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Tavares-Marcos C, Correia M, de Jesus BB. Telomeres as hallmarks of iPSC aging: a review on telomere dynamics during stemness and cellular reprogramming. Ageing Res Rev 2025:102773. [PMID: 40414363 DOI: 10.1016/j.arr.2025.102773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/03/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025]
Abstract
Telomeres, the protective ends of chromosome, are key to tissue repair and regeneration. Telomere shortening is linked to aging and age-related disorders, while excessive telomerase activity may support tissue regeneration or transformation. Some of the functions of telomeres and telomerase may be mediated by its important role in the process of stemness. Active telomerase, and subsequent telomerase-dependent telomere extension, supports stem-cells self-renewal and pluripotency - essential for tissue healing. During cellular reprogramming, differentiated cells are converted into induced pluripotent stem cells (iPSCs), which resemble embryonic stem cells. During iPSC derivation, telomere length is reset, enhancing iPSCs' regenerative potential. During this process, incomplete telomerase activation and telomere extension can lead to genomic instability and/or haltered cell functionality. Understanding the intricate relation of telomeres, telomerase and stemness may be critical when designing novel cell-based therapies targeting degenerative diseases or to unlock strategies to delay aging. Here, we explore the recent bibliography linking these areas, raising awareness of their important when designing novel breakthroughs in health and longevity.
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Affiliation(s)
- Carlota Tavares-Marcos
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Magda Correia
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruno Bernardes de Jesus
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal.
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2
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Page J, Stephens C, Richard M, Lyons E, Baumler E, Verklan MT, Lorenzo E. The relationship between physical activity and telomere length in women: A systematic review. Mech Ageing Dev 2025; 224:112042. [PMID: 39983997 PMCID: PMC11957325 DOI: 10.1016/j.mad.2025.112042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/29/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A narrative synthesis of study findings indicated PA did not have a significant relationship with TL in women. However, a possible positive relationship was noted between specific types of PA and TL, specific to combined aerobic and strength-training PA and high intensity interval training interventions. The impact of PA on TL appeared to be age-dependent as well, showing significant positive relationships between PA and TL in early and later adulthood but not in middle adulthood. Findings related to race or ethnicity were inconclusive due to limited analyses from the included studies. The studies varied greatly by PA type, intensity, duration, and frequency, which, along with the reliance on self-reported PA measures in the observational studies, impacted the ability to draw firm conclusions. This review underscores the necessity for future research in large cohort studies using objectively measured PA interventions to further clarify the complex associations between PA and TL in women.
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Affiliation(s)
- Jeni Page
- School of Nursing, University of Texas Medical Branch, 1114 Mechanic St, Galveston, TX 77550, USA.
| | - Catherine Stephens
- School of Nursing, University of Texas Medical Branch, 1114 Mechanic St, Galveston, TX 77550, USA.
| | - Melissa Richard
- Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
| | - Elizabeth Lyons
- School of Health Professions, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, USA.
| | - Elizabeth Baumler
- McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin, Houston, TX, USA.
| | - M Terese Verklan
- School of Nursing, University of Texas Medical Branch, 1114 Mechanic St, Galveston, TX 77550, USA.
| | - Elizabeth Lorenzo
- School of Nursing, University of Texas Medical Branch, 1114 Mechanic St, Galveston, TX 77550, USA.
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Kattaru S, Echambadi Loganathan S, Kodavala S, Chodimella CS, Potukuchi VGKS. Platelet-Derived Growth Factor Promotes Glomerular Mesangial Cells Differentiation of Human Bone Marrow Hematopoietic Stem Cells - An In Vitro Study. J Cell Biochem 2025; 126:e70012. [PMID: 40065657 DOI: 10.1002/jcb.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/24/2025] [Accepted: 02/20/2025] [Indexed: 05/13/2025]
Abstract
Glomerular filtration function and homeostasis are largely due to the cross-talk between podocytes, endothelial cells, and mesangial cells (MCs). Any disturbance in this association causes glomerular diseases (GD). Cell-based therapies are the best option in the treatment of GD. It is contemplated that hematopoietic stem cells (HSCs) are best suited to regenerate these cells; earlier, we have shown the differentiation of HSCs into podocytes. In this study, MCs formation was initiated with retinoic acid (RA), BMP-7, and Activin A, resulting in comma-shaped intermediate mesoderm (IM) cells prominently expressing Osr1. Followed by inducing with EGF, FGF, and BMP-7, which resulted in elongated metanephric mesenchyme (MM) cells conspicuously expressing Pax2, Wt1, Foxd1, and Eya1. Finally, MM cells were induced with platelet-derived growth factor to form polygonal-shaped MCs expressing α-smooth muscle actin, desmin, CD44, and PDGFRβ. The growing MCs showed positivity to periodic acid Schiff's, and ANAE staining with a prominent expression of the Itga8 elucidating phagocytic property of MCs. These MCs showed conspicuous expression of CD133, notch-2, and telomerase, determining the quiescence nature with a 31.2% proliferation rate revealed through Ki-67 staining. The functionality of MCs was assessed by growing MCs in 5.5 and 25 mM glucose concentrations, and noticeable expression of angiotensinogen, angiotensin-I and II, angiotensin-converting enzyme, collagen-4, fibronectin, and TGFβ1 was observed in 25 mM concentration, while lowered expression of these genes was observed in 5.5 mM concentration explaining the role of MCs in regulating the filtration pressure. All these findings demonstrate that HSCs can rejuvenate the insulted glomerulus.
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Affiliation(s)
- Surekha Kattaru
- Stem Cell Laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | | | - Sireesha Kodavala
- Stem Cell Laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Chandra Sekhar Chodimella
- Department of Hematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
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Liu YC, Eldomery MK, Maciaszek JL, Klco JM. Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications. ANNUAL REVIEW OF PATHOLOGY 2025; 20:87-114. [PMID: 39357070 PMCID: PMC12048009 DOI: 10.1146/annurev-pathmechdis-111523-023420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.
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Affiliation(s)
- Yen-Chun Liu
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Mohammad K Eldomery
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Jamie L Maciaszek
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
| | - Jeffery M Klco
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA;
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5
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Samundeshwari EL, Kattaru S, Kodavala S, Chandrasekhar C, Sarma PVGK. Differentiation ability of hematopoietic stem cells and mesenchymal stem cells isolated from human peripheral blood. Front Cell Dev Biol 2024; 12:1450543. [PMID: 39744010 PMCID: PMC11688275 DOI: 10.3389/fcell.2024.1450543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/21/2024] [Indexed: 01/04/2025] Open
Abstract
Human hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the major stem cells of the bone marrow and are usually isolated from the peripheral blood. In the present study, we isolated these stem cells by an apheresis method from a donor who was administered granulocyte colony-stimulating factor (G-CSF). In vitro propagation of these stem cells showed a plastic-adherence property expressing CD73 and CD105 surface markers, which is a characteristic feature of MSCs. HSCs are non-adherent cells growing as a suspension culture, expressing CD150, CD133, CD34, and CD45 on their surface, which regulate the quiescence nature, and they derive energy from anaerobic glycolysis. The HSCs grow slowly compared to MSCs, are more viable, and survive for long periods under in vitro conditions, which are due to the expression of telomerase, BCL2, and Notch1 genes. The poor viability of MSCs in the culture due to the prominent expression of apoptotic genes BAX, caspase-3, and caspase-9 leads to rapid apoptosis. This was evident even in cells (astrocytes, osteocytes, and beta cells of the islets of Langerhans) differentiated from HSCs and MSCs, thus highlighting the importance of HSCs, the naive stem cells, in regeneration of tissues.
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Affiliation(s)
| | - Surekha Kattaru
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Sireesha Kodavala
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Chodimella Chandrasekhar
- Department of Hematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
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Shaldam MA, Mousa MHA, Tawfik HO, El-Dessouki AM, Sharaky M, Saleh MM, Alzahrani AYA, Moussa SB, Al-Karmalawy AA. Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations. Bioorg Chem 2024; 153:107843. [PMID: 39332072 DOI: 10.1016/j.bioorg.2024.107843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 09/11/2024] [Accepted: 09/22/2024] [Indexed: 09/29/2024]
Abstract
In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful "multitarget-directed drug" for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.
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Affiliation(s)
- Moataz A Shaldam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
| | - Mai H A Mousa
- Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt.
| | - Haytham O Tawfik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Ahmed M El-Dessouki
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
| | - Marwa Sharaky
- Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
| | - Mohamed M Saleh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | | | - Sana Ben Moussa
- Department of Chemistry, Faculty of Science and Arts, King Khalid University, Mohail Assir 61421, Saudi Arabia
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Mashreq, Baghdad 10023, Iraq; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
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7
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Di Pietro E, Burla R, La Torre M, González-García MP, Dello Ioio R, Saggio I. Telomeres: an organized string linking plants and mammals. Biol Direct 2024; 19:119. [PMID: 39568075 PMCID: PMC11577926 DOI: 10.1186/s13062-024-00558-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/03/2024] [Indexed: 11/22/2024] Open
Abstract
Telomeres are pivotal determinants of cell stemness, organismal aging, and lifespan. Herein, we examined similarities in telomeres of Arabidopsis thaliana, mice, and humans. We report the common traits, which include their composition in multimers of TTAGGG sequences and their protection by specialized proteins. Moreover, given the link between telomeres, on the one hand, and cell proliferation and stemness on the other, we discuss the counterintuitive convergence between plants and mammals in this regard, focusing on the impact of niches on cell stemness. Finally, we suggest that tackling the study of telomere function and cell stemness by taking into consideration both plants and mammals can aid in the understanding of interconnections and contribute to research focusing on aging and organismal lifespan determinants.
