Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis

Clonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH at unprecedented scale. We increase the number of European-ancestry genome-wide significant (P<5x10-8) germline associations with CH from four to 14 and identify one new transcriptome-wide significant (P<3.2x10-6) association. Genes at new loci implicate DNA damage repair (PARP1, ATM, and CHEK2), hematopoietic stem cell migration/homing (CD164), and myeloid oncogenesis (SETBP1) in CH development. Several associations were CH-subtype specific and, strikingly, variants at TCL1A and CD164 had opposite associations with DNMT3A- versus TET2-mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.

Mathematical modeling of therapeutic neural stem cell migration in mouse brain with and without brain tumors

<abstract><p>Neural stem cells (NSCs) offer a potential solution to treating brain tumors. This is because NSCs can circumvent the blood-brain barrier and migrate to areas of damage in the central nervous system, including tumors, stroke, and wound injuries. However, for successful clinical application of NSC treatment, a sufficient number of viable cells must reach the diseased or damaged area(s) in the brain, and evidence suggests that it may be affected by the paths the NSCs take through the brain, as well as the locations of tumors. To study the NSC migration in brain, we develop a mathematical model of therapeutic NSC migration towards brain tumor, that provides a low cost platform to investigate NSC treatment efficacy. Our model is an extension of the model developed in Rockne et al. (PLoS ONE 13, e0199967, 2018) that considers NSC migration in non-tumor bearing naive mouse brain. Here we modify the model in Rockne et al. in three ways: (i) we consider three-dimensional mouse brain geometry, (ii) we add chemotaxis to model the tumor-tropic nature of NSCs into tumor sites, and (iii) we model stochasticity of migration speed and chemosensitivity. The proposed model is used to study migration patterns of NSCs to sites of tumors for different injection strategies, in particular, intranasal and intracerebral delivery. We observe that intracerebral injection results in more NSCs arriving at the tumor site(s), but the relative fraction of NSCs depends on the location of injection relative to the target site(s). On the other hand, intranasal injection results in fewer NSCs at the tumor site, but yields a more even distribution of NSCs within and around the target tumor site(s).</p></abstract>

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer’s Disease

Neurogenesis in the adult brain takes place in two neurogenic niches: the ventricular-subventricular zone (V-SVZ) and the subgranular zone. After differentiation, neural precursor cells (neuroblasts) have to move to an adequate position, a process known as neuronal migration. Some studies show that in Alzheimer’s disease, the adult neurogenesis is impaired. Our main aim was to investigate some proteins involved both in the physiopathology of Alzheimer’s disease and in the neuronal migration process using the APP/PS1 Alzheimer’s mouse model. Progenitor migrating cells are accumulated in the V-SVZ of the APP/PS1 mice. Furthermore, we find an increase of Cdh1 levels and a decrease of Cdk5/p35 and cyclin B1, indicating that these cells have an alteration of the cell cycle, which triggers a senescence state. We find less cells in the rostral migratory stream and less mature neurons in the olfactory bulbs from APP/PS1 mice, leading to an impaired odour discriminatory ability compared with WT mice. Alzheimer’s disease mice present a deficit in cell migration from V-SVZ due to a senescent phenotype. Therefore, these results can contribute to a new approach of Alzheimer’s based on senolytic compounds or pro-neurogenic factors.

Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.

Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury.

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, EEs release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in ISCs, promoting actin-based protrusion formation and ISC migration towards a wound. We find that this migratory behavior is closely linked to ISC proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify EE-released ligands as critical coordinators of ISC migration.

Stem Cell Migration: A Possible Mechanism for the Tissue-Sparing Effect of Spatially Fractionated Radiation

Stem cell responses in tissues after exposure to radiation are of significance for maintaining tissue functions. From the point of view of stem cell characteristics, this article seeks to illustrate some contributions of microbeam research to spatially fractionated radiotherapy (SFRT), such as grid radiotherapy and microbeam radiotherapy. Although the tissue-sparing response after SFRT was first reported more than a century ago, current radiation dose–volume metrics are still unable to accurately predict such tissue-level changes in response to spatially fractionated radiation fields. However, microbeam approaches could contribute to uncovering the mechanisms of tissue response, significantly improving the outcomes of SFRT and reducing its adverse effects. Studies with microbeams have shown that the testicular tissue-sparing effect for maintaining spermatogenesis after exposure to spatially fractionated radiation depends on biological parameters, such as the radiation dose distribution at the microscale level for tissue-specific stem cells and the microenvironment, or niche. This indicates that stem cell survival, migration, and repopulation are involved in the tissue-level changes during or after SFRT. The illustration of microbeam applications in this article focuses on the stem cell migration as a possible mechanism of the tissue-sparing effect for preserving functionality.

ANALYSIS OF CANCER-TESTIS ANTIGENS AS POTENTIAL MARKERS FOR DISSEMINATION OF PRIMARY HUMAN SKIN MELANOMA

Purpose of the study: to analyze characteristics of cancer-testis antigens (Ctas) as potential biomarkers for dissemination of primary human skin melanoma (sm).Material and Methods. Recent publications from Pubmed, scopus and elibrary databases were analyzed for the available appropriate literature review. In total, 176 papers reported the description of Ctas and encoding genes and their potential for prognosis of primary sm dissemination. The authors included 52 of them in the given review.Results. Two sections of the paper comprise clinically significant characteristics of Ctas and their genes, including overexpression, which is selective for the heterogeneous tumor cell populations and mediated by humoral and/or cellular immune reactions; the association of tumor process and activation of Cta genes by demethylation of promotor sites, which is correlated with tumor progression; and the conditions required for effective immunotherapy involving Ctas and/or their genes.Conclusion. At present, there are no standards or clinical recommendations for the Cta-based prognosis of the early dissemination of primary skin melanoma. Therefore, it is important to study and analyze the Cta and encoding gene characteristics that reveal the connection between primary sm progression and tumor genesis including the role of circulating tumor cells (ctc), similar to stem cells, which have epithelial-mesenchymal transition (emt) phenotype, for clinical diagnostics of early sm dissemination. As a result of the study, the following Ctas could be considered as significant biomarkers of the early sm dissemination: mage-a1, mage-a4 and ny-eso-1, which expression correlates with the clinical pathological description of the disease progression, as well as with the relapse-free period and overall survival of the patients; magea3, which expression correlates with spag5 activation and Cd8+ t-cell abundance; ssx, a marker for stem cell migration including identification of the cells with emt and/or ctcs; and prame, signaling marker for dissemination of the uveal melanoma.