Innate Immune Memory and Transcriptional Profiling of Microglia
Heng, Yang
DOI:
10.33612/diss.151944032
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Publication date: 2021
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Heng, Y. (2021). Innate Immune Memory and Transcriptional Profiling of Microglia. University of Groningen. https://doi.org/10.33612/diss.151944032
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Chapter H
Nederlandse samenvatting
Acknowledgements
Curriculum vitae
Nederlandse samenvatting
Onze hersenen bestaan grotendeels uit zenuwcellen en drie soorten glia cellen: oligodendrocyten, astrocyten en microglia. Oligodendrocyten zijn belangrijk voor de geleiding van elektrische signalen door zenuwcellen. Astrocyten geven steun aan het hersenweefsel, dragen bij aan de energievoorziening van zenuwcellen en vormen de bloed-hersen barrière. Microglia spelen een belangrijke rol bij het gezond houden van het zenuwstelsel en deze cellen zijn het onderwerp van de studies beschreven in dit proefschrift.
Microglia hebben dunne, beweeglijke uitlopers waarmee ze voortdurend het omliggende hersenweefsel aftasten. In het geval van weefselschade of een mogelijke infectie, raken microglia geactiveerd, en nemen het beschadigde weefsel of microben op. Daarnaast zijn microglia belangrijk voor het maken en onderhouden van verbindingen tussen zenuwcellen.
Ons erfelijke materiaal, het DNA, bevindt zich in de kern van cellen. Het DNA bevat genen, die de informatie bevatten om eiwitten mee te maken. Als een gen actief is, wordt er door middel van transcriptie van het DNA een RNA-kopie afgeschreven. Deze RNAs worden vervolgend vertaald in eiwitten door middel van translatie. Welke RNAs aanwezig zijn in een cel geeft inzicht in welke functies een cel kan uitvoeren.
Het afgelopen decennium zijn onze inzichten in microglia-biologie aanzienlijk uitgebreid dankzij de vooruitgang in beeldvorming en microscopie, het bepalen van welke genen actief zijn in microglia door middel van RNA-sequencing, en het volgen van microglia in de tijd door specifieke genetische modellen in combinatie met beeldvormingstechnieken.
Hoofdstuk 1 geeft een algemene inleiding op dit proefschrift. Een selectie van recente
studies die deze technieken gebruiken met betrekking tot de oorsprong van microglia, hoe lang ze onder normale omstandigheden overleven, hun eigenschappen en verschillen onder normale omstandigheden en bij ziektes.
Voor veel hersenaandoeningen is leeftijd de grootste risicofactor, zoals bijvoorbeeld voor de ziekte van Alzheimer. In hoofdstuk 2 wordt een aantal veel gebruikte muis
Nederlandse samenvatting
8
modellen besproken die gebruikt worden om veroudering van het centrale zenuwstelsel te bestuderen, met speciale aandacht voor neuronen, astrocyten, oligodendrocyten en microglia.
Microglia kunnen chronisch worden geactiveerd door hun lokale omgeving, wat resulteert in een versterkte reactie op een ontsteking, een fenomeen genaamd microglia priming. Dit is in muizen waargenomen tijdens veroudering en in muizen met uitgebreide schade of degeneratie van het hersenweefsel. Muizen waarin een eiwit (Ercc1) dat nodig is voor het herstel van DNA-schade niet meer functioneert, lijden aan versnelde veroudering. Ook in Ercc1-deficiente muizen treedt microglia priming op. In hoofdstuk 3 werd het Ercc1 gen specifiek verwijderd uit microglia, en zijn de gevolgen daarvan in kaart gebracht. Twee maanden na het verwijderen van Ercc1, werd een uitgebreid verlies van microglia waargenomen in verschillende hersenregio's. Als reactie op dit verlies, nam een deel van de resterende microglia aanzienlijk toe in grootte. Deze vermindering in aantal en veranderingen in de grootte van microglia hielden aan tot 12 maanden na uitschakeling van Ercc1. Geleidelijk aan werden de microglia die geen functioneel Ercc1 gen hadden, vervangen door cellen met intact
Ercc1 gen en herstelden zowel het aantal als de grootte van microglia.