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Affiliation(s)
- Edison Di Pietro
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
| | - Romina Burla
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
- CNR Institute of Biology and Pathology, Rome, Italy
| | - Mattia La Torre
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
| | - Mary-Paz González-García
- Centro de Biotecnología y Genómica de Plantas (Universidad Politécnica de Madrid - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria), UPM-INIA/CSIC. Campus de Montegancedo, Pozuelo de Alarcón, 28223, Madrid, Spain
- Departamento de Biotecnología-Biología Vegetal, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas, Universidad Politécnica de Madrid (UPM), Madrid, Spain
| | - Raffaele Dello Ioio
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy.
| | - Isabella Saggio
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy.
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Mohajer F, Khoradmehr A, Riazalhosseini B, Zendehboudi T, Nabipour I, Baghban N. In vitro detection of marine invertebrate stem cells: utilizing molecular and cellular biology techniques and exploring markers. Front Cell Dev Biol 2024; 12:1440091. [PMID: 39239558 PMCID: PMC11374967 DOI: 10.3389/fcell.2024.1440091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/07/2024] [Indexed: 09/07/2024] Open
Abstract
Marine invertebrate stem cells (MISCs) represent a distinct category of pluripotent and totipotent cells with remarkable abilities for self-renewal and differentiation into multiple germ layers, akin to their vertebrate counterparts. These unique cells persist throughout an organism's adult life and have been observed in various adult marine invertebrate phyla. MISCs play crucial roles in numerous biological processes, including developmental biology phenomena specific to marine invertebrates, such as senescence, delayed senescence, whole-body regeneration, and asexual reproduction. Furthermore, they serve as valuable models for studying stem cell biology. Despite their significance, information about MISCs remains scarce and scattered in the scientific literature. In this review, we have carefully collected and summarized valuable information about MISC detection by perusing the articles that study and detect MISCs in various marine invertebrate organisms. The review begins by defining MISCs and highlighting their unique features compared to vertebrates. It then discusses the common markers for MISC detection and in vitro techniques employed in invertebrate and vertebrates investigation. This comprehensive review provides researchers and scientists with a cohesive and succinct overview of MISC characteristics, detection methods, and associated biological phenomena in marine invertebrate organisms. We aim to offer a valuable resource to researchers and scientists interested in marine invertebrate stem cells, fostering a better understanding of their broader implications in biology. With ongoing advancements in scientific techniques and the continued exploration of marine invertebrate species, we anticipate that further discoveries will expand our knowledge of MISCs and their broader implications in biology.
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Affiliation(s)
- Fatemeh Mohajer
- Student Research and Technology Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Behnaz Riazalhosseini
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Tuba Zendehboudi
- Student Research and Technology Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Neda Baghban
- Food Control Laboratory, Food and Drug Deputy, Bushehr University of Medical Sciences, Bushehr, Iran
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Pardo-Cea MA, Farré X, Esteve A, Palade J, Espín R, Mateo F, Alsop E, Alorda M, Blay N, Baiges A, Shabbir A, Comellas F, Gómez A, Arnan M, Teulé A, Salinas M, Berrocal L, Brunet J, Rofes P, Lázaro C, Conesa M, Rojas JJ, Velten L, Fendler W, Smyczynska U, Chowdhury D, Zeng Y, He HH, Li R, Van Keuren-Jensen K, de Cid R, Pujana MA. Biological basis of extensive pleiotropy between blood traits and cancer risk. Genome Med 2024; 16:21. [PMID: 38308367 PMCID: PMC10837955 DOI: 10.1186/s13073-024-01294-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/22/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.
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Affiliation(s)
- Miguel Angel Pardo-Cea
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Xavier Farré
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Anna Esteve
- Badalona Applied Research Group in Oncology (B-ARGO), Catalan Institute of Oncology, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Joanna Palade
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA
| | - Roderic Espín
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Francesca Mateo
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Eric Alsop
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA
| | - Marc Alorda
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Natalia Blay
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain
| | - Alexandra Baiges
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Arzoo Shabbir
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Francesc Comellas
- Department of Mathematics, Technical University of Catalonia, Castelldefels, 08860, Barcelona, Catalonia, Spain
| | - Antonio Gómez
- Department of Biosciences, Faculty of Sciences and Technology (FCT), University of Vic - Central University of Catalonia (UVic-UCC), Vic, 08500, Barcelona, Catalonia, Spain
| | - Montserrat Arnan
- Department of Hematology, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Alex Teulé
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Monica Salinas
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Laura Berrocal
- OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Paula Rofes
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
- Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Miquel Conesa
- Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Juan Jose Rojas
- Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain
| | - Lars Velten
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003, Barcelona, Spain
- University Pompeu Fabra (UPF), 08002, Barcelona, Spain
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Urszula Smyczynska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland
| | - Dipanjan Chowdhury
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Center for BRCA and Related Genes, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Yong Zeng
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada
| | - Housheng Hansen He
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Rong Li
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20052, USA
| | - Kendall Van Keuren-Jensen
- Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA.
| | - Rafael de Cid
- Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain.
| | - Miquel Angel Pujana
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
- Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, 28222, Madrid, Spain.
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10
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Lasho T, Patnaik MM. Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders. Curr Hematol Malig Rep 2024; 19:35-44. [PMID: 38095828 DOI: 10.1007/s11899-023-00719-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2023] [Indexed: 01/30/2024]
Abstract
PURPOSE OF REVIEW Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive. RECENT FINDINGS Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis. TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.
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Affiliation(s)
- Terra Lasho
- Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA
| | - Mrinal M Patnaik
- Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
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11
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Waksal JA, Bruedigam C, Komrokji RS, Jamieson CHM, Mascarenhas JO. Telomerase-targeted therapies in myeloid malignancies. Blood Adv 2023; 7:4302-4314. [PMID: 37216228 PMCID: PMC10424149 DOI: 10.1182/bloodadvances.2023009903] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/08/2023] [Accepted: 05/14/2023] [Indexed: 05/24/2023] Open
Abstract
Human telomeres are tandem arrays that are predominantly composed of 5'-TTAGGG-3' nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres within rapidly dividing cells and is upregulated across nearly all malignant cells. Accordingly, targeting telomerase to inhibit uncontrolled cell growth has been an area of great interest for decades. In this review, we summarize telomere and telomerase biology because it relates to both physiologic and malignant cells. We discuss the development of telomere- and telomerase-targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development, with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.
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Affiliation(s)
- Julian A. Waksal
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Claudia Bruedigam
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
- School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | | | | | - John O. Mascarenhas
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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12
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Ding W, Xu W, Lu D, Sheng H, Xu X, Xu B, Zheng A. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis. Open Med (Wars) 2023; 18:20220619. [PMID: 36742154 PMCID: PMC9883688 DOI: 10.1515/med-2022-0619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 01/25/2023] Open
Abstract
This study investigated the function of telomerase RNA component (TERC) in spinal cord injury (SCI). SCI models were established in rats via laminectomy and PC-12 cells were treated with lipopolysaccharide (LPS). TERC and miR-34a-5p expressions in cells and rat spinal cords were detected by quantitative reverse transcription polymerase chain reaction, followed by overexpression/knockdown of TERC/miR-34a-5p. Spinal cord histopathological changes were examined via hematoxylin-eosin staining. miR-34a-5p' relation with TERC and XBP-1 was predicted by TargetScan and checked by dual-luciferase reporter/RNA immunoprecipitation assays. Cell biological behaviors were assessed by Cell counting kit-8, wound healing, Transwell, and flow cytometry assays. XBP-1 and inflammation/apoptosis-related protein expressions were analyzed by western blot. TERC was upregulated and miR-34a-5p was low-expressed in SCI tissues and LPS-induced PC-12 cells. TERC-knockdown alleviated histopathological abnormalities yet upregulated miR-34a-5p in SCI tissues. In LPS-induced PC-12 cells, TERC knockdown promoted cell viability, migration, invasion, and inhibited apoptosis, while TERC overexpression ran oppositely. TERC knockdown downregulated the XBP-1, IL-6, TNF-α, Bax, p-p38/t-p38, and cleaved caspase-9/-3, but upregulated Bcl-2 and p-Akt/t-Akt. TERC targeted miR-34a-5p, which further targeted XBP-1. miR-34a-5p downregulation exerted effects opposite to and offset TERC knockdown-induced effects. TERC knockdown facilitated the regeneration of neuron tissues yet inhibited inflammation in SCI through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis.
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Affiliation(s)
- Weiguo Ding
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Weixing Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Di Lu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Hongfeng Sheng
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Xinwei Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Bin Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Aote Zheng
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
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13
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Sonoda S, Yamaza T. Extracellular vesicles rejuvenate the microenvironmental modulating function of recipient tissue-specific mesenchymal stem cells in osteopenia treatment. Front Endocrinol (Lausanne) 2023; 14:1151429. [PMID: 37033255 PMCID: PMC10073676 DOI: 10.3389/fendo.2023.1151429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Systemic transplantation of mesenchymal stem cells (MSCs), such as bone marrow MSCs (BMMSCs) and stem cells from human exfoliated deciduous teeth (SHED), is considered a prominent treatment for osteopenia. However, the mechanism of action of the transplanted MSCs has been poorly elucidated. In the recipient target tissue, including bone and bone marrow, only a few donor MSCs can be detected, suggesting that the direct contribution of donor MSCs may not be expected for osteopenia treatment. Meanwhile, secretomes, especially contents within extracellular vesicles (EVs) released from donor MSCs (MSC-EVs), play key roles in the treatment of several diseases. In this context, administrated donor MSC-EVs may affect bone-forming function of recipient cells. In this review, we discuss how MSC-EVs contribute to bone recovery recipient tissue in osteopenia. We also summarize a novel mechanism of action of systemic administration of SHED-derived EVs (SHED-EVs) in osteopenia. We found that reduced telomerase activity in recipient BMMSCs caused the deficiency of microenvironmental modulating function, including bone and bone marrow-like niche formation and immunomodulation in estrogen-deficient osteopenia model mice. Systemic administration of SHED-EVs could exert therapeutic effects on bone reduction via recovering the telomerase activity, leading to the rejuvenation of the microenvironmental modulating function in recipient BMMSCs, as seen in systemic transplantation of SHED. RNase-preconditioned donor SHED-EVs diminished the therapeutic benefits of administrated SHED-EVs in the recipient osteopenia model mice. These facts suggest that MSC-EV therapy targets the recipient BMMSCs to rejuvenate the microenvironmental modulating function via telomerase activity, recovering bone density. We then introduce future challenges to develop the reproducible MSC-EV therapy in osteopenia.
