5.2+) mice. B: Frequency of elderly donors (Ly5.1+ cells)+/casein in total leukocytes (PB) in peripheral blood of young and old OPN KO recipients (Ly5.2+) mice. C: Frequency of +/casein in senescent B cells. D: Senescent T cells+/casein. E: Aged myeloid cells+/casein in donor-derived Ly5.1+ cells in PB of young and aged OPN KO recipient (Ly5.2+) mice. F: Frequency of aged LT-HSCs+/CASIN in bone marrow in donor-derived Ly5.1+ LSK cells from young, aged and young OPN KO recipient (Ly5.2+) mice. Data are based on 5 replicates of 3 recipient mice per group.
In conclusion, After rejuvenated aged hematopoietic stem cells transplanted into young recipients, their continued youthful function depends on a combination of stem cell intrinsic and stem cell extrinsic factors (niche/microenvironment). When the regenerated aged hematopoietic stem cells were transplanted into young mice, some features of their aging reverted to the aging phenotype . For some phenotypes, this may be due to reduced osteopontin levels in the aged niche . Therefore, in order to restore senescent hematopoietic stem cells in vivo, the impact of niche on regenerating hematopoietic stem cells needs to be considered.
Human embryonic neural stem cells cultures retain regional features and recapitulate the transcriptional signature of PHGGs.
Image source: doi:10.1016/j.stem.2021.01.016
[4] Cell Stem Cell: Scientists reveal the regional characteristics of human neural stem cells The team led by Professor Steven M Pollard of the Institute of Healing and Repair published a research paper entitled "Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants" in Cell Stem Cell, a sub-journal of Cell.
Previous studies have shown that the use of tissue-derived cell models overcomes the shortcomings associated with embryonic stem cell (ESC) or induced pluripotent stem cell (ipsC-based) models, which are fickle, require lengthy differentiation protocols, and result in a heterogeneous mixture of cells Notably, in addition to dissecting the role of the H3.3-cancer histone , the established origin and identity of the research team's primary fetal NSC line may also contribute to the emergence of other CNS compartments Modeling of pediatric tumors such as medulloblastoma or ependymoma . Given this, the research team and others are developing a large number of human fetal NSC cell lines spanning different temporal and spatial signatures , these The cell lines should enable functional dissection of different brain tumor drivers and make them available to the research community. Further using the research team's syngeneic model, the researchers were able to obtain insights into H3.3-G34R's mode of action in relevant cellular contexts Molecular insights. Through a combination of mRNA profiling and histone post-translational modification mapping, the research team observed that H3.3-G34R does not induce pervasive transcriptional or epigenetic changes in , but rather on genes that are already highly expressed functions, including key forebrain NSC transcription factors.These findings contrast sharply with the reported role of H3.3-K27M in midline pHGG and other H3.3 driver mutations present in pediatric sarcomas, where the oncogene appears to cause a broad reset of the epigenetic landscape.
In conclusion, The research team's findings suggest that cell-intrinsic programs associated with the region signature of human neural progenitors provide unique vulnerabilities to distinct H3.3 cancer histones, which may explain the high-grade glue in children Unique anatomical distribution of plasmoma. Further work will now be required to fully dissect why regional progenitor states are differentially sensitive to each H3.3 mutation, and whether mechanisms that maintain forebrain and hindbrain identity can be targeted for therapeutic purposes. The research team hopes that this identification of key target cells, the population, and underlying susceptibility mechanisms, may ultimately lead to more effective therapies for this devastating disease.
[5]Stem Cell Res: extracellular special laminin may regulate the hematopoietic potential of pluripotent stem cells and differentiate into all types of cells, so that the initial small number of iPSCs can be used to make large numbers of cells in the body; however, some cells have been shown to be easier to generate and make than others, which translates to research on iPSCs into clinical therapies The cost and expense of pluripotent stem cells may have a significant impact; recently, a research report titled "Extracellular laminin regulates hematopoietic potential of pluripotent stem cells through integrin β1-ILK-β-catenin-JUN axis" was published in the international journal Stem Cell Research. , Scientists from Japan's Kyoto University and other institutions have found through research that a special molecule, laminin, which is widely present in the human body and used for iPSCs therapy, may affect the hematopoietic differentiation of iPSCs.
The researchers used the LM511-E8 to differentiate iPSCs into various types of blood cells , including the platelets they infused into patients, based on the Sac method that the researchers discovered more than 10 years ago. The Sac method is mainly aimed at the hematopoietic differentiation of iPSCs, which can follow the state of primitive streak structure, mesoderm, and vascular endothelium to generate hematopoietic progenitor stem cells. In other words, this approach attempts to reproduce native hematopoiesis to generate hematopoietic progenitors , a cell type from which all other blood cells can be derived. This approach was not without its flaws, however, and the researchers noticed that the numbers of hematopoietic progenitors they obtained were considerably smaller than the numbers of ipsCs.
