scholarly journals The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

2020 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Progenitor Cells ◽  
Hippocampal Neurogenesis ◽  
Gene Set Enrichment Analysis ◽  
Telomere Maintenance ◽  
Proliferative Capacity ◽  
Telomere Shortening ◽  
Age Related ◽  
Disorder Risk

AbstractTelomere shortening is one hallmark of cell ageing that can limit the proliferative capacity of cell populations and increase risk for age-related disease. It has been hypothesized that short telomeres, and subsequently a limited proliferative capacity of hippocampal progenitor cells, could contribute to smaller hippocampal volumes and impaired cognition, amongst psychiatric disorder patients. The current study employed a systematic, multidisciplinary approach which aimed to model the effects of telomere shortening on human hippocampal neurogenesis, and to explore its relationship with cognition and psychiatric disorder risk. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Aged progenitors demonstrated shorter telomeres (p<0.05), and reduced rates of cell proliferation, as marked by bromodeoxyuridine staining (p<0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene set enrichment analysis revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts showed a significant overlap with genes regulating cognitive function and risk for schizophrenia and bipolar disorder. Collectively, our results suggest that reductions in adult hippocampal neurogenesis, caused by telomere shortening, could represent a cellular mechanism contributing to age-related cognitive impairment and psychiatric disorder risk.

scholarly journals Telomere length and human hippocampal neurogenesis

2020 ◽  
Vol 45 (13) ◽  
pp. 2239-2247 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Telomere Length ◽  
Gene Networks ◽  
Hippocampal Neurogenesis ◽  
Telomere Maintenance ◽  
Adult Hippocampal Neurogenesis ◽  
Telomere Shortening ◽  
Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

Conditional TRF1 Knockout in Haematopoietic Progenitor Cells Causes Telomere Shortening and Bone Marrow Failure by Induction of Cellular Senescence

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 49-49
Author(s):  
Fabian Beier ◽  
Miguel Foronda ◽  
Jose A Palacios ◽  
Paula Martinez ◽  
Maria A Blasco
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Conditional Knockout ◽  
Telomere Maintenance ◽  
Loss Of Function ◽  
Telomere Shortening ◽  
Exon 1

Abstract Abstract 49 Introduction: Mutations in the telomerase complex may cause bone marrow failure syndromes due to loss-of-function and consecutive telomere shortening. In addition to the telomerase complex, the six “shelterin” proteins (TRF1, TRF2, TIN2, RAP1, POT1 and TPP1) are required for telomere maintenance. TRF1 has a prominent role in chromosome capping function and prevents the recognition of telomeres by DNA repair mechanisms. At the moment, only TIN2 mutations have been linked to bone marrow failure. Here we aimed to identify other shelterin proteins might cause bone marrow failures. A previous study reported an clinical association between TRF1 mutations and acquired aplastic anemia, however the proof-of-principle that TRF1 can cause bone marrow failure is still missing (Savage SA Exp Hematol 2006). Material and Methods: To address this issue, we used the Mx1-Cre system in combination with the recently generated TRF1 allele in which the exon 1 of TRF1 is flanked by floxP (Martinez P Gen Dev 2009). The bone marrow of the bitransgenic mice was transplanted into B6 wildtype mice and poly (P:I) injections allowed the conditional knockout of TRF1. Results: Initiation of poly (P:I) injections 4 weeks after transplantation resulted in a failure of all three haematopoietic lineages after 17 days and histopathology revealed massive hypocellular bone marrow consistent with a bone marrow failure. Transplanted control animals showed normal histopathology and even increased neutrophil and thrombocyte counts. Further detailed FACS analysis 7 days after initiation of poly (P:I) injections showed a significant depletion of common myeloid, megakaryocte-erythocyte and common lymphoid progenitor cells, but only a slight decrease of lin-, c-kit+,Sca-1+ haematopoietic stem cells. Interesting, we found no increased rate of apoptosis for the decrease of the progenitor cells, but ß-galactosidase staining showed significant higher amounts of senescent cells in the bone marrow. Further detailed analysis of FACS sorted bone marrow cells showed that especially the c-kit positive progenitor fraction underwent senescence and cell cycle analysis showed an increased G2-M phase indicating a G2-M arrest. In line with these findings RT-PCR of FACS sorted BM revealed increased levels of p21 in the c-kit positive fraction. In addition BrdU injections into the mice on day 7 after poly (P:I) initiation showed increased incorporation and telomere length analysis of transplanted animals with and without poly (P:I) injections revealed massive telomere shortening on day 17. Conclusions: Our data indicates that TRF1 knockout especially affects haematopoietic progenitor cells by inducing G2-M arrest, induction of p21, and subsequent senescence. Further, compensation of the progenitor cell depletion leads to higher cell turnover and consecutively massive telomere shortening. Taken together this is the first report proving that TRF1 can cause a bone marrow failure and is accompanied with significant telomere shortening. Disclosures: No relevant conflicts of interest to declare.