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14
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Udroiu I, Marinaccio J, Sgura A. Many Functions of Telomerase Components: Certainties, Doubts, and Inconsistencies. Int J Mol Sci 2022; 23:ijms232315189. [PMID: 36499514 PMCID: PMC9736166 DOI: 10.3390/ijms232315189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
A growing number of studies have evidenced non-telomeric functions of "telomerase". Almost all of them, however, investigated the non-canonical effects of the catalytic subunit TERT, and not the telomerase ribonucleoprotein holoenzyme. These functions mainly comprise signal transduction, gene regulation and the increase of anti-oxidative systems. Although less studied, TERC (the RNA component of telomerase) has also been shown to be involved in gene regulation, as well as other functions. All this has led to the publication of many reviews on the subject, which, however, are often disseminating personal interpretations of experimental studies of other researchers as original proofs. Indeed, while some functions such as gene regulation seem ascertained, especially because mechanistic findings have been provided, other ones remain dubious and/or are contradicted by other direct or indirect evidence (e.g., telomerase activity at double-strand break site, RNA polymerase activity of TERT, translation of TERC, mitochondrion-processed TERC). In a critical study of the primary evidence so far obtained, we show those functions for which there is consensus, those showing contradictory results and those needing confirmation. The resulting picture, together with some usually neglected aspects, seems to indicate a link between TERT and TERC functions and cellular stemness and gives possible directions for future research.
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15
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Brown TJ, Spurgin LG, Dugdale HL, Komdeur J, Burke T, Richardson DS. Causes and consequences of telomere lengthening in a wild vertebrate population. Mol Ecol 2022; 31:5933-5945. [PMID: 34219315 DOI: 10.1111/mec.16059] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/24/2021] [Accepted: 06/21/2021] [Indexed: 01/31/2023]
Abstract
Telomeres have been advocated to be important markers of biological age in evolutionary and ecological studies. Telomeres usually shorten with age and shortening is frequently associated with environmental stressors and increased subsequent mortality. Telomere lengthening - an apparent increase in telomere length between repeated samples from the same individual - also occurs. However, the exact circumstances, and consequences, of telomere lengthening are poorly understood. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we tested whether telomere lengthening - which occurs in adults of this species - is associated with specific stressors (reproductive effort, food availability, malarial infection and cooperative breeding) and predicts subsequent survival. In females, telomere shortening was observed under greater stress (i.e., low food availability, malaria infection), while telomere lengthening was observed in females experiencing lower stress (i.e., high food availability, assisted by helpers, without malaria). The telomere dynamics of males were not associated with the key stressors tested. These results indicate that, at least for females, telomere lengthening occurs in circumstances more conducive to self-maintenance. Importantly, both females and males with lengthened telomeres had improved subsequent survival relative to individuals that displayed unchanged, or shortened, telomeres - indicating that telomere lengthening is associated with individual fitness. These results demonstrate that telomere dynamics are bidirectionally responsive to the level of stress that an individual faces, but may poorly reflect the accumulation of stress over an individuals lifetime.
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Affiliation(s)
- Thomas J Brown
- School of Biological Sciences, University of East Anglia, Norwich, UK
| | - Lewis G Spurgin
- School of Biological Sciences, University of East Anglia, Norwich, UK
| | - Hannah L Dugdale
- Behavioural and Physiological Ecology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Jan Komdeur
- Behavioural and Physiological Ecology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Terry Burke
- Department of Animal and Plant Sciences, University of Sheffield, Sheffield, UK
| | - David S Richardson
- School of Biological Sciences, University of East Anglia, Norwich, UK.,Nature Seychelles, Victoria, Mahé, Seychelles
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16
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Smith S, Hoelzl F, Zahn S, Criscuolo F. Telomerase activity in ecological studies: What are its consequences for individual physiology and is there evidence for effects and trade-offs in wild populations. Mol Ecol 2022; 31:6239-6251. [PMID: 34664335 PMCID: PMC9788021 DOI: 10.1111/mec.16233] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/10/2021] [Accepted: 09/24/2021] [Indexed: 02/02/2023]
Abstract
Increasing evidence at the cellular level is helping to provide proximate explanations for the balance between investment in growth, reproduction and somatic maintenance in wild populations. Studies of telomere dynamics have informed researchers about the loss and gain of telomere length both on a seasonal scale and across the lifespan of individuals. In addition, telomere length and telomere rate of loss seems to have evolved differently among taxonomic groups, and relate differently to organismal diversity of lifespan. So far, the mechanisms behind telomere maintenance remain elusive, although many studies have inferred a role for telomerase, an enzyme/RNA complex known to induce telomere elongation from laboratory studies. Exciting further work is also emerging that suggests telomerase (and/or its individual component parts) has a role in fitness that goes beyond the maintenance of telomere length. Here, we review the literature on telomerase biology and examine the evidence from ecological studies for the timing and extent of telomerase activation in relation to life history events associated with telomere maintenance. We suggest that the underlying mechanism is more complicated than originally anticipated, possibly involves several complimentary pathways, and is probably associated with high energetic costs. Potential pathways for future research are numerous and we outline what we see as the most promising prospects to expand our understanding of individual differences in immunity or reproduction efficiency.
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Affiliation(s)
- Steve Smith
- Konrad Lorenz Institute of EthologyUniversity of Veterinary Medicine, ViennaViennaAustria
| | - Franz Hoelzl
- Konrad Lorenz Institute of EthologyUniversity of Veterinary Medicine, ViennaViennaAustria
| | - Sandrine Zahn
- Department of Physiology, Evolution and BehaviourInstitut Pluridisciplinaire Hubert CurienCNRSUniversity of StrasbourgStrasbourgFrance
| | - François Criscuolo
- Department of Physiology, Evolution and BehaviourInstitut Pluridisciplinaire Hubert CurienCNRSUniversity of StrasbourgStrasbourgFrance
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17
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Afshari N, Al-Gazally ME, Rasulova I, Jalil AT, Matinfar S, Momeninejad M. Sensitive bioanalytical methods for telomerase activity detection: a cancer biomarker. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2022; 14:4174-4184. [PMID: 36254582 DOI: 10.1039/d2ay01315k] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Telomerase is an enzyme that protects the length of telomeres by adding guanine-rich repetitive sequences. In tumors, gametes, and stem cells, telomerase activity is exerted. Telomerase activity can be a cancer biomarker for therapeutic and diagnosis approaches. So, a number of studies concentrating on the discovery of telomerase activity were reported. Bioanalytical devices, in comparison with other tests, have numerous advantages including low expense, simplicity, and excellent sensitivity and specificity. In this article we reviewed recent studies on the subject of various bioanalytical methods based on different nanomaterials. Optical, electrochemical, and quartz crystal microbalance (QCM) are prominent analytical techniques that are mentioned in this paper.
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Affiliation(s)
- Nasim Afshari
- Department of Microbiology, Islamic Azad University Science & Research Branch, Tehran, Iran
| | | | - Iroda Rasulova
- "Kasmed" Private Medical Centre, Tashkent, Uzbekistan
- School of Medicine, Akfa University, Tashkent, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Solmaz Matinfar
- Department of Microbiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohsen Momeninejad
- Department of Social Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
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18
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Kotasová H, Capandová M, Pelková V, Dumková J, Koledová Z, Remšík J, Souček K, Garlíková Z, Sedláková V, Rabata A, Vaňhara P, Moráň L, Pečinka L, Porokh V, Kučírek M, Streit L, Havel J, Hampl A. Expandable Lung Epithelium Differentiated from Human Embryonic Stem Cells. Tissue Eng Regen Med 2022; 19:1033-1050. [PMID: 35670910 PMCID: PMC9478014 DOI: 10.1007/s13770-022-00458-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/09/2022] [Accepted: 04/08/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The progenitors to lung airway epithelium that are capable of long-term propagation may represent an attractive source of cells for cell-based therapies, disease modeling, toxicity testing, and others. Principally, there are two main options for obtaining lung epithelial progenitors: (i) direct isolation of endogenous progenitors from human lungs and (ii) in vitro differentiation from some other cell type. The prime candidates for the second approach are pluripotent stem cells, which may provide autologous and/or allogeneic cell resource in clinically relevant quality and quantity. METHODS By exploiting the differentiation potential of human embryonic stem cells (hESC), here we derived expandable lung epithelium (ELEP) and established culture conditions for their long-term propagation (more than 6 months) in a monolayer culture without a need of 3D culture conditions and/or cell sorting steps, which minimizes potential variability of the outcome. RESULTS These hESC-derived ELEP express NK2 Homeobox 1 (NKX2.1), a marker of early lung epithelial lineage, display properties of cells in early stages of surfactant production and are able to differentiate to cells exhibitting molecular and morphological characteristics of both respiratory epithelium of airway and alveolar regions. CONCLUSION Expandable lung epithelium thus offer a stable, convenient, easily scalable and high-yielding cell source for applications in biomedicine.