Naast de lokale omgeving hebben eerdere blootstellingen aan weefselschade of ontstekingsreacties invloed op de reactie van microglia op een nieuwe stimulus. Dit vermogen van microglia om eerdere stimuli te ‘onthouden’ is onderzocht in hoofdstuk 4. Daarin is vastgesteld of systemische toediening van β-glucan, een component van de celwand van schimmels, of lipopolysaccharide (LPS), een component van de celwand van Gram-negatieve bacteriën, het geheugen van microglia kan beïnvloeden. Muizen werden eerst blootgesteld aan β-glucan of LPS, en de reactie van microglia op deze stimuli bepaald. Microglia vertoonden een klassieke ontstekingsreactie in reactie op LPS maar niet na blootstelling aan β-glucan. Ook werden muizen eerst met β-glucan of LPS behandeld en daarna blootgesteld aan een tweede stimulus, LPS. Als muizen eerst werden blootgesteld werden aan β-glucan of LPS, en binnen 2 dagen een tweede stimulatie met LPS ontvingen, zagen we een versterkte reactie op deze tweede LPS-toediening. Deze versterkte reactie was niet langer aanwezig wanneer de tweede
stimulus 7 of 14 dagen na de eerste blootstelling werd gegeven, en in geval van een LPS-voorbehandeling werd de reactie op een tweede LPS-stimulatie zelfs minder sterk, oftewel immuun tolerantie. Deze resultaten laten zien dat microglia een ‘geheugen’ hebben, en dat herhaalde blootstelling van microglia aan dergelijke stimuli hun reactie op een volgende stimulatie kan versterken of onderdrukken.
In hoofdstuk 5 werden de genexpressie profielen van microglia cellen en kernen uit vers en bevroren hersenweefsel van muizen en mensen met elkaar vergeleken. Het gemeten genexpressie patroon in kernen van zowel muis- als menselijke microglia bleek vrijwel gelijk te zijn aan het genexpressie profiel van microglia cellen. Ook veranderingen in genexpressie in reactie op een stimulatie met LPS was zowel in microglia cellen als kernen goed te meten en vergelijkbaar. Een belangrijke observatie was dat het RNA-profiel van menselijke microglia-kernen, geïsoleerd uit bevroren hersenweefsel, sterk lijkt op het genexpressieprofiel van vers geïsoleerde kernen en cellen. Daarmee is het namelijk mogelijk om betrouwbare genexpressie profielen te genereren van al in hersenbanken ingevroren en goed gekarakteriseerde weefsels. In hoofdstuk 6 werd het effect van postmortem interval (PMI) op het genexpressie patroon van microglia onderzocht. Microglia werden geïsoleerd uit muizen met een toenemende PMI: 0, 4, 6, 12 en 24 uur. Het aantal levensvatbare microglia nam duidelijk af met toenemende PMI, maar kwalitatief hoogwaardig RNA kon nog steeds worden verkregen, zelfs na 12 uur PMI. Het genexpressie profiel van microglia met verschillende PMI liet zien dat slechts 50 van de 15.554 gedetecteerde genen differentieel tot expressie kwamen tussen verschillende PMI-tijdstippen. Vervolgens is onderzocht of de expressie van de menselijke homologen van deze PMI-gerelateerde muis microglia-genen ook verandert in menselijke microglia in relatie tot PMI. De expressie van deze genen correleerde negatief in humane microglia met PMI, met andere woorden, de expressie nam af met toenemende PMI. Deze resultaten laten zien dat tot aan 12 uur, het effect van PMI op microglia-transcriptomen zeer beperkt is. In hoofdstuk 7 wordt een samenvatting gegeven van de resultaten die in dit proefschrift beschreven zijn en worden de gegevens bediscussieerd in de context van relevante literatuur. Daarnaast worden de implicaties en perspectieven van de behaalde resultaten besproken, en suggesties gedaan voor mogelijk vervolgonderzoek.
Acknowledgements 8 Acknowledgements Times goes by surprisingly fast. Looking back this more than 4-years journey, now, I can convincedly say that I have never regretted to pursue my PhD in the Netherlands, never regretted to come to Groningen, and never regretted to work in Section Molecular Neurobiology (previous Section Medical Physiology). This is not only because of my personal development both inside and outside academia during these years. This is even more because of the wonderful and lovely people I met during this journey. I feel blessed to have all of you in my life.
First, I would like to express my deepest gratitude to my promoters Prof. dr. Bart
Eggen and Prof. dr. Jon Laman, and co-promoter Dr. Susanne Kooistra.
