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Early Life Microbiota, Neonatal Immune Maturation and Hematopoiesis

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THE NATIONAL FOOD INSTITUTE TECHNICAL UNIVERSITY OF DENMARK PhD thesis Matilde Bylov Kristensen Early Life Microbiota, Neonatal Immune Maturation and Hematopoiesis Submitted: 11.03.2014 Early life microbiota, neonatal immune maturation and hematopoiesis PhD thesis · 2014 Matilde Bylov Kristensen Institute: The National Food Institute Name of department: Department of Food Microbiology Author: Matilde Bylov Kristensen Title: Early Life Microbiota, Neonatal Immune Maturation and Hematopoiesis Academic advisors: Professor Tine Rask Licht, Technical University of Denmark Professor Hanne Frøkiær, University of Copenhagen Submitted: 11.03.2014 Front-page figure: Histology, hematoxylin and eosin (H&E) staining, of tissue sections of murine spleens isolated the day after birth. Liver from a germfree neonate mouse (Left) and liver from a CONV neonate mouse (Right) showing notably less hematopoietic clusters (tissue with groups of cells with darkly stained nuclei) in the liver on the right, from the conventionally colonized mouse. 10x magnification. PREFACE This thesis is submitted to the Technical University of Denmark to obtain the PhD degree. The work presented has been carried out in two groups; The first part at Department of Food Microbiology at The National Food Institute, Technical University of Denmark under supervision of Professor Tine Rask Licht, and the last part in Molecular Immunology Group at Department of Veterinary Disease Biology, Section of Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen under supervision of Professor Hanne Frøkiær. All animals were housed and bred at The National Food Institute. Experimental procedures on animals and tissues as well as some cellular analyses were carried out here. All immunologic assays, microscopic analyses and the rest of the cellular analyses were carried out at the Faculty of Health and Medical Sciences at University of Copenhagen. This study was supported by ‘globalization funds’ given as a grant to Professor Tine Rask Licht and Professor Hanne Frøkiær in 2007. 1 ACKNOWLEDGEMENTS Present thesis was never completed without the help and encouragements from so many skilled and great people. Most importantly, I want to thank both my supervisors: Professor Hanne Frøkiær for invaluable scientific guiding and constant inspiration, patience and encouragement. I am grateful for the time I have had in your fantastic group. Professor Tine Rask Licht thanks for listening and guiding me through this work, and for your effort, advices and flexibility that made it possible for me to finish this work. I also want to express my gratitude for the skilled scientists, I have had the pleasure to work with during my PhD years; Stine Broeng Metzdorff, Lisbeth Nielsen Fink, Louise Hjerrild Zeuthen and Anders Bergström. Thank you for the inspiration, effort and collaboration. Anni Mehlsen and Marianne Petersen, thank you for your skilled help and fantastic company! I am further very grateful for the technical help from Heidi Letting and Bodil Madsen at DTU FOOD, and for the great help and communication from Maja Danielsen and Anne Ørngreen, and their fellow co-workers in the stable at DTU FOOD, during the first years of my PhD. Thank you for your immense patience with the troubled breeding of germfree mice. Working in two different groups has given me the opportunity to work with many inspiring and skilled PhD students, masterstudents and Post-docs; Anne Petersen, Tine Ebersbach, Louise Kristine Vigsnæs and Lene Hemmingsen, thank you for the great time we had together in our basement office at DTU FOOD. Dina Silke Malling Damlund, Louise Hemmingsen, Lisbeth Drodz Lund, Eva Fuglsang, Rasmus Baadsgaard Mærkedahl, Gudrun Weiss, Kristina Maetoft Udsen and Ronja Mathiesen thanks for a great time at KU and for sharing the ‘tough months and the fantastic days’ with me. Additionally I had the pleasure to supervise the master students Christina Kjærgaard and Line Rieck Schmidt during their work at DTU FOOD. I hope you had a good time too. I also want to thank Professor Fredrik Bäckhed and technician Anna Hállen for valuable help with the germfree mice during my stay at Sahlgrenska Academia, University of Gothenburg in October 2010, and Erwin L. Roggen for giving a very important scientific advice in late 2012 that turned the present work upside down. Lastly, I want to thank my dear family, especially Sinus, Magnus, Jens and Anna, Mor and Far. Your love and care have been the most important factors through all the years. Matilde, March 2014 2 DANSK RESUMÉ Epidemiologiske data støtter i tiltagende grad hypotesen om at mikrobiotaen hos det nyfødte barn spiller en vigtig rolle i udviklingen af et balanceret