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Affiliation(s)
- Hana Kotasová
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Michaela Capandová
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Vendula Pelková
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Jana Dumková
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Zuzana Koledová
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Ján Remšík
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Current Address: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Karel Souček
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Zuzana Garlíková
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Veronika Sedláková
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Anas Rabata
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Petr Vaňhara
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Lukáš Moráň
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
- Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Lukáš Pečinka
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Volodymyr Porokh
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Martin Kučírek
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic
| | - Libor Streit
- Department of Plastic and Cosmetic Surgery, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Plastic and Cosmetic Surgery, St. Anne's Faculty Hospital, Brno, Czech Republic
| | - Josef Havel
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
- Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Aleš Hampl
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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19
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Brown DW, Zhou W, Wang Y, Jones K, Luo W, Dagnall C, Teshome K, Klein A, Zhang T, Lin SH, Lee OW, Khan S, Vo JB, Hutchinson A, Liu J, Wang J, Zhu B, Hicks B, Martin AS, Spellman SR, Wang T, Deeg HJ, Gupta V, Lee SJ, Freedman ND, Yeager M, Chanock SJ, Savage SA, Saber W, Gadalla SM, Machiela MJ. Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis. Nat Commun 2022; 13:5284. [PMID: 36075929 PMCID: PMC9458655 DOI: 10.1038/s41467-022-32986-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 08/25/2022] [Indexed: 12/13/2022] Open
Abstract
Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.
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Affiliation(s)
- Derek W Brown
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
| | - Weiyin Zhou
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Youjin Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Kristine Jones
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Wen Luo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Casey Dagnall
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Kedest Teshome
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Alyssa Klein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Shu-Hong Lin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Olivia W Lee
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Sairah Khan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Jacqueline B Vo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA
| | - Amy Hutchinson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Jia Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Jiahui Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Bin Zhu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Belynda Hicks
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Andrew St Martin
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN, USA
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - H Joachim Deeg
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Vikas Gupta
- MPN Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Neal D Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Meredith Yeager
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Sharon A Savage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Wael Saber
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Shahinaz M Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Mitchell J Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
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20
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Yi L, Yang L. Stem-like T cells and niches: Implications in human health and disease. Front Immunol 2022; 13:907172. [PMID: 36059484 PMCID: PMC9428355 DOI: 10.3389/fimmu.2022.907172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Recently, accumulating evidence has elucidated the important role of T cells with stem-like characteristics in long-term maintenance of T cell responses and better patient outcomes after immunotherapy. The fate of TSL cells has been correlated with many physiological and pathological human processes. In this review, we described present advances demonstrating that stem-like T (TSL) cells are central players in human health and disease. We interpreted the evolutionary characteristics, mechanism and functions of TSL cells. Moreover, we discuss the import role of distinct niches and how they affect the stemness of TSL cells. Furthermore, we also outlined currently available strategies to generate TSL cells and associated affecting factors. Moreover, we summarized implication of TSL cells in therapies in two areas: stemness enhancement for vaccines, ICB, and adoptive T cell therapies, and stemness disruption for autoimmune disorders.
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21
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Lázničková P, Bendíčková K, Kepák T, Frič J. Immunosenescence in Childhood Cancer Survivors and in Elderly: A Comparison and Implication for Risk Stratification. FRONTIERS IN AGING 2022; 2:708788. [PMID: 35822014 PMCID: PMC9261368 DOI: 10.3389/fragi.2021.708788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/05/2021] [Indexed: 12/14/2022]
Abstract
The population of childhood cancer survivors (CCS) has grown rapidly in recent decades. Although cured of their original malignancy, these individuals are at increased risk of serious late effects, including age-associated complications. An impaired immune system has been linked to the emergence of these conditions in the elderly and CCS, likely due to senescent immune cell phenotypes accompanied by low-grade inflammation, which in the elderly is known as "inflammaging." Whether these observations in the elderly and CCS are underpinned by similar mechanisms is unclear. If so, existing knowledge on immunosenescent phenotypes and inflammaging might potentially serve to benefit CCS. We summarize recent findings on the immune changes in CCS and the elderly, and highlight the similarities and identify areas for future research. Improving our understanding of the underlying mechanisms and immunosenescent markers of accelerated immune aging might help us to identify individuals at increased risk of serious health complications.
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Affiliation(s)
- Petra Lázničková
- International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Kamila Bendíčková
- International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Tomáš Kepák
- International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.,Department of Pediatric Oncology, University Hospital Brno, Brno, Czech Republic
| | - Jan Frič
- International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.,Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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22
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Yang C, Pang Y, Huang Y, Ye F, Chen X, Gao Y, Zhang C, Yao L, Gao J. Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow. GeroScience 2022; 44:2139-2155. [PMID: 35545739 DOI: 10.1007/s11357-022-00578-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/22/2022] [Indexed: 11/29/2022] Open
Abstract
Aging is a progressive loss of physiological function and increased susceptibility to major pathologies. Degenerative diseases in both brain and bone including Alzheimer disease (AD) and osteoporosis are common in aging groups. TERC is RNA component of telomerase, and its deficiency accelerates aging-related phenotypes including impaired life span, organ failure, bone loss, and brain dysfunction. In this study, we investigated the traits of bone marrow-brain cross-tissue communications in young mice, natural aging mice, and premature aging (TERC deficient, TERC-KO) mice by single-cell transcriptome sequencing. Differentially expressed gene analysis of brain as well as bone marrow between premature aging mouse and young mouse demonstrated aging-related inflammatory response and suppression of neuron development. Further analysis of senescence-associated secretory phenotype (SASP) landscape indicated that TERC-KO perturbation was enriched in oligodendrocyte progenitor cells (OPCs) and hematopoietic stem and progenitor cells (HSPC). Series of inflammatory associated myeloid cells was activated in premature aging mice brain and bone marrow. Cross-tissue comparison of TERC-KO mice brain and bone marrow illustrated obvious ligand-receptor communications between brain glia cells, macrophages, and bone marrow myeloid cells in premature aging-induced inflammation. Enrichment of co-regulation modules between brain and bone marrow identified premature aging response genes such as Dusp1 and Ifitm3. Our study provides a rich resource for understanding premature aging-associated perturbation in brain and bone marrow and supporting myeloid cells and endothelial cells as promising therapy targeting for age-related brain-bone diseases.
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Affiliation(s)
- Chunying Yang
- Department of Neurology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yigang Huang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Fang Ye
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xiaoyi Chen
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315000, Zhejiang, China
| | - Youshui Gao
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Lufeng Yao
- Department of Orthopaedic Surgery, Ningbo No. 6 Hospital, Ningbo, 315040, Zhejiang, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. .,Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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23
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Vaidyanathan S, Baik R, Chen L, Bravo DT, Suarez CJ, Abazari SM, Salahudeen AA, Dudek AM, Teran CA, Davis TH, Lee CM, Bao G, Randell SH, Artandi SE, Wine JJ, Kuo CJ, Desai TJ, Nayak JV, Sellers ZM, Porteus MH. Targeted replacement of full-length CFTR in human airway stem cells by CRISPR-Cas9 for pan-mutation correction in the endogenous locus. Mol Ther 2022; 30:223-237. [PMID: 33794364 PMCID: PMC8753290 DOI: 10.1016/j.ymthe.2021.03.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/23/2021] [Accepted: 03/25/2021] [Indexed: 01/07/2023] Open
Abstract
Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the CF transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR-Cas9 and two adeno-associated viruses (AAVs) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial epithelial cells (HBECs). The modified cells were enriched to obtain 60%-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.
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Affiliation(s)
| | - Ron Baik
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Lu Chen
- Department of Internal Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dawn T Bravo
- Department of Otolaryngology-Head and Neck Surgery, Stanford, CA 94305, USA
| | - Carlos J Suarez
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Shayda M Abazari
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Ameen A Salahudeen
- Department of Internal Medicine, Stanford University, Stanford, CA 94305, USA
| | - Amanda M Dudek
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | | | - Timothy H Davis
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Ciaran M Lee
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Gang Bao
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Scott H Randell
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Steven E Artandi
- Department of Internal Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jeffrey J Wine
- Department of Psychology, Stanford University, Stanford, CA 94305, USA
| | - Calvin J Kuo
- Department of Internal Medicine, Stanford University, Stanford, CA 94305, USA
| | - Tushar J Desai
- Department of Internal Medicine, Stanford University, Stanford, CA 94305, USA
| | - Jayakar V Nayak
- Department of Otolaryngology-Head and Neck Surgery, Stanford, CA 94305, USA
| | - Zachary M Sellers
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Matthew H Porteus
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
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24
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Harada M, Hu B, Lu J, Wang J, Rinke AE, Wu Z, Liu T, Phan SH. The dual distinct role of telomerase in repression of senescence and myofibroblast differentiation. Aging (Albany NY) 2021; 13:16957-16973. [PMID: 34253690 PMCID: PMC8312426 DOI: 10.18632/aging.203246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/04/2021] [Indexed: 12/13/2022]
Abstract
Many aging related diseases such as cancer implicate the myofibroblast in disease progression. Furthermore genesis of the myofibroblast is associated with manifestation of cellular senescence of unclear significance. In this study we investigated the role of a common regulator, namely telomerase reverse transcriptase (TERT), in order to evaluate the potential significance of this association between both processes. We analyzed the effects of TERT overexpression or deficiency on expression of CDKN2A and ACTA2 as indicators of senescence and differentiation, respectively. We assess binding of TERT or YB-1, a repressor of both genes, to their promoters. TERT repressed both CDKN2A and ACTA2 expression, and abolished stress-induced expression of both genes. Conversely, TERT deficiency enhanced their expression. Altering CDKN2A expression had no effect on ACTA2 expression. Both TERT and YB-1 were shown to bind the CDKN2A promoter but only YB-1 was shown to bind the ACTA2 promoter. TERT overexpression inhibited CDKN2A promoter activity while stimulating YB-1 expression and activation to repress ACTA2 gene. TERT repressed myofibroblast differentiation and senescence via distinct mechanisms. The latter was associated with TERT binding to the CDKN2A promoter, but not to the ACTA2 promoter, which may require interaction with co-factors such as YB-1.