Defective Hematopoiesis and Erythroid Differentiation Resulting From Telomerase Deficiency

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2410-2410
Author(s):  
Aparna Raval ◽  
Brenda Kusler ◽  
Steven Artandi ◽  
Beverly S. Mitchell
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Failure ◽  
Telomere Maintenance ◽  
P Value ◽  
Erythroid Cells ◽  
Erythroid Progenitor ◽  
Telomere Shortening ◽  
Cell Numbers ◽  
Bone Marrow Failure Syndromes

Abstract Abstract 2410 Telomere shortening and anemia are common in bone marrow failure syndromes (BMF) such as dyskeratosis congenita (DKC), acquired aplastic anemia and myelodysplastic syndromes (MDS). Components of the telomerase complex including TERT, TERC and Dyskerin are mutated in multiple BMF syndromes, strongly suggesting a link between aberrant telomere maintenance and BMF. However, the specific defects in hematopoiesis that lead to BMF have not been completely defined. To better understand the effects of telomere shortening on hematopoiesis, we crossed Tert−/− mice for five successive generations to derive 5th generation Tert−/− (G5 Tert−/−) mice with short telomeres. The G5 Tert−/− mice were smaller in size and their peripheral blood cell counts had significantly reduced numbers of red blood cells and hemoglobin content (p-value < 0.01). There was also a significant reduction in immature erythroid (CD71+; p-value < 0.03) and mature erythroid (CD71-Ter119+; p-value < 0.05) cells in the bone marrows of these mice as compared to the G0 Tert+/− controls, while myeloid (Mac-1, Gr1+) cell numbers were not decreased. Annexin V and PI staining showed increased apoptosis in immature erythroid cells from G5 Tert−/− mice. In order to determine if the reduction in erythrocytes was due to defective hematopoiesis, we studied hematopoietic stem cell (HSC), committed erythroid progenitor (MEP) and myeloid progenitor (GMP) cell numbers in these mice. We observed a marked decrease in MEP (Lin-cKit+Sca1-CD34-CD16/CD32lo; p-value < 0.02) and HSC (Lin-cKit+Sca1+CD34-CD150+; p-value < 0.03) populations in G5 Tert−/− mice marrow, while GMP (Lin-cKit+Sca1-CD34+CD16/CD34hi; p-value < 0.6) cells were not affected. In contrast, there was an increase in the number of immature erythroid cells (CD71+), hematopoietic progenitor cells (Lin-cKit+Sca1+) and HSC in the spleens of G5 Tert−/− mice, strongly suggesting extramedullary hematopoiesis. These data demonstrate that there is a defect in the regulation of hematopoiesis, starting at the level of HSC, in the bone marrow of G5 Tert−/− mice. MEPs from G5 Tert−/− mice showed increased DNA damage, as demonstrated by phospho-H2Ax staining by flow cytometry, although enhanced apoptosis was not present. In contrast, GMPs did not show any difference in phospho-H2Ax staining, suggesting that MEPs may be selectively sensitive to telomere shortening or that telomeres shorten more rapidly in these cells. Total bone marrow cells from G0 Tert+/− and G5 Tert−/− mice were plated in Methocult supporting erythroid colony formation; we observed that the G5 Tert−/− cells had significantly reduced numbers of CFU-E and BFU-E colonies (p-value < 0.01) compared to cells from the G0 mice, suggesting that the ability of erythroid progenitor cells to differentiate is compromised by dysfunctional telomeres. These data show for the first time a direct and distinctive link between the loss of telomerase function and erythropoiesis. These results, in conjunction with single-cell “mass cytometry” experiments to explore the molecular pathways that are selectively deregulated in the HSC and erythroid precursors of G5 Tert−/− mice, will elucidate the mechanisms underlying the cell-specific effects of telomere shortening on erythropoiesis and help to elucidate the relationship between shortened telomeres and the anemia of bone marrow failure syndromes. Disclosures: No relevant conflicts of interest to declare.