In summary , extracellular laminin scaffolds may regulate the differentiation potential of hematopoietic stem progenitor cells by activating the ITGB1-ILK-β-catenin-JUN axis at the undifferentiated stage; while low concentrations of LM511-E8 and modified The combination of the hematopoietic stem progenitor cell-Sac method may result in a higher yield of hematopoietic progenitor cells and a higher final hematopoietic rate. scheme or steps.
[6] Nature Sub-Journal: Scientists Reveal the Hematopoietic Mechanism of Hematopoietic Stem Cells
doi:10.1038/s41467-021-22053-y
Somatic mutations in the epigenetic regulators ASXL1, TET2 and DNMT3A were repeatedly detected in hematopoietic stem cells. Deficiency of TET2 or DNMT3A in mice enhanced self-renewal of LT-HSCs, suggesting that mutations in TET2 and DNMT3A induce expansion of the clone in hematopoietic cells, resulting in clonal hematopoiesis in humans. In contrast, ASXL1 mutations in mice reduced the number and function of HSCs.
Based on this, Professor Makoto Suematsu from the Department of Cell Therapy, Tokyo University Medical Research Institute, Minato-ku, Tokyo, Japan, led a team to put the research on hematopoietic stem cells as "Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway” was published online March 23, 2021 in the journal Nature Communications. The research team observed age-related enhancement of hematopoietic phenotypes, including anemia , myeloid-biased differentiation, hypocellular bone marrow, and expansion of surface marker-defined LT-HSCs in aged ASXL1-MT KI mice. These phenotypes were partially rescued by inhibition of the Akt/mTOR pathway, suggesting that ASXL1-MT-induced activation of the Akt/mTOR pathway is associated with enhanced aging of in the hematopoietic system.Furthermore, RNA-sequence analysis revealed that ASXL1-MT promotes age-related patterns of gene expression. These results suggest that ASXL1-MT may promote HSC senescence by activating the Akt/mTOR pathway.
In conclusion, the research team showed that ASXL1-MT cooperates with BAP1 to activate the Akt/mTOR pathway in a -epigenetic -independent manner. Activated Akt/mTOR pathway leads to abnormal expansion of PlT-HSCs during aging, occupying HSc compartments. Hyperactive Akt/mTOR signaling also leads to mitochondrial activation, ROS overproduction, increased DNA damage , and subsequent hematopoietic stem cell dysfunction. Expansion of pLT-HSCs and increased DNA damage caused by mutations in ASXL1 can lead to the development of CH, leading to secondary mutations in hematopoietic malignancies. Pharmacological inhibition of the Akt/mTOR pathway may pave the way for preventive intervention in congenital heart disease patients harboring ASXL1 mutations.
[7] PNAS: A dynamic map of hematopoietic stem cell expansion revealed at the single-cell level blood lineage and exhibits self-renewing properties. To establish the HSPC pool, nascent HSPCs will first migrate to the temporary hematopoietic organ called fetal liver (FL, in mammalian ) or tail hematopoietic tissue (CHT, in zebrafish). Clinically, in vitro HSPC expansion is a viable approach to obtain sufficient transplantable HSPCs, but remains technically challenging. Therefore, decoding the complex regulatory mechanisms of HSPC expansion within hematopoietic organs is crucial.
Based on this, the team of Professor Liu Fengke from the Institute of Zoology, Chinese Academy of Sciences published a research paper entitled "A single-cell resolution developmental atlas of hematopoietic stem and progenitor cell expansion in zebrafish" in the journal PNAS. The research team revealed the conservation and differences in developmental hematopoiesis between human fetal liver and zebrafish CHT. In this study, the research team used scRNA-seq in combination with functional assays to decode developing CHT. First, the research team addressed fetal HSPC heterogeneity, manifested in lineage initiation and metabolic gene signatures. The research team further analyzed the cellular interactions between non-hematopoietic niche components and HSPCs, and identified the endothelial cell-specific factor Gpr182, which was subsequently experimentally validated for its role in promoting HSPC expansion. Finally, The research team revealed conservation and differences in developmental hematopoiesis between human fetal liver and zebrafish CHT. The research team's research provides a valuable resource for fetal HSPC development and a favorable research basis for establishing support for HSPC expansion in vitro.
corticosterone restores normal hair cycle progression in ADX mice.