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Affiliation(s)
- Masanori Harada
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,Department of Respiratory Medicine, Fujieda Municipal General Hospital, Fujieda, Japan
| | - Biao Hu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jeffrey Lu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jing Wang
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.,Xinjiang Key Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China
| | - Andrew E Rinke
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Zhe Wu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Tianju Liu
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sem H Phan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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25
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Udroiu I, Sgura A. Growing and aging of hematopoietic stem cells. World J Stem Cells 2021; 13:594-604. [PMID: 34249229 PMCID: PMC8246248 DOI: 10.4252/wjsc.v13.i6.594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/22/2020] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
In the hematopoietic system, a small number of stem cells produce a progeny of several distinct lineages. During ontogeny, they arise in the aorta-gonad-mesonephros region of the embryo and the placenta, afterwards colonise the liver and finally the bone marrow. After this fetal phase of rapid expansion, the number of hematopoietic stem cells continues to grow, in order to sustain the increasing blood volume of the developing newborn, and eventually reaches a steady-state. The kinetics of this growth are mirrored by the rates of telomere shortening in leukocytes. During adulthood, hematopoietic stem cells undergo a very small number of cell divisions. Nonetheless, they are subjected to aging, eventually reducing their potential to produce differentiated progeny. The causal relationships between telomere shortening, DNA damage, epigenetic changes, and aging have still to be elucidated.
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Affiliation(s)
- Ion Udroiu
- Department of Science, Roma Tre University, Rome 00146, Italy
| | - Antonella Sgura
- Department of Science, Roma Tre University, Rome 00146, Italy
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26
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Jacczak B, Rubiś B, Totoń E. Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. Int J Mol Sci 2021; 22:6381. [PMID: 34203694 PMCID: PMC8232155 DOI: 10.3390/ijms22126381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/26/2021] [Accepted: 06/07/2021] [Indexed: 12/14/2022] Open
Abstract
Proper functioning of cells-their ability to divide, differentiate, and regenerate-is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.
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Affiliation(s)
| | | | - Ewa Totoń
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 49 Przybyszewskiego St., 60-355 Poznań, Poland; (B.J.); (B.R.)
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27
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Bao EL, Nandakumar SK, Liao X, Bick AG, Karjalainen J, Tabaka M, Gan OI, Havulinna AS, Kiiskinen TTJ, Lareau CA, de Lapuente Portilla AL, Li B, Emdin C, Codd V, Nelson CP, Walker CJ, Churchhouse C, de la Chapelle A, Klein DE, Nilsson B, Wilson PWF, Cho K, Pyarajan S, Gaziano JM, Samani NJ, Regev A, Palotie A, Neale BM, Dick JE, Natarajan P, O'Donnell CJ, Daly MJ, Milyavsky M, Kathiresan S, Sankaran VG. Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells. Nature 2020; 586:769-775. [PMID: 33057200 PMCID: PMC7606745 DOI: 10.1038/s41586-020-2786-7] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 07/03/2020] [Indexed: 12/17/2022]
Abstract
Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10-8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
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Affiliation(s)
- Erik L Bao
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Satish K Nandakumar
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Xiaotian Liao
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Alexander G Bick
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- VA Boston Healthcare, Section of Cardiology, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Juha Karjalainen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Marcin Tabaka
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Olga I Gan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Aki S Havulinna
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Tuomo T J Kiiskinen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Caleb A Lareau
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
| | | | - Bo Li
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
| | - Connor Emdin
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Veryan Codd
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Centre, Glenfield Hospital, Leicester, UK
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Centre, Glenfield Hospital, Leicester, UK
| | - Christopher J Walker
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Albert de la Chapelle
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Daryl E Klein
- Department of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT, USA
| | - Björn Nilsson
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Peter W F Wilson
- Atlanta VA Medical Center, Atlanta, GA, USA
- Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA
| | - Kelly Cho
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Saiju Pyarajan
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
| | - J Michael Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Centre, Glenfield Hospital, Leicester, UK
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
- Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Aarno Palotie
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | | | - John E Dick
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Pradeep Natarajan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Christopher J O'Donnell
- VA Boston Healthcare, Section of Cardiology, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Mark J Daly
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Michael Milyavsky
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sekar Kathiresan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Verve Therapeutics, Cambridge, MA, USA
| | - Vijay G Sankaran
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
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28
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Abstract
We report a systematic unbiased analysis of small RNA molecule expression in 11 different tissues of the model organism mouse. We discovered uncharacterized noncoding RNA molecules and identified that ∼30% of total noncoding small RNA transcriptome are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. Distinct distribution patterns of small RNA across the body suggest the existence of tissue-specific mechanisms involved in noncoding RNA processing. Small noncoding RNAs (ncRNAs) play a vital role in a broad range of biological processes both in health and disease. A comprehensive quantitative reference of small ncRNA expression would significantly advance our understanding of ncRNA roles in shaping tissue functions. Here, we systematically profiled the levels of five ncRNA classes (microRNA [miRNA], small nucleolar RNA [snoRNA], small nuclear RNA [snRNA], small Cajal body-specific RNA [scaRNA], and transfer RNA [tRNA] fragments) across 11 mouse tissues by deep sequencing. Using 14 biological replicates spanning both sexes, we identified that ∼30% of small ncRNAs are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. We found that some miRNAs are subject to “arm switching” between healthy tissues and that tRNA fragments are retained within tissues in both a gene- and a tissue-specific manner. Out of 11 profiled tissues, we confirmed that brain contains the largest number of unique small ncRNA transcripts, some of which were previously annotated while others are identified in this study. Furthermore, by combining these findings with single-cell chromatin accessibility (scATAC-seq) data, we were able to connect identified brain-specific ncRNAs with their cell types of origin. These results yield the most comprehensive characterization of specific and ubiquitous small RNAs in individual murine tissues to date, and we expect that these data will be a resource for the further identification of ncRNAs involved in tissue function in health and dysfunction in disease.
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29
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Guterres AN, Villanueva J. Targeting telomerase for cancer therapy. Oncogene 2020; 39:5811-5824. [PMID: 32733068 PMCID: PMC7678952 DOI: 10.1038/s41388-020-01405-w] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 07/02/2020] [Accepted: 07/23/2020] [Indexed: 12/20/2022]
Abstract
Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. In contrast, telomerase activity is silenced in most adult somatic cells. Thus, telomerase represents an attractive target for highly selective cancer therapeutics. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase.
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Affiliation(s)
- Adam N Guterres
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
| | - Jessie Villanueva
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
- Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
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30
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Abstract
PURPOSE OF REVIEW Protein homeostasis (proteostasis) is maintained by an integrated network of physiological mechanisms and stress response pathways that regulate the content and quality of the proteome. Maintenance of cellular proteostasis is key to ensuring normal development, resistance to environmental stress, coping with infection, and promoting healthy aging and lifespan. Recent studies have revealed that several proteostasis mechanisms can function in a cell-type-specific manner within hematopoietic stem cells (HSCs). Here, we review recent studies demonstrating that the proteostasis network functions uniquely in HSCs to promote their maintenance and regenerative function. RECENT FINDINGS The proteostasis network is regulated differently in HSCs as compared with restricted hematopoietic progenitors. Disruptions in proteostasis are particularly detrimental to HSC maintenance and function. These findings suggest that multiple aspects of cellular physiology are uniquely regulated in HSCs to maintain proteostasis, and that precise control of proteostasis is particularly important to support life-long HSC maintenance and regenerative function. SUMMARY The proteostasis network is uniquely configured within HSCs to promote their longevity and hematopoietic function. Future work uncovering cell-type-specific differences in proteostasis network configuration, integration, and function will be essential for understanding how HSCs function during homeostasis, in response to stress, and in disease.
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Affiliation(s)
- Bernadette A Chua
- Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center, University of California San Diego, La Jolla, California, USA
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31
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Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol 2020; 21:384-397. [PMID: 32242127 PMCID: PMC7377944 DOI: 10.1038/s41580-020-0234-z] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2020] [Indexed: 12/14/2022]
Abstract
Telomerase is a ribonucleoprotein complex, the catalytic core of which includes the telomerase reverse transcriptase (TERT) and the non-coding human telomerase RNA (hTR), which serves as a template for the addition of telomeric repeats to chromosome ends. Telomerase expression is restricted in humans to certain cell types, and telomerase levels are tightly controlled in normal conditions. Increased levels of telomerase are found in the vast majority of human cancers, and we have recently begun to understand the mechanisms by which cancer cells increase telomerase activity. Conversely, germline mutations in telomerase-relevant genes that decrease telomerase function cause a range of genetic disorders, including dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure. In this Review, we discuss the transcriptional regulation of human TERT, hTR processing, assembly of the telomerase complex, the cellular localization of telomerase and its recruitment to telomeres, and the regulation of telomerase activity. We also discuss the disease relevance of each of these steps of telomerase biogenesis.
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Affiliation(s)
- Caitlin M Roake
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA
| | - Steven E Artandi
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
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Hidaka D, Onozawa M, Miyashita N, Yokoyama S, Nakagawa M, Hashimoto D, Teshima T. Short-term treatment with imetelstat sensitizes hematopoietic malignant cells to a genotoxic agent via suppression of the telomerase-mediated DNA repair process. Leuk Lymphoma 2020; 61:2722-2732. [PMID: 32571117 DOI: 10.1080/10428194.2020.1779256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Imetelstat is a specific and competitive inhibitor of telomerase enzymatic activity. We demonstrated that imetelstat could interfere with the DNA repair process and enhance the effect of DNA damaging agents using hematological tumor cell lines. Short-term administration of imetelstat enhanced growth suppression by anticancer agents and radiation. It also upregulated γH2AX expression induced by irradiation. Immunofluorescence staining showed that both human telomerase reverse transcriptase (hTERT) and γH2AX were upregulated and co-localized in the nucleus of peripheral blood mononuclear cells after irradiation, suggesting that hTERT was involved in the DNA-DSB repair process. Imetelstat enhanced growth inhibitory effect of cytotoxic agents in short-term culture without shortening of telomeres, indicating that this effect was attributed by telomere length independent mechanism. Our results suggest that the combination of short-term treatment with imetelstat and cytotoxic agent is a promising strategy to treat a wide variety of hematopoietic malignancies.
