Dual Origins of Tissue Macrophages

Health & Medicine ︱ Professor Christian Schulz

ost people with an interest in Fate mapping (green) of yolk-sac- biology will be able to tell you derived alveolar Dual origins of Mthat macrophage cells are an macrophages important component of our immune system. By enguling and digesting microbes, cellular debris, foreign substances and anything else that isn’t tissue macrophages a healthy body cell, they help to protect us against injury and infection. It is now clear that macrophages are present in Macrophages – large white blood cells that play a role in tissue homeostasis and immunity – have long been thought all tissues under steady state conditions, to derive solely from monocyte cells in the circulating blood. Accumulating evidence now shows that a large and that these tissue-resident cells play proportion of the macrophage populations ‘resident’ within tissues is in fact derived during embryonic development, tissue-speciic roles: tissue remodelling, independent of monocytes. Professor Christian Schulz from Ludwig-Maximilians-Universitat, Munich, is at the angiogenesis (blood vessel formation) forefront of this research. He hopes that understanding the molecular regulation of these cells during development and regulation of cell metabolism, to and within their tissue of residence will help design interventions to treat a wide spectrum of diseases in which they name a few. Tissue-resident macrophages have been implicated. are exquisitely adapted to their local environment, acting as regulatory cells of tissue function, and this makes them an attractive target for modern medicine. Understanding the origin and regulation of these cells will be an important irst tissue macrophages have been reported in the liver) a second population of step in the development of intervention to persist for many years in transplanted macrophages appeared. strategies to control and instruct liver and skin in human patients. The Prof Schulz and colleagues set out macrophage populations. hypothesis was therefore raised of two to determine the origin of these distinct origins of macrophages: the irst newcomers. They re-examined TWO BEGINNINGS being yolk sac haematopoiesis which macrophage development, this time During development, haematopoiesis produces mature macrophages, the using mice with a deleted Myb gene. (including macrophage production) second being foetal haematopoiesis The team had previously used this irst takes place in the yolk sac (yolk sac which produces blood monocytes. mouse model to show that the protein haematopoiesis). Soon thereafter the Professor Christian Schulz and colleagues Myb is required for foetal but not yolk foetal liver becomes a hematopoietic therefore decided to reinvestigate sac haematopoiesis. The results were as site expanding hematopoietic stem the origin and development of tissue- hypothesised: YS-derived macrophages cells that migrated from the aorto- resident macrophages. developed as normal but the second gonado-mesonephros region (foetal population of macrophages did not haematopoiesis) but also of macrophage TWO POPULATIONS appear, indicating that they are indeed progenitors that derived from the yolk Among various biological tools, the of the foetal haematopoiesis. YS-derived sac. Towards the end of gestation, foetal team used a technique known as pulse- macrophages accounted for most haematopoiesis switches from the liver to labelling to map the fate of developing macrophages in tissues of embryos at 16 the bone marrow. macrophage cells in mouse embryos. days after fertilisation. They showed that macrophages derived Until recently, it was believed that tissue- from the yolk sac (YS) circulate in the Importantly, fate mapping models resident macrophages were constantly blood and colonise the embryo, starting provided evidence that YS-derived replenished from pools of circulating with the head region, nine to ten days macrophages persist in many tissues of monocytes (macrophage precursors) after fertilisation. By ten days after adult mice, in some of them (i.e., brain, produced by foetal haematopoiesis. fertilisation, the cells could be detected liver) throughout life. These indings However, this concept has been in most tissues, where they continued support the view that there are two questioned following reports that to divide. They remained detectable origins of macrophages in adult tissues; macrophages in the brain, liver, skin, in tissues throughout development. the irst are derived from the yolk sac and many other organs proliferate and From twelve days onwards (around the during early embryonic development self-renew. For example, donor-derived time that foetal haematopoiesis begins and the second are derived from foetal haematopoiesis in the liver and later the The team used a technique known as pulse- bone marrow. labelling to map the fate of developing A CLEARER VISION Thanks to this work and further work macrophage cells in mouse embryos by Prof Schulz and others, we now

www.researchoutreach.org www.researchoutreach.org Behind the Bench Prof Christian Schulz

