Faculty Bibliography

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment^1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis^3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions¹. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8⁺ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

Study question: Do young women with idiopathic early ovarian ageing have changes in telomere length and epigenetic age indicating accelerated biological aging? Summary answer: The telomere length and epigenetic age were comparable to those in young women with normal ovarian ageing. What is known already: Increased risk of several health events usually considered to be age-related such as cardiovascular disease, osteoporosis, over-all morbidity and mortality have been associated with premature and early menopause when compared to the risk in women with normal menopausal age suggesting an accelerated general ageing process associated to early ovarian ageing. It is unclear whether the onset of this process may start before menopause. Study design, size, duration: A prospective cohort study. Young women (<= 37 years) having ART at two Danish Public fertility clinics during the period 2016 to 2018 were divided into two groups dependent on their ovarian reserve status: early ovarian ageing (EOA) (N=55) and normal ovarian ageing (NOA)( N=52). Number of oocytes harvested in first and subsequent cycles was used as a marker of ovarian reserve. Blood samples was drawn at time of oocyte retrieval to assess biological age. Participants/materials, setting, methods: EOA was defined as >= 2 IVF cycles with <= 5 harvested oocytes despite sufficient stimulation with FSH and NOA as >=8 oocytes harvested in minimum 1 cycle. Known causes influencing the ovarian reserve (endometriosis, ovarian surgery, etc.) was reason for exclusion. Relative telomere length (qPCR) and epigenetic age acceleration (DNA methylation levels) were measured in white blood cells as markers of accelerated biological ageing. Main results and the role of chance: Relative telomere length was comparable with a mean of 0.46 (+/- sd 0.12) in the EOA group and 0.47 (0.14) in the normal ovarian ageing group (p=0.64). The difference of predicted mean epigenetic age and mean chronological age (i.e. epigenetic age acceleration) was, insignificantly, 0.5 years older in the EOA group when compared to the NOA group( (-1.02 years (2.62) and -1.57 years (2.56), respectively, p=0.27)), but this difference disappeared when adjusting for chronological age. Limitations, reasons for caution: Discrete changes in epigenetic age acceleration may not have been captured as the study only had power to detect an age acceleration of >= 2 years. Wider implications of the findings: By analysis of biomarkers for ageing in whole blood, we did not find any indications of a premenopausal accelerated aging in young women with idiopathic EOA. Further investigations in a similar cohort of premenopausal women is needed to fully elucidate the potential relationship between premenopausal accelerated biological ageing and EOA

Importance/UNASSIGNED:It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction. Objective/UNASSIGNED:In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos. Evidence Acquisition/UNASSIGNED:We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development. Results/UNASSIGNED:Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos. Conclusions and Relevance/UNASSIGNED:Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.

Mesenchymal stem cells (MSCs) obtained from various sources, including bone marrow, have been proposed as a therapeutic strategy for the improvement of tissue repair/regeneration, including the repair of cartilage defects or lesions. Often the highly inflammatory environment after injury or during diseases, however, greatly diminishes the therapeutic and reparative effectiveness of MSCs. Therefore, the identification of novel factors that can protect MSCs against an inflammatory environment may enhance the effectiveness of these cells in repairing tissues, such as articular cartilage. In this study, we investigated whether a peptide (P15-1) that binds to hyaluronan (HA), a major component of the extracellular matrix of cartilage, protects bone-marrow-derived MSCs (BMSCs) in an inflammatory environment. The results showed that P15-1 reduced the mRNA levels of catabolic and inflammatory markers in interleukin-1beta (IL-1β)-treated human BMSCs. In addition, P15-1 enhanced the attachment of BMSCs to HA-coated tissue culture dishes and stimulated the chondrogenic differentiation of the multipotential murine C3H/10T1/2 MSC line in a micromass culture. In conclusion, our findings suggest that P15-1 may increase the capacity of BMSCs to repair cartilage via the protection of these cells in an inflammatory environment and the stimulation of their attachment to an HA-containing matrix and chondrogenic differentiation.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal, and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.

Organogenesis requires exquisite spatiotemporal coordination of cell morphogenesis, migration, proliferation, and differentiation of multiple cell types. For gonads, this involves complex interactions between somatic and germline tissues. During Drosophila ovary morphogenesis, primordial germ cells (PGCs) either are sequestered in stem cell niches and are maintained in an undifferentiated germline stem cell state or transition directly toward differentiation. Here, we identify a mechanism that links hormonal triggers of somatic tissue morphogenesis with PGC differentiation. An early ecdysone pulse initiates somatic swarm cell (SwC) migration, positioning these cells close to PGCs. A second hormone peak activates Torso-like signal in SwCs, which stimulates the Torso receptor tyrosine kinase (RTK) signaling pathway in PGCs promoting their differentiation by de-repression of the differentiation gene, bag of marbles. Thus, systemic temporal cues generate a transitory signaling center that coordinates ovarian morphogenesis with stem cell self-renewal and differentiation programs, highlighting a more general role for such centers in reproductive and developmental biology.

Nutrient sensors allow animals to identify foods rich in specific nutrients. The Drosophila nutrient sensor, diuretic hormone 44 (DH44) neurons, helps the fly to detect nutritive sugar. This sensor becomes operational during starvation; however, the mechanisms by which DH44 neurons or other nutrient sensors are regulated remain unclear. Here, we identified two satiety signals that inhibit DH44 neurons: (1) Piezo-mediated stomach/crop stretch after food ingestion and (2) Neuromedin/Hugin neurosecretory neurons in the ventral nerve cord (VNC) activated by an increase in the internal glucose level. A subset of Piezo⁺ neurons that express DH44 neuropeptide project to the crop. We found that DH44 neuronal activity and food intake were stimulated following a knockdown of piezo in DH44 neurons or silencing of Hugin neurons in the VNC, even in fed flies. Together, we propose that these two qualitatively distinct peripheral signals work in concert to regulate the DH44 nutrient sensor during the fed state.

»:The induced membrane technique (IMT) takes advantage of an osteoinductive environment that is created by the placement of a cement spacer into a bone defect. »:Most commonly, a polymethylmethacrylate (PMMA) spacer has been used, but spacers made from other materials have emerged and achieved good clinical outcomes. »:The IMT has demonstrated good results for long-bone repair; however, more research is required in order to optimize union rates as well as delineate more precise indications and surgical timing.