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Affiliation(s)
- Daisuke Hidaka
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Masahiro Onozawa
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Naohiro Miyashita
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Shota Yokoyama
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Masao Nakagawa
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Daigo Hashimoto
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan
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33
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Human Telomerase RNA: Telomerase Component or More? Biomolecules 2020; 10:biom10060873. [PMID: 32517215 PMCID: PMC7355840 DOI: 10.3390/biom10060873] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 12/16/2022] Open
Abstract
Telomerase is a ribonucleoprotein complex that maintains the lengths of telomeres. Most studies of telomerase function have focused on the involvement of telomerase activation in the immortalization of cancer cells and cellular rejuvenation. However, some studies demonstrated that the results do not meet expectations for telomerase action in telomere maintenance. Recent results give reason to think that major telomerase components-the reverse transcriptase protein subunit and telomerase RNA-may participate in many cellular processes, including the regulation of apoptosis and autophagy, cell survival, pro-proliferative effects, regulation of gene expression, and protection against oxidative stress. However, the difficulties faced by scientist when researching telomerase component functions often reduce confidence in the minor effects observed in experiments. In this review, we focus on the analysis of the functions of telomerase components (paying more attention to the telomerase RNA component), both as a complex and as independent components, providing effects that are not associated with telomerase activity and telomere length maintenance. Despite the fact that the data on alternative roles of telomerase components look illusory, it would be wrong to completely reject the possibility of their involvement in other biological processes excluded from research/discussion. Investigations to improve the understanding of every aspect of the functioning of telomerase components will provide the basis for a more precise development of approaches to regulate cellular homeostasis, which is important for carcinogenesis and aging.
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Liu H, Yang Y, Ge Y, Liu J, Zhao Y. TERC promotes cellular inflammatory response independent of telomerase. Nucleic Acids Res 2019; 47:8084-8095. [PMID: 31294790 PMCID: PMC6735767 DOI: 10.1093/nar/gkz584] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/09/2019] [Accepted: 07/05/2019] [Indexed: 12/19/2022] Open
Abstract
TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don't have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-κB pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified 'binding motif' of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-κB pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA-DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.
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Affiliation(s)
- Haiying Liu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Yiding Yang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Yuanlong Ge
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Juanhong Liu
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yong Zhao
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
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35
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Günes C, Wezel F, Southgate J, Bolenz C. Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis. Nat Rev Urol 2019; 15:386-393. [PMID: 29599449 DOI: 10.1038/s41585-018-0001-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Telomerase activity imparts eukaryotic cells with unlimited proliferation capacity, one of the cancer hallmarks. Over 90% of human urothelial carcinoma of the bladder (UCB) tumours are positive for telomerase activity. Telomerase activation can occur through several mechanisms. Mutations in the core promoter region of the human telomerase reverse transcriptase gene (TERT) cause telomerase reactivation in 60-80% of UCBs, whereas the prevalence of these mutations is lower in urothelial cancers of other origins. TERT promoter mutations are the most frequent genetic alteration across all stages of UCB, indicating a strong selection pressure during neoplastic transformation. TERT promoter mutations could arise during regeneration of normal urothelium and, owing to consequential telomerase reactivation, might be the basis of UCB initiation, which represents a new model of urothelial cancer origination. In the future, TERT promoter mutations and telomerase activity might have diagnostic and therapeutic applications in UCB.
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Affiliation(s)
- Cagatay Günes
- Department of Urology, University of Ulm, Ulm, Germany.
| | - Felix Wezel
- Department of Urology, University of Ulm, Ulm, Germany
| | - Jennifer Southgate
- Department of Biology, Jack Birch Unit of Molecular Carcinogenesis, University of York, York, UK
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36
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Amon S, Meier-Abt F, Gillet LC, Dimitrieva S, Theocharides APA, Manz MG, Aebersold R. Sensitive Quantitative Proteomics of Human Hematopoietic Stem and Progenitor Cells by Data-independent Acquisition Mass Spectrometry. Mol Cell Proteomics 2019; 18:1454-1467. [PMID: 30975897 PMCID: PMC6601215 DOI: 10.1074/mcp.tir119.001431] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/08/2019] [Indexed: 12/14/2022] Open
Abstract
Physiological processes in multicellular organisms depend on the function and interactions of specialized cell types operating in context. Some of these cell types are rare and thus obtainable only in minute quantities. For example, tissue-specific stem and progenitor cells are numerically scarce, but functionally highly relevant, and fulfill critical roles in development, tissue maintenance, and disease. Whereas low numbers of cells are routinely analyzed by genomics and transcriptomics, corresponding proteomic analyses have so far not been possible due to methodological limitations. Here we describe a sensitive and robust quantitative technique based on data-independent acquisition mass spectrometry. We quantified the proteome of sets of 25,000 human hematopoietic stem/multipotent progenitor cells (HSC/MPP) and three committed progenitor cell subpopulations of the myeloid differentiation pathway (common myeloid progenitors, megakaryocyte-erythrocyte progenitors, and granulocyte-macrophage progenitors), isolated by fluorescence-activated cell sorting from five healthy donors. On average, 5,851 protein groups were identified per sample. A subset of 4,131 stringently filtered protein groups was quantitatively compared across the 20 samples, defining unique signatures for each subpopulation. A comparison of proteomic and transcriptomic profiles indicated HSC/MPP-specific divergent regulation of biochemical functions such as telomerase maintenance and quiescence-inducing enzymes, including isocitrate dehydrogenases. These are essential for maintaining stemness and were detected at proteome, but not transcriptome, level. The method is equally applicable to almost any rare cell type, including healthy and cancer stem cells or physiologically and pathologically infiltrating cell populations. It thus provides essential new information toward the detailed biochemical understanding of cell development and functionality in health and disease.
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Affiliation(s)
- Sabine Amon
- From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Fabienne Meier-Abt
- From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland;; §Hematology, University and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Ludovic C Gillet
- From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Slavica Dimitrieva
- ¶Functional Genomics Center Zurich, ETH Zurich and University of Zurich, 8057 Zurich, Switzerland
| | | | - Markus G Manz
- §Hematology, University and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Ruedi Aebersold
- From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland;; ‖Faculty of Science, University of Zurich, 8057 Zurich, Switzerland.
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37
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Abstract
Telomeres are specialised structures at the end of linear chromosomes. They consist of tandem repeats of the hexanucleotide sequence TTAGGG, as well as a protein complex called shelterin. Together, they form a protective loop structure against chromosome fusion and degradation. Shortening or damage to telomeres and opening of the loop induce an uncapped state that triggers a DNA damage response resulting in senescence or apoptosis.Average telomere length, usually measured in human blood lymphocytes, was thought to be a biomarker for ageing, survival and mortality. However, it becomes obvious that regulation of telomere length is very complex and involves multiple processes. For example, the "end replication problem" during DNA replication as well as oxidative stress are responsible for the shortening of telomeres. In contrast, telomerase activity can potentially counteract telomere shortening when it is able to access and interact with telomeres. However, while highly active during development and in cancer cells, the enzyme is down-regulated in most human somatic cells with a few exceptions such as human lymphocytes. In addition, telomeres can be transcribed, and the transcription products called TERRA are involved in telomere length regulation.Thus, telomere length and their integrity are regulated at many different levels, and we only start to understand this process under conditions of increased oxidative stress, inflammation and during diseases as well as the ageing process.This chapter aims to describe our current state of knowledge on telomeres and telomerase and their regulation in order to better understand their role for the ageing process.
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38
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Chahine MN, Toupance S, El-Hakim S, Labat C, Gautier S, Moussallem T, Yared P, Asmar R, Benetos A. Telomere length and age-dependent telomere attrition: the blood-and-muscle model. Can J Physiol Pharmacol 2019; 97:328-334. [DOI: 10.1139/cjpp-2018-0582] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL–LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL–LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.