immunsystem. Forhold tidligt i livet, som fødselsmåde og spædbarnets ernæring, har vist sig at have indflydelse på udviklingen af immunrelaterede sygdomme senere i livet. Sygdomme som diabetes, astma og inflammatoriske tarmsygdomme er relateret til den tidlige kolonisering af tarmen. Tarmepitelet udgør en fysisk og kemisk barriere mellem bakterierne i tarm lumen og immuncellerne i det submukosale væv. Tarmens epitelceller danner en meget stort mono-lags overflade og er af stor betydning for den synergistiske sameksistens mellem milliarder af bakterier i tarmen og deres mammale vært. Tarmens epitel celler kommunikerer aktivt med bakterierne i tarmen, og denne sameksistens er med til at etablere en nyttig tolerancetilstand i tarmen. Tarmens homeostase fremmes af en balanceret og kontrolleret kommunikation mellem tarmcellerne og de kommensale bakterier i tarmen. Hematopoietiske stamceller fra den føtale lever distribueres via blodet til den føtale/neonatale milt og marv i den perinatale fase. I spædbørn og nyfødte mus beskrives en markant øgning af granulære celler i blodet i de første dage efter fødsel. Dette er en naturlig del af den neonatale hematopoiese. Tilstedeværelse af granulære myeloide suppressor celler i humant navlestrengsblod er beskrevet i en helt ny artikel. Disse granulære suppressor celler er tidligere beskrevet i forbindelse med cancer, inflammation og under sepsis. De dannes i forbindelse med den myeloide hematopoiese og flere nyligt beskrevne studier viser en immunregulerende rolle for disse celler i den nyfødte. I nærværende studie viste vi tilstedeværelsen af en dominerende gruppe af CD11b+Gr-1+ celler in den nyfødte musemilt. Tilstedeværelse af disse celler var mikrobiota afhængig, idet kimfrie mus havde markant færre af disse celler i milten i den første leveuge. Mikroskopidata indikerede at disse celler stammede fra hematopoietisk væv i den nyfødte mus, og at mobilisering og aktivering af dette væv blev fremmet af en konventionel kolonisering af tarmen. Regulering af tarmens barriere var påvirket af mikrobiotaen, idet ekspressionsstudier af tight junction protein gener viste en hurtigere og strammere regulering af disse gener i nyfødte mus med en konventionel mikrobiota end i den kimfrie mus. Den komplekse mikrobiota fremmer desuden ekspression af gener involveret i mucin sekretion, TLR signalering og cytokin produktion i tarmen, mens den nedregulerer gener for chemokin ekspression samme sted. Ny viden indikerer at den dominerende CD11b+Gr-1+ cellegruppe kan være immunregulerende celler af betydning for den tidlige etablering af tolerance i den nyfødte, men det er ikke bevist i dette studie. 3 ABSTRACT Emerging epidemiologic data supports the hypothesis that early life colonization is a key player in development of a balanced immune system. Events in early life, as birth mode and infant diet, are shown to influence development of immune related diseases, like asthma, diabetes and inflammatory bowl disease, later in life. The intestinal epithelium makes up a physical and biochemical barrier between the bacteria in the gut lumen and the immune cells in the submocusal tissue. This monolayer of intestinal epithelial cells (IEC) makes up an extremely large surface and is highly important for the synergistic coexistence between trillions of bacteria in the gastrointestinal tract and their mammalian hosts. The IEC actively communicate with the microbiota of the gut lumen and tolerance establishment in the intestine is induced as a result of a balanced and controlled communication between IEC and the commensals in the gut. Hematopoietic stem cells from the fetal liver seed the fetal spleen and bone marrow in perinatal phase. Granulocytosis in neonate mice and man just after birth is a natural event of early life hematopoiesis and likely contributes to elevated counts of neutrophil-like cells in the peripheral blood of newborns. Granular myeloid derived suppressor cells (MDSC) have recently been described in human cord blood. MDSC are potential immunosuppressive cells often described in cancer, inflammation and during sepsis. They evolve from immature myeloid cells during hematopoiesis. Several recent studies show a role for various myeloid derived and immune suppressive cellular subsets in the newborn. In the present work we showed the presence of a prominent group of CD11b+Gr-1+ cells in the neonate murine spleen. The presence of these cells were dependent on the colonizing microbiota, as germfree neonate mice held notably fewer of these cells in the spleen. Microscopy of spleens and livers indicated that these cells derived from hematopoietic tissue in the liver of the neonate mouse, and that mobilization and activation of the hematopoietic tissue is promoted by the presence of colonizing microbes. The regulation of epithelial barrier integrity
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