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Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease. Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.

Hepatitis B virus infection represents a major global health problem. Currently, there are more than 240 million chronically infected people worldwide. The development of chronic hepatitis B virus-mediated liver disease may lead to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Recently, the discovery of the viral entry receptor sodium taurocholate cotransporting polypeptide has facilitated new approaches for a better understanding of viral physiopathology. Hopefully, these novel insights may give rise to the development of more effective antiviral therapy concepts during the next years. In this review, we will discuss the natural history of hepatitis B virus infection including the viral biology, the clinical course of infection and the role of the immune response.

Background: Multiple Sclerosis (MS) influences the relationships of affected couples, whereby the disease-related stress can lead to a deterioration of communication. This, in turn, makes it difficult for the couples to cope successfully. To support couples affected by MS for coping with the disease, the first step in developing an intervention is to examine whether this situation also applies in the Swiss context. Methods: A cross-sectional study was conducted to examine the psychosocial situation of couples where 1 partner has MS, regarding anxiety, depression, and stress communication. The Hospital Anxiety and Depression Scales (HADS-D) were used to assess depression and anxiety in both partners of 462 couples, while their stress communication was assessed using questions formulated according to the corresponding subscales of the Dyadic Coping Inventory (DCI). A comparison of the assessments of both partners was performed using the Mann-Whitney U test. Furthermore, the relationship between their stress communication and the severity of anxiety and depression was calculated using Spearman’s rank correlation. Results: Life partners rated the stress communication of their partners with MS significantly higher than the partners with MS themselves. Moreover, life partners could not distinguish whether their partners with MS expressed a sense of burden or a need for support. These findings indicate that the stress communication skills of both partners show potential for optimization. Health status regarding depression and anxiety revealed the following: 34.2% of the persons with MS and 34% of their life partners experienced clinically high levels of anxiety (HADS-D/A ≥ 8.0), and 31.4% of those with MS and 20.2% of the life partners showed clinically high levels of depression (HADS-D/D ≥ 8.0). Conclusion: In the Swiss context, psychosocial intervention, which includes communication training for both partners, might be effective in improving the health status regarding depression and anxiety as well as the stress communication.

Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC ( Ctnnb1 OE-SEC ) generated by using a BM-SEC-restricted Cre mouse line ( Stab2-iCreF3 ) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII–PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1 OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1 OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease. Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.

Background: The elderly represents the fastest growing group in our population. Since there is a close relationship between the number of older people and health care expenditure, promoting healthy aging has become an important topic. However, it is essential to understand first the needs of this population in order to create suitable programs and activities. Methods: A qualitative design was used in this study to explore the subjective views of elderly people and to learn more about their health-related needs. A total of 12 participants were recruited using a consecutive sampling strategy. The data were collected through semi-structured interviews and analyzed by employing a summarizing content analysis. Results: This study has identified 4 areas of health-related needs: Independence and autonomy, social security, structure in daily life and community and belonging, where all categories are interrelated and interact with one other. Conclusion: Focusing more on community-based approaches would support creating a conducive environment. Also, home visits undertaken by a specialized nurse focused on health risks and disabilities could be an adequate approach to support the elderly population in an efficient way and to offer targeted programs and activities.

To determine the origin of adult tissue-resident macrophages, a mouse lineage tracing study has revealed that these cells derive from erythro-myeloid progenitors in the yolk sac that are distinct from fetal and adult haematopoietic stem cells. The origin of adult myeloid cells The developmental origin of tissue-resident macrophage progenitors and their contribution to macrophages in fetal and adult organs relative to bone marrow macrophages are still unclear. Using lineage tracing, Elisa Gomez Perdiguero et al . identify a population of yolk-sac-derived progenitors — distinct from fetal and adult haematopoetic stem cells — that gives rise to erythrocytes, macrophages, granulocytes and monocytes in the young mouse fetus, and to the vast majority of adult tissue-resident macrophages. Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs) 1 , 2 , 3 , however, macrophages in adult tissues can self-maintain independently of HSCs 4 , 5 , 6 , 7 . Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs 8 , 9 , 10 , 11 , 12 , 13 , and fetal macrophages 13 , 14 , 15 can develop independently of Myb 4 , a transcription factor required for HSC 16 , and can persist in adult tissues 4 , 17 , 18 . Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear 19 . Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2 + (also known as Tek ) cellular pathway generating Csf1r + erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