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Affiliation(s)
- Mirna N. Chahine
- Foundation-Medical Research Institutes, Beirut, Lebanon
- Faculty of Medical Sciences, Lebanese University, Hadath, Lebanon
| | - Simon Toupance
- Université de Lorraine, Inserm, DCAC, F-54000 Nancy, France
- Université de Lorraine, CHRU-Nancy, Pôle “Maladies du Vieillissement, Gérontologie et Soins Palliatifs”, F-54000, France
- Nancyclotep-GIE, F-54000 Nancy, France
| | - Sandy El-Hakim
- Faculty of Public Health II, Lebanese University, Fanar, Lebanon
| | - Carlos Labat
- Université de Lorraine, Inserm, DCAC, F-54000 Nancy, France
| | - Sylvie Gautier
- Université de Lorraine, CHRU-Nancy, Pôle “Maladies du Vieillissement, Gérontologie et Soins Palliatifs”, F-54000, France
| | | | - Pierre Yared
- Faculty of Medical Sciences, Lebanese University, Hadath, Lebanon
| | - Roland Asmar
- Foundation-Medical Research Institutes, Beirut, Lebanon
| | - Athanase Benetos
- Université de Lorraine, Inserm, DCAC, F-54000 Nancy, France
- Université de Lorraine, CHRU-Nancy, Pôle “Maladies du Vieillissement, Gérontologie et Soins Palliatifs”, F-54000, France
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39
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Jose SS, Tidu F, Burilova P, Kepak T, Bendickova K, Fric J. The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy. Front Genet 2018; 9:345. [PMID: 30210531 PMCID: PMC6123533 DOI: 10.3389/fgene.2018.00345] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 08/09/2018] [Indexed: 01/16/2023] Open
Abstract
Telomeropathies are rare disorders associated with impaired telomere length control mechanisms that frequently result from genetic mutations in the telomerase complex. Dyskeratosis congenita is a congenital progressive telomeropathy in which mutation in the telomerase RNA component (TERC) impairs telomere maintenance leading to accelerated cellular senescence and clinical outcomes resembling premature aging. The most severe clinical feature is perturbed hematopoiesis and bone-marrow failure, but the underlying mechanisms are not fully understood. Here, we developed a model of telomerase function imbalance using shRNA to knockdown TERC expression in human induced pluripotent stem cells (iPSCs). We then promoted in vitro hematopoiesis in these cells to analyze the effects of TERC impairment. Reduced TERC expression impaired hematopoietic stem-cell (HSC) differentiation and increased the expression of cellular senescence markers and production of reactive oxygen species. Interestingly, telomere length was unaffected in shTERC knockdown iPSCs, leading to conclusion that the phenotype is controlled by non-telomeric functions of telomerase. We then assessed the effects of TERC-depletion in THP-1 myeloid cells and again observed reduced hematopoietic and myelopoietic differentiative potential. However, these cells exhibited impaired telomerase activity as verified by accelerated telomere shortening. shTERC-depleted iPSC-derived and THP-1-derived myeloid precursors had lower phagocytic capacity and increased ROS production, indicative of senescence. These findings were confirmed using a BIBR1532 TERT inhibitor, suggesting that these phenotypes are dependent on telomerase function but not directly linked to telomere length. These data provide a better understanding of the molecular processes driving the clinical signs of telomeropathies and identify novel roles of the telomerase complex other than regulating telomere length.
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Affiliation(s)
- Shyam Sushama Jose
- Cellular and Molecular Immunoregulation Group, Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia.,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Federico Tidu
- Cellular and Molecular Immunoregulation Group, Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia.,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Petra Burilova
- Cellular and Molecular Immunoregulation Group, Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia.,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Tomas Kepak
- Pediatric Oncology Translational Research, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia.,Pediatric Hematology and Oncology, The University Hospital Brno, Brno, Czechia
| | - Kamila Bendickova
- Cellular and Molecular Immunoregulation Group, Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia
| | - Jan Fric
- Cellular and Molecular Immunoregulation Group, Center for Translational Medicine, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia
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40
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Wang Q, Wang X, Lai D, Deng J, Hou Z, Liang H, Liu D. BIX-01294 promotes the differentiation of adipose mesenchymal stem cells into adipocytes and neural cells in Arbas Cashmere goats. Res Vet Sci 2018; 119:9-18. [PMID: 29783122 DOI: 10.1016/j.rvsc.2018.05.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 04/02/2018] [Accepted: 05/12/2018] [Indexed: 01/06/2023]
Affiliation(s)
- Qing Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Xiao Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Defang Lai
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Jin Deng
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Zhuang Hou
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Hao Liang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Dongjun Liu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China.
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41
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Melicher D, Illés A, Pállinger É, Kovács ÁF, Littvay L, Tárnoki ÁD, Tárnoki DL, Bikov A, Molnár MJ, Buzás EI, Falus A. Tight co-twin similarity of monozygotic twins for hTERT protein level of T cell subsets, for telomere length and mitochondrial DNA copy number, but not for telomerase activity. Cell Mol Life Sci 2018; 75:2447-2456. [PMID: 29290038 PMCID: PMC11105316 DOI: 10.1007/s00018-017-2738-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/30/2017] [Accepted: 12/21/2017] [Indexed: 01/02/2023]
Abstract
Our study analyzed lymphocyte subpopulations of 32 monozygotic twins and compared the level of the catalytic reverse transcriptase protein subunit (hTERT) in T lymphocytes (Tly), helper- (Th), cytotoxic- (Tc) and regulatory T cell (Treg) subgroups. Four variables related to telomere and mitochondrial biology were simultaneously assessed, applying multi-parametric flow cytometry, TRAP-ELISA assay and qPCR standard curve method on peripheral blood mononuclear cell (PBMC) samples of genetically matched individuals. Twin data of telomerase activity (TA), hTERT protein level, telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were analyzed for co-twin similarity. The present study has provided novel information by demonstrating very high intraclass correlation (ICC) of hTERT protein level in T lymphocytes (0.891) and in both Th (0.896), Treg (0.885) and Tc (0.798) cell subgroups. When comparing results measured from PBMCs, intraclass correlation was also high for telomere length (0.815) and considerable for mtDNA copy number (0.524), and again exceptionally high for the rate-limiting telomerase subunit, hTERT protein level (0.946). In contrast, telomerase activity showed no co-twin similarity (ICC 0). By comparing relative amounts of hTERT protein levels in different lymphocyte subgroups of twin subjects, in Treg cells significantly higher level could be detected compared to Tly, Th or Tc cell subgroups. This is the first study that simultaneously analyzed co-twin similarity in MZ twins for the above four variables and alongside assessed their relationship, whereby positive association was found between TL and mtDNAcn.
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Affiliation(s)
- Dóra Melicher
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
- Hungarian Twin Registry, Budapest, Hungary
- MTA-SE Immunproteogenomics Extracellular Vesicle Research Group, Budapest, Hungary
| | - Anett Illés
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Árpád Ferenc Kovács
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Levente Littvay
- Hungarian Twin Registry, Budapest, Hungary
- Central European University, Budapest, Hungary
| | - Ádám Domonkos Tárnoki
- Hungarian Twin Registry, Budapest, Hungary
- Department of Radiology, Semmelweis University, Budapest, Hungary
| | - Dávid László Tárnoki
- Hungarian Twin Registry, Budapest, Hungary
- Department of Radiology, Semmelweis University, Budapest, Hungary
| | - András Bikov
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Mária Judit Molnár
- Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary
| | - Edit Irén Buzás
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
- MTA-SE Immunproteogenomics Extracellular Vesicle Research Group, Budapest, Hungary
| | - András Falus
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary.
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Cianflone E, Aquila I, Scalise M, Marotta P, Torella M, Nadal-Ginard B, Torella D. Molecular basis of functional myogenic specification of Bona Fide multipotent adult cardiac stem cells. Cell Cycle 2018; 17:927-946. [PMID: 29862928 PMCID: PMC6103696 DOI: 10.1080/15384101.2018.1464852] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/01/2018] [Accepted: 04/08/2018] [Indexed: 01/14/2023] Open
Abstract
Ischemic Heart Disease (IHD) remains the developed world's number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapies can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona-fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.
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Affiliation(s)
- Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania Campus “Salvatore Venuta” Viale Europa- Loc. Germaneto “L. Vanvitelli”, Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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Abstract
Purpose of Review Functional decline of hematopoiesis that occurs in the elderly, or in patients who receive therapies that trigger cellular senescence effects, results in a progressive reduction in the immune response and an increased incidence of myeloid malignancy. Intracellular signals in hematopoietic stem cells and progenitors (HSC/P) mediate systemic, microenvironment, and cell-intrinsic effector aging signals that induce their decline. This review intends to summarize and critically review our advances in the understanding of the intracellular signaling pathways responsible for HSC decline during aging and opportunities for intervention. Recent Findings For a long time, aging of HSC has been thought to be an irreversible process imprinted in stem cells due to the cell intrinsic nature of aging. However, recent murine models and human correlative studies provide evidence that aging is associated with molecular signaling pathways, including oxidative stress, metabolic dysfunction, loss of polarity and an altered epigenome. These signaling pathways provide potential targets for prevention or reversal of age-related changes. Summary Here we review our current understanding of the signalling pathways that are differentially activated or repressed during HSC/P aging, focusing on the oxidative, metabolic, biochemical and structural consequences downstream, and cell-intrinsic, systemic, and environmental influences.
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Brazvan B, Ebrahimi-Kalan A, Velaei K, Mehdipour A, Aliyari Serej Z, Ebrahimi A, Ghorbani M, Cheraghi O, Nozad Charoudeh H. Telomerase activity and telomere on stem progeny senescence. Biomed Pharmacother 2018; 102:9-17. [PMID: 29547744 DOI: 10.1016/j.biopha.2018.02.073] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 02/03/2018] [Accepted: 02/19/2018] [Indexed: 12/19/2022] Open
Abstract
The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme. Human Telomerase Reverse Transcriptase (hTERT) gene expression plays an important role in maintaining telomere length and high proliferative property of cells. Except a low activity of telomerase enzyme in hematopoietic and few types of stem cells, most of somatic cells didn't showed telomerase activity. Moreover, cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation. Also, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. In this review we have tried to talk about effects of immune cell cytokines on telomerase expression/telomere length and the induction of telomerase expression by cytokines.
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Affiliation(s)
- Balal Brazvan
- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Velaei
- Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Mehdipour
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeynab Aliyari Serej
- Applied Cell Sciences Department, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayyub Ebrahimi
- Department of Molecular Biology and Genetic, Faculty of Arts and Sciences, Halic Uuniversity, Istanbul, Turkey
| | - Mohammad Ghorbani
- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Omid Cheraghi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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Tichy ED, Sidibe DK, Tierney MT, Stec MJ, Sharifi-Sanjani M, Hosalkar H, Mubarak S, Johnson FB, Sacco A, Mourkioti F. Single Stem Cell Imaging and Analysis Reveals Telomere Length Differences in Diseased Human and Mouse Skeletal Muscles. Stem Cell Reports 2017; 9:1328-1341. [PMID: 28890163 PMCID: PMC5639167 DOI: 10.1016/j.stemcr.2017.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 12/12/2022] Open
Abstract
Muscle stem cells (MuSCs) contribute to muscle regeneration following injury. In many muscle disorders, the repeated cycles of damage and repair lead to stem cell dysfunction. While telomere attrition may contribute to aberrant stem cell functions, methods to accurately measure telomere length in stem cells from skeletal muscles have not been demonstrated. Here, we have optimized and validated such a method, named MuQ-FISH, for analyzing telomere length in MuSCs from either mice or humans. Our analysis showed no differences in telomere length between young and aged MuSCs from uninjured wild-type mice, but MuSCs isolated from young dystrophic mice exhibited significantly shortened telomeres. In corroboration, we demonstrated that telomere attrition is present in human dystrophic MuSCs, which underscores its importance in diseased regenerative failure. The robust technique described herein provides analysis at a single-cell resolution and may be utilized for other cell types, especially rare populations of cells.