Image source: Nature, 2021, doi:10.1038/s41586-021-03417-2
[8]Nature: Take it easy, maybe you can treat hair loss ! New study reveals mechanism of chronic stress regulating hair follicle stem cells This also gives advice on hair care. His advice is especially useful now, a year after the COVID-19 pandemic.About a quarter of people infected with Covid-19 experience hair loss six months after the onset of symptoms, likely due to the systemic shock from the torment of infection and recovery. Chronic stress (also known as chronic stress) has long been associated with hair loss, but the underlying mechanisms linking stress to hair follicle stem cell dysfunction have not been understood. Dr. Ya-Chieh Hsu and his team at Harvard University have uncovered this link in a new study in mice. The relevant research results were published online in the journal Nature on March 31, 2021. The title of the paper is "Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence". In the
article, the researchers first removed the adrenal gland , which produces stress hormones (also known as stress hormones) and is a Important endocrine organ. The hair follicles of the adrenal-removed mice, which the team called the ADX mice, had a shorter telogen than the control group (less than 20 days, compared with 60 to 100 days in the control group), and the frequency of hair follicle involvement in hair growth was approximately three times that of the control group. By feeding ADX mice corticosterone, a stress hormone normally produced by the mouse's adrenal glands, they were able to suppress this frequent hair growth and restore normal hair cycles. Interestingly, when they unpredictably applied various mild stresses to normal mice for nine weeks, they observed an increase in corticosterone levels, accompanied by a reduction in hair growth, supporting the production of adrenal glands under chronic stress. The idea that corticosterone inhibits hair growth.
To understand how the dermal papilla transmits this stress signal to the HFSC, Hsu's team analyzed the messenger RNA expressed in the dermal papilla (used as a template for protein expression). This suggests that a -secreted protein called GAS6 (growth arrest-specific 6) could serve as a candidate molecular messenger. Indeed, delivery of GAS6 into the skin using the adenoviral vector , a common tool in gene therapy, not only stimulated hair growth in normal mice , but also restored hair growth during chronic stress or corticosterone feeding .
[9] Nature sub-issue: Revealing that a chemical cocktail can generate large numbers of muscle stem cells A chemical cocktail that produces large numbers of muscle stem cells that can self-renew and give rise to all types of skeletal muscle cells. This advance could lead to the development of stem cell-based therapies to treat muscle loss or damage due to injury, age or disease. The results of the study were recently published in the journal Nature Biomedical Engineering under the title "Skeletal muscle regeneration via the chemical induction and expansion of myogenic stem cells in situ or in vitro".
Muscle stem cells are responsible for muscle growth, repair and regeneration after injury throughout a person's life. In fully grown adults, muscle stem cells are quiescent—they remain inactive until they are called upon to respond to injury by replicating themselves and producing all the cell types needed to repair damaged tissue. However, this regenerative capacity declines as people age; it is also impaired by trauma and inherited diseases such as Duchenne muscular dystrophy.The researchers say muscle stem cell-based therapies hold great promise for improving muscle regeneration, but current methods to generate patient-specific muscle stem cells can take months. "
Li and colleagues found that this chemical cocktail -- a combination of the rhizome extract forskolin and the small molecule RepSox -- can efficiently generate large numbers of muscle stem cells within 10 days. In mouse studies, these studies The researchers showed two potential ways the chemical cocktail could be used as a therapy. The first approach uses cells found in the skin called dermal myogenic cells, which have the ability to become muscle cells. Li and his team found that , treating dermal myogenic cells with this chemical mixture caused them to produce large numbers of muscle stem cells, which could then be transplanted into injured tissue.
[10]Cell Stem Cell: New discovery! ribosomal assembly is very important for the regeneration of hematopoietic stem cells! Scientists have identified key genes involved in the regeneration of hematopoietic stem cells (HSCs) through the assembly of ribosomes, the protein-manufacturing factories in cells that convert mRNA sequences into amino acid sequences; the results of this paper Highlighting the importance of proper protein assembly for stem cell regeneration and identifying potential targets may help develop novel therapies for ribosomopathies and childhood disorders that induce bone marrow failure.
Researcher Wei Tong said, "Although previous studies have shown that mutations affecting ribosome assembly are directly related to the development of human diseases that are involved in bone marrow dysfunction, we do not know the molecular mechanism by which ribosome assembly is regulated in hematopoietic stem cells and its consequences." how the disease occurs. In the article, the researchers identify the molecular mechanism that prevents the proper assembly of ribosomes in mammalian cells to induce hematopoietic stem cell deficiency, which may lead to the development of novel disease intervention strategies in the future.
The researchers also found that knocking out the ZNF622 gene in Hectd1-deficient hematopoietic stem cells restored the ability of the large subunit and the small subunit to properly bind, thereby restoring protein synthesis and hematopoietic stem cell generation. Finally, researcher Tong said, the results not only highlight the relationship between protein degradation, ribosome assembly, and stem cell generation, but also reveal the importance of knockout ZNF622 to restore normal bone marrow function, which is important for child development. critical. Later researchers also hope to further study this mechanism as a potential target to help develop novel therapies for related diseases.
Source: cell WeChat official account