Regulation And Effect Of Telomerase And Telomeric Length In Stem Cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Basak Celtikci ◽  
Gulnihal Kulaksiz Erkmen ◽  
Zeliha Gunnur Dikmen
Keyword(s):  
Telomere Length ◽  
Somatic Cells ◽  
Telomere Maintenance ◽  
The Other ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Telomere Shortening ◽  
Maintenance Mechanism ◽  
Associated Diseases ◽  
Human Telomerase

: Telomeres are the protective end caps of eukaryotic chromosomes and they decide the proliferative lifespan of somatic cells, as the guardians of the cell replication. Telomere length in leucocytes reflects telomere length in other somatic cells. Leucocyte telomere length can be a biomarker of human ageing. The risk of diseases, which are associated with reduced cell proliferation and tissue degeneration, including aging or aging-associated diseases, such as dyskeratosis congenita, cardiovascular diseases, pulmonary fibrosis and aplastic anemia, are correlated with an increase in short telomeres. On the other hand, the risk of diseases, which are associated with increased proliferative growth, including major cancers, is correlated with long telomeres. In most of the cancers, a telomere maintenance mechanism during DNA replication is essential. The reactivation of the functional ribonucleoprotein holoenzyme complex [telomerase] starts the cascade from normal and premalignant somatic cells to advanced malignant cells. Telomerase is overexpressed during the development of cancer and embryonic stem cells, through controlling genome integrity, cancer formation and stemness. Cancer cells have mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis, and halting cell division by critically short telomeres. Modulation of the human telomerase reverse transcriptase is the ratelimiting step for the production of functional telomerase and the telomere maintenance. Human telomerase reverse transcriptase promoter promotes its gene expression only in tumor cells, but not in normal cells. Some cancers activate an alternative lengthening of telomeres maintenance mechanism via DNA recombination to unshorten their telomeres. Not only heritability but also oxidative stress, inflammation, environmental factors, and therapeutic interventions have an effect on telomere shortening, explaining the variability in telomere length across individuals. There have been a large number of publications, which correlate human diseases with progressive telomere shortening. Telomere length of an individual at birth is also important to follow up telomere shortening, and it can be used as biomarkers for healthy aging. On the other hand, understanding of cellular stress factors, which affect stem cell behavior, will be useful in regeneration or treatment in cancer and age-associated diseases. In this review, we will understand the connection between stem cell and telomere biology, cancer, and aging-associated diseases. This connection may be useful for discovering novel drug targets and improve outcomes for patients having cancer and aging-associated diseases.

scholarly journals Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1776
Author(s):  
Elham Pishavar ◽  
Hongrong Luo ◽  
Johanna Bolander ◽  
Antony Atala ◽  
Seeram Ramakrishna
Keyword(s):  
Drug Delivery ◽  
Progenitor Cells ◽  
Transfection Efficiency ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Nanofibrous Scaffolds ◽  
The Stability

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

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