MuQ-FISH is a telomere analysis assay of mouse and human muscle stem cells Highly sensitive telomere analysis on small numbers of cells Detection of both telomere length and number of telomere foci with MuQ-FISH assay Telomere analysis is now possible in quiescent and/or cycling stem cells
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Affiliation(s)
- Elisia D Tichy
- Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, 112A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA
| | - David K Sidibe
- Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, 112A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA
| | - Matthew T Tierney
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Michael J Stec
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Maryam Sharifi-Sanjani
- Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, 112A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA
| | - Harish Hosalkar
- Joint Preservation Center, Tricity Medical Center, Joint Preservation & Deformity Correction Center & Traumatic Brain Injury Program, Paradise Valley Hospital, National City, CA 91950, USA
| | - Scott Mubarak
- Department of Orthopedic Surgery, Rady Children's Hospital, 3030 Children's Way, San Diego, CA 92123, USA
| | - F Brad Johnson
- Department of Pathology and Laboratory Medicine, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alessandra Sacco
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Foteini Mourkioti
- Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, 112A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA.
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Abstract
BACKGROUND Telomeres are protein DNA structures present at the ends of chromosomes and are essential for genetic stability and cell replication. Telomerase is the enzyme complex that maintains telomere integrity. Hematopoietic stem cells express telomerase and contain long telomeres, which become shorter as cells differentiate and mature. The extent of telomere shortening and the level of telomerase activity often correlate with the presence and severity of some hematopoietic diseases. METHODS The fundamentals of telomeres and telomerase are reviewed, and the telomere biology of human hematopoietic cells is discussed. RESULTS Telomere length and telomerase activity are important in the self-renewal of hematopoietic stem cells. Changes within these compartments affect both normal hematopoietic cells and the generation of hematopoietic disease. Telomere length provides information pertaining to the proliferative history and potential of a hematopoietic cell. CONCLUSIONS The role of telomerase and telomeres within the hematopoietic compartment needs further clarification. Advances in our knowledge in this field may improve clinical outcomes for the treatment of hematologic disease.
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Affiliation(s)
- Ngaire Elwood
- Leukaemia Research Fund Stem Cell Laboratory, Department of Clinical Haematology and Oncology, Murdoch Children's Research Institute, Melbourne, Australia.
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p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita. Stem Cell Reports 2017; 9:409-418. [PMID: 28757166 PMCID: PMC5550027 DOI: 10.1016/j.stemcr.2017.06.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/27/2017] [Accepted: 06/27/2017] [Indexed: 12/23/2022] Open
Abstract
Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients.
CRISPR/Cas9 was used to generate different DC-associated mutations in hESCs Telomere shortening specifically impairs definitive hematopoietic specification Genetic instability and p53 activation regulate hematopoietic specification in DC In vitro hematopoietic failure resembles phenotypes of aplastic anemia in DC
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Eastley N, Ottolini B, Garrido C, Shaw JA, McCulloch TA, Ashford RU, Royle NJ. Telomere maintenance in soft tissue sarcomas. J Clin Pathol 2017; 70:371-377. [PMID: 28183782 PMCID: PMC5484030 DOI: 10.1136/jclinpath-2016-204151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 12/15/2016] [Indexed: 01/27/2023]
Abstract
Soft tissue sarcomas (STS) are a diverse group of heterogeneous malignant tumours derived from mesenchymal tissues. Over 50 different STS subtypes are recognised by WHO, which show a wide range of different biological behaviours and prognoses. At present, clinicians managing this complex group of tumours face several challenges. This is reflected by the relatively poor outcome of patients with STSs compared with many other solid malignant tumours. These include difficulties securing accurate diagnoses, a lack of effective systemic treatments and absence of any sensitive circulating biomarkers to monitor patients throughout their treatment and follow-up. In order to progress STS's cells must evade the usual cellular proliferative checkpoints, and then activate a telomere maintenance mechanism in order to achieve replicative immortality. The purpose of this review is to provide an overview of STS genetics focusing particularly on these mechanisms. We will also highlight some of the key barriers to improving outcome for patients with STS, and hypothesise how a better understanding of these genetic characteristics may impact on future STS management.
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Affiliation(s)
| | - Barbara Ottolini
- Department of Cancer Studies, University of Leicester, Leicester, UK
| | - Carmen Garrido
- Department of Genetics, University of Leicester, Leicester, UK
| | - Jacqueline A Shaw
- Department of Cancer Studies, University of Leicester, Leicester, UK
| | | | | | - Nicola J Royle
- Department of Genetics, University of Leicester, Leicester, UK
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Berardinelli F, Coluzzi E, Sgura A, Antoccia A. Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2017; 773:204-219. [PMID: 28927529 DOI: 10.1016/j.mrrev.2017.02.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/13/2017] [Accepted: 02/14/2017] [Indexed: 01/05/2023]
Abstract
One of the hallmarks of cancer consists in the ability of tumor cells to divide indefinitely, and to maintain stable telomere lengths throughout the activation of specific telomere maintenance mechanisms (TMM). Therefore in the last fifteen years, researchers proposed to target telomerase or telomeric structure in order to block limitless replicative potential of cancer cells providing a fascinating strategy for a broad-spectrum cancer therapy. In the present review, we report in vitro and in vivo evidence regarding the use of chemical agents targeting both telomerase or telomere structure and showing promising antitumor effects when used in combination with ionizing radiation (IR). RNA interference, antisense oligonucleotides (e.g., GRN163L), non-nucleoside inhibitors (e.g., BIBR1532) and nucleoside analogs (e.g., AZT) represent some of the most potent strategies to inhibit telomerase activity used in combination with IR. Furthermore, radiosensitizing effects were demonstrated also for agents acting directly on the telomeric structure such as G4-ligands (e.g., RHPS4 and Telomestatin) or telomeric-oligos (T-oligos). To date, some of these compounds are under clinical evaluation (e.g., GRN163L and KML001). Advantages of Telomere/Telomerase Targeting Compounds (T/TTCs) coupled with radiotherapy may be relevant in the treatment of radioresistant tumors and in the development of new optimized treatment plans with reduced dose adsorbed by patients and consequent attenuation of short- end long-term side effects. Pros and cons of possible future applications in cancer therapy based on the combination of T/TCCs and radiation treatment are discussed.
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Affiliation(s)
- F Berardinelli
- Dipartimento di Scienze, Università Roma Tre, Rome Italy; Istituto Nazionale di Fisica Nucleare, INFN, Sezione di Roma Tre, Rome, Italy.
| | - E Coluzzi
- Dipartimento di Scienze, Università Roma Tre, Rome Italy
| | - A Sgura
- Dipartimento di Scienze, Università Roma Tre, Rome Italy; Istituto Nazionale di Fisica Nucleare, INFN, Sezione di Roma Tre, Rome, Italy
| | - A Antoccia
- Dipartimento di Scienze, Università Roma Tre, Rome Italy; Istituto Nazionale di Fisica Nucleare, INFN, Sezione di Roma Tre, Rome, Italy
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50
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Liggett LA, DeGregori J. Changing mutational and adaptive landscapes and the genesis of cancer. Biochim Biophys Acta Rev Cancer 2017; 1867:84-94. [PMID: 28167050 DOI: 10.1016/j.bbcan.2017.01.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 01/27/2017] [Accepted: 01/28/2017] [Indexed: 12/31/2022]
Abstract
By the time the process of oncogenesis has produced an advanced cancer, tumor cells have undergone extensive evolution. The cellular phenotypes resulting from this evolution have been well studied, and include accelerated growth rates, apoptosis resistance, immortality, invasiveness, and immune evasion. Yet with all of our current knowledge of tumor biology, the details of early oncogenesis have been difficult to observe and understand. Where different oncogenic mutations may work together to enhance the survival of a tumor cell, in isolation they are often pro-apoptotic, pro-differentiative or pro-senescent, and therefore often, somewhat paradoxically, disadvantageous to a cell. It is also becoming clear that somatic mutations, including those in known oncogenic drivers, are common in tissues starting at a young age. These observations raise the question: how do we largely avoid cancer for most of our lives? Here we propose that evolutionary forces can help explain this paradox. As humans and other organisms age or experience external insults such as radiation or smoking, the structure and function of tissues progressively degrade, resulting in altered stem cell niche microenvironments. As tissue integrity declines, it becomes less capable of supporting and maintaining resident stem cells. These stem cells then find themselves in a microenvironment to which they are poorly adapted, providing a competitive advantage to those cells that can restore their functionality and fitness through mutations or epigenetic changes. The resulting oncogenic clonal expansions then increase the odds of further cancer progression. Understanding how the causes of cancer, such as aging or smoking, affect tissue microenvironments to control the impact of mutations on somatic cell fitness can help reconcile the discrepancy between marked mutation accumulation starting early in life and the somatic evolution that leads to cancer at advanced ages or following carcinogenic insults. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.
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Affiliation(s)
- L Alexander Liggett
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, United States
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, United States; Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045, United States; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, United States; Department of Medicine, Section of Hematology, University of Colorado School of Medicine, Aurora, CO 80045, United States.
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