Macaque Age-Related Clonal Hematopoiesis Model Demonstrates Expansion of TET2-Disrupted Clones and Utility for Testing Therapeutic Approaches

2020 ◽  
Author(s):  
Tae-Hoon Shin ◽  
Shirley Chen ◽  
Stefan Cordes ◽  
Yifan Zhou ◽  
Aisha AlJanahi ◽  
...  
Keyword(s):  
Therapeutic Approaches ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Hematopoiesis Model

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.

HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults

2021 ◽  
Author(s):  
Nila J. Dharan ◽  
Paul Yeh ◽  
Mark Bloch ◽  
Miriam M. Yeung ◽  
David Baker ◽  
...  
Keyword(s):  
Older Adults ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Increased Risk

TET2 is Iron-Dependent so its Activity may be Compromised in SF3B1 Mutated Age-Related Clonal Hematopoiesis of Indeterminate Potential

2017 ◽  
Vol 55 ◽  
pp. S22-S23
Author(s):  
T. Radivoyevitch ◽  
C. Hirsch ◽  
V. Adema ◽  
B. Jha ◽  
D. Lindner ◽  
...  
Keyword(s):  
Clonal Hematopoiesis ◽  
Age Related

3154 – RHESUS MACAQUES AS NATURAL MODELS FOR AGE-RELATED CLONAL HEMATOPOIESIS

2020 ◽  
Vol 88 ◽  
pp. S86
Author(s):  
Yifan Zhou ◽  
Kyung-Rok Yu ◽  
Tae-Hoon Shin ◽  
Xing Fan ◽  
Margarete Fabre ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Clonal Hematopoiesis ◽  
Age Related

scholarly journals Age-Related Inflammation: the Contribution of Different Organs, Tissues and Systems. How to Face it for Therapeutic Approaches

2010 ◽  
Vol 16 (6) ◽  
pp. 609-618 ◽  
Author(s):  
E. Cevenini ◽  
C. Caruso ◽  
G. Candore ◽  
M. Capri ◽  
D. Nuzzo ◽  
...  
Keyword(s):  
Therapeutic Approaches ◽  
Age Related

scholarly journals Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9867
Author(s):  
Yi-Chun Huang ◽  
Chao-Yung Wang
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methyltransferase ◽  
Gene Mutations ◽  
Cvd Risk ◽  
Telomere Attrition ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Cell Clones ◽  
Important Relationship ◽  
Increased Risk

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

CHIP & HIPs: Clonal Hematopoiesis is Common in Hip Arthroplasty Patients and Associates with Autoimmune Disease

Blood ◽  
2021 ◽  
Author(s):  
Judith S. Hecker ◽  
Luise Hartmann ◽  
Jennifer Rivière ◽  
Michèle Constanze Buck ◽  
Mark van der Garde ◽  
...  
Keyword(s):  
Hip Arthroplasty ◽  
Inflammatory Diseases ◽  
Low Grade ◽  
Related Condition ◽  
Clonal Hematopoiesis ◽  
Mild Anemia ◽  
Age Related ◽  
Mutation Burden ◽  
Clinical Associations ◽  
Low Grade Inflammation

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.

scholarly journals Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation

2020 ◽  
Vol 12 (526) ◽  
pp. eaax6249 ◽  
Author(s):  
Wing Hing Wong ◽  
Sima Bhatt ◽  
Kathryn Trinkaus ◽  
Iskra Pusic ◽  
Kevin Elliott ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
High Throughput Sequencing ◽  
Limit Of Detection ◽  
Cell Transplant ◽  
Younger Adults ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Over Time

Clonal hematopoiesis is associated with various age-related morbidities. Error-corrected sequencing (ECS) of human blood samples, with a limit of detection of ≥0.0001, has demonstrated that nearly every healthy individual >50 years old harbors rare hematopoietic clones below the detection limit of standard high-throughput sequencing. If these rare mutations confer survival or proliferation advantages, then the clone(s) could expand after a selective pressure such as chemotherapy, radiotherapy, or chronic immunosuppression. Given these observations and the lack of quantitative data regarding clonal hematopoiesis in adolescents and young adults, who are more likely to serve as unrelated hematopoietic stem cell donors, we completed this pilot study to determine whether younger adults harbored hematopoietic clones with pathogenic mutations, how often those clones were transferred to recipients, and what happened to these clones over time after transplantation. We performed ECS on 125 blood and marrow samples from 25 matched unrelated donors and recipients. Clonal mutations, with a median variant allele frequency of 0.00247, were found in 11 donors (44%; median, 36 years old). Of the mutated clones, 84.2% of mutations were predicted to be molecularly pathogenic and 100% engrafted in recipients. Recipients also demonstrated de novo clonal expansion within the first 100 days after hematopoietic stem cell transplant (HSCT). Given this pilot demonstration that rare, pathogenic clonal mutations are far more prevalent in younger adults than previously appreciated, and they engraft in recipients and persist over time, larger studies with longer follow-up are necessary to correlate clonal engraftment with post-HSCT morbidity.

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