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Research Objectives Collaborators Munich. He then moved to the United Prof Schulz’s work focuses on the • Jon Frampton (University of Kingdom for postdoctoral work at the role of macrophages in tissue Birmingham) Centre for Molecular & Cellular Biology homoeostasis and inlammation, • Frederic Geissmann (Memorial Sloan of Inlammation and later became a speciically processes associated with Kettering Cancer Center New York) Senior Lecturer at King’s College in cardiovascular disease. • Elisa Gomez Perdiguero (Institute London. Pasteur Paris) Funding • Jeff Molkentin (Cincinnati Children’s Contact • The German Research Foundation Hospital Medical Center) Prof Christian Schulz (DFG), speciically the Collaborative Medizinische Klinik und Poliklinik I Research Centre (SFB) 914 (project BIO Klinikum der Universität München A10) Dr Christian Schulz is Professor of Ludwig-Maximilians-Universität • The German Center for Cardiovascular Immunology at the München Cardiovascular Research (DZHK) LMU Munich. He trained in Internal Campus Großhadern • Leopoldina National Academy of Medicine and worked as a Postdoctoral Marchioninistraße 15 Above: Yolk sac-derived macrophages develop Sciences Fellow at the Technical University 81377 München, Germany in tissues in the absence of foetal deinitive hematopoiesis E9.75

derived macrophages in adult tissue- It produces haematopoietic cells, which Right: Appearance of macrophages in the mouse Yolk sac Q&A embryo 9.75 days after fertilisation (before the Macrophages resident macrophage populations. Can are thought to enter the foetus in early initiation of foetal deinitive hematopoiesis) What irst piqued your interest in you explain briely how this worked? life. However, whether this concept tissue-resident macrophages? We used a so-called inducible Cre/lox identiied in mice (and zebraish) holds I was intrigued by previous reports system, which enabled us to generate true in humans is unknown. Notably, have a clearer vision of the origin that in organ transplant patients cell type- and time-speciic expression tissue macrophages in humans and development of macrophages. Embryo tissue macrophages of donor origin of a luorescent protein. By inducing can persist autonomously for years Macrophage progenitor cells appear persisted for years. This indicated expression speciically during early yolk [see comment above on transplant in the yolk sac and then invade the their self-renewal capacity and their sac haematopoiesis, we were able to patients]. developing embryo. They colonise all independence of bone marrow identify these luorescent YS-derived 500 µm foetal tissues, particularly in the head haematopoiesis. cells later in embryonic development as What are the potential therapeutic where they give rise to all of the brain well as in adult animals. targets of your research? microglia, which will continue to self- Can you give some examples of the We need to understand the regulation renew throughout adulthood. tissue-speciic functions of tissue- The development of tissue-resident and programming of macrophages Thanks to this work... we now have resident macrophages? macrophages has been characterised that fulil tissue-speciic functions in Later, foetal haematopoiesis produces • Initiation and resolution of using mouse models. Are there humans. This could potentially be used monocytes. They circulate in blood a clearer vision of the origin and inlammationx likely to be differences between as therapeutic targets in chronic tissue and need to be continuously renewed • Clearance/waste disposal (liver, macrophage development in mice and inlammation to induce inlammation by deinitive haematopoiesis. In some development of macrophages spleen) humans? resolution and improve metabolism organs, they differentiate and replace • Regulation of metabolism A yolk sac also exists in humans. and remodelling. tissue macrophages over time (e.g., MOVING ON The team also carries out genomic • Angiogenesis and vascular lung). However, this population seems Professor Schulz has now turned his analysis and proteomics to determine remodelling more important in the setting of tissue attention to the biology of macrophages macrophage programming by the • Development: bone I was intrigued by previous reports injury or inlammation. Here, monocytes in relation to their developmental paths local environment and disease-speciic morphogenesis, ductal branching, are recruited from blood into tissues, in cardiovascular disease. Similar to the signals. This work could eventually aid neuronal connectivity that in organ transplant patients tissue where they differentiate into phagocytes work described in this article, current the development of strategies to control macrophages of donor origin persisted to fulil speciic jobs/duties. They may projects utilise in vivo lineage tracing the remodelling of cardiovascular tissues, A fate mapping model was used to also renew resident macrophages if and fate mapping, as well as models for for example, after myocardial infarction. report the persistence of yolk-sac- for years needed. time- and site-speciic gene deletion.