Inducible genetic labelling of haematopoietic stem cells (HSCs) and linked mathematical modelling show that at least 30% of all HSCs are productive, and that adult haematopoiesis is largely sustained by ‘short-term’ downstream stem cells that operate near self-renewal in the steady state; HSC fate mapping provides a quantitative model for better understanding of HSC functions in health and disease. Following haematopoiesis in vivo Most of what we know of the properties of haematopoietic stem cells (HSCs) is derived from transplantation and reconstitution of an emptied blood and immune system. Relatively little is known about how HSCs behave under physiological conditions. It was reported recently that normal haematopoeisis in adults is driven by thousands of long-lived progenitors rather than classic HSCs. Hans-Reimer Rodewald and colleagues have used inducible genetic labelling of primitive HSCs in a mouse model, combined with mathematical modelling, to show that although HSCs participate in establishment of the blood system in early life, steady-state haematopoiesis depends mainly on progenitors that are able to self-renew but also receive rare input from long-term HSCs. This input is increased following physiological challenges. Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation 1 , 2 , 3 , 4 , 5 . Chromosomal marking 6 , viral integration 7 , 8 , 9 and barcoding 10 , 11 , 12 of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2 + HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ∼5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse’s life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated ‘short-term’ stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.

An artificial recombination locus, Polylox , that can generate hundreds of thousands of individual barcodes is used to trace the fates of haematopoietic stem cells in mice. Barcode tracking blood stem cells Transplantation-based assays of haematopoietic stem cells (HSCs) and progenitors isolated on the basis of the expression of their surface markers have inferred that the haematopoietic lineage follows a tree-like structure that starts from a long-term multipotent HSC at its base and splits into a few major branches. However, recent data question the existence of this structure, instead supporting the idea that the blood lineage is sustained by several fate-restricted progenitors. Hans-Reimer Rodewald and colleagues have developed a DNA recombination locus based on the Cre– loxP system that can tag single cells using several hundred thousand barcodes. They introduce the labelling in mouse embryos and track HSCs during their life. Surprisingly, the adult HSC compartment is a mosaic of HSC clones derived from embryos and contributes with different proportion to blood lineage, some multilineage and others of restricted fates, according to a pattern that is consistent within clones. However, they define an early split of fate between myeloid erythroid and lymphocyte development which agrees with the tree-like structure. Developmental deconvolution of complex organs and tissues at the level of individual cells remains challenging. Non-invasive genetic fate mapping 1 has been widely used, but the low number of distinct fluorescent marker proteins limits its resolution. Much higher numbers of cell markers have been generated using viral integration sites 2 , viral barcodes 3 , and strategies based on transposons 4 and CRISPR–Cas9 genome editing 5 ; however, temporal and tissue-specific induction of barcodes in situ has not been achieved. Here we report the development of an artificial DNA recombination locus (termed Polylox ) that enables broadly applicable endogenous barcoding based on the Cre– loxP recombination system 6 , 7 . Polylox recombination in situ reaches a practical diversity of several hundred thousand barcodes, allowing tagging of single cells. We have used this experimental system, combined with fate mapping, to assess haematopoietic stem cell (HSC) fates in vivo . Classical models of haematopoietic lineage specification assume a tree with few major branches. More recently, driven in part by the development of more efficient single-cell assays and improved transplantation efficiencies, different models have been proposed, in which unilineage priming may occur in mice and humans at the level of HSCs 8 , 9 , 10 . We have introduced barcodes into HSC progenitors in embryonic mice, and found that the adult HSC compartment is a mosaic of embryo-derived HSC clones, some of which are unexpectedly large. Most HSC clones gave rise to multilineage or oligolineage fates, arguing against unilineage priming, and suggesting coherent usage of the potential of cells in a clone. The spreading of barcodes, both after induction in embryos and in adult mice, revealed a basic split between common myeloid–erythroid development and common lymphocyte development, supporting the long-held but contested view of a tree-like haematopoietic structure.

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between ‘young’ bone-marrow-derived and ‘old’ thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1 , transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1 . Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors. T cells develop from thymic precursor cells that are constantly replaced with newly arriving bone marrow progenitor cells, and the ‘old’ and ‘new’ cells are shown here to compete; in the absence of cell competition, when the influx of new bone marrow progenitor cells is blocked, the old cells acquire the ability to self-renew and eventually become transformed, leading to the development of a form of leukaemia. New T cells for old in the thymus In the thymus, T cells develop from precursor cells that are constantly replaced by newly arriving bone marrow progenitor cells. Hans-Reimer Rodewald and colleagues show that this is the result of competition between the 'old' and 'new' cells. In the absence of cell competition, when the influx of new bone marrow progenitor cells is blocked in mice, old cells reacquire the ability to self-renew and eventually become transformed, leading to the development of T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease. At the same time there are changes in gene expression and the appearance of genetic mutations often also found in human T-ALL. Thus cell competition can act as a tumour-suppressor mechanism. This work may also help to explain the widely discussed T-cell leukaemia seen in X-linked severe combined immune deficiency patients after therapy with gene-corrected autologous progenitors.

Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.