Dear Bart, I enjoyed a lot working under your supervision during my PhD. What you impressed me most is that your endless enthusiasm for science, your good taste for research, and at same time, being an approachable person. I still remember, when I first came to the lab and took over the Ercc1 project from Xiaoming. At that time, I had no idea about Cre-loxp system and breeding strategy. You explained every single uncertainty I had, and started to draw on the paper to help me to understand the strategy. In the end, I had 3 or 4 pages of your ‘drawing’. This is just an example. In the past four years, you have always been supportive and patient to me. This is even more true when I come across failure in my heterogeneity project and tdtomato reporter breeding line. I could feel that you were also frustrated or upset about it. But you shared your stories in the US, and kept encouraging me. Also, you pointed out that the good thing about PhD is that you are allowed to have failure or mistakes, and learn from it. Of course, you are also a charming person privately. Especially now during this corona time, I really miss the loud and clear laugh coming from your room through the corridor. You are a wonderful supervisor to me, and I have learned tremendously from you both professionally and privately. With words, I think I can’t thank you enough for the help and support that you had given me in the past years. I wish you all the very best and lots of success in the microglia filed.
Dear Jon, first of all, thank you for giving me the opportunity to study in UMCG. I still remember how excited I was to talk with you via the phone in early 2016 (if I remember correctly). Thanks for your efforts in guiding me through thesis writing, especially on introduction and discussion, the two chapters which troubled me a lot. You basically helped me correct the two chapters word by word, and taught me how to make the sentence more understandable for the readers. I benefit a lot from the important details you pointed out in my thesis. I really appreciate that every now and then, you just come by my office and give me relevant papers, books, thesis to me. I am also grateful that you always give your compliments and suggestions to me after my presentation. It has been a pleasure experience to do PhD under your supervision. I wish you the very best of luck and lots of success in your future research and career. Dear Suus, in the past 4 years, I have received tremendous helps from you. You helped me to setup Ercc1 breeding pair, gave me suggestions on RNA-seq library preparation, taught me how to do ATAC-seq, provided me constructive inputs on manuscripts and thesis... I have enjoyed a lot working with you, and you have always been the person I would like to find when I have practical problems. I still remember you helped me sorting several times after working hours. Thank you from my bottom of my heart for being so patient and supportive to me. Freeman once said to me that, Suus is so brilliant that as if she comes with an aurora. Indeed, I completely agree that you have very good sense of doing science and usually can come up with very crucial opinions or suggestions. May you have new and exciting findings in the microglia epigenetic research. Also, wish you and your daughters all the best. I would also like to express my gratitude towards Prof. dr. Erik Boddeke. Dear Erik, actually, you are the first person I met from UMCG. We had an interview back to Nov, 2015 in the PhD workshop in Beijing. Thank you for forwarding my information to my supervisors, which makes it possible for me to pursue my PhD here. Your dedication to work and your passion to the cutting-edge research impressed me most. I truly appreciate the suggestions you gave me and discussions we had for my projects. I wish you many successes both as a researcher and as the dean of research in UMCG.
Acknowledgements
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I would like to acknowledge the members of my thesis assessment committee: Prof. dr.
H.E. de Vries, Prof. dr. L.A.B. Joosten, and Prof. dr. J.W. Jonker for the carefully
reading and approving my thesis.
Working in Section Molecular Neurobiology (previous Section Medical Physiology) has always been a pleasant experience for me. I do not need to worry about ordering, equipment, and consumables. There are always hands around when you need technical help. Also, I really enjoyed the working atmosphere in our section. The colleagues here are warm-hearted and down-to-earth people. Here, I would like to express my sincere appreciation to my dear colleagues, Trix van der Sluis-Rozema, Dr. Hilmar van
Weering, Nieske Brouwer, Evelyn Wesseling, Maaike Brummer, Michel Meijer, Tjalling Nijboer, Dr. Rob Bakels, Dr. Inge Zijdewind, Dr. Inge Holtman, Ietje Mantingh-Otter, Prof. Dr. Armagan Kocer, Dr. Hiske van Duinen, Sharon Brouwer, Harry Moes, Henk Heidekamp, Wytze Hogewerf and Dr. Wieb Patberg.
Dear Trix, the best secretary ever! Thank you so much for your always timely and effective helps on all the documentations related to my work. Without you, life would be much much harder for me. Thank you for organizing the lab day, Xmas party and always remembering everyone’s birthday. I will miss so much the ‘teeeeeeeeeea’ or ‘caaaaaaaaaake’ sound coming through the corridor around 10 o’clock. I wish you all the happiness and health. Dear Hilmar, we worked together closely in the past 4 years. Thank you for developing the morphometric pipeline, which enables us to finalize Ercc1 and beta-glucan project. I was quite moved that you worked so hard on the cell selection, thresholding, and statistics. You always have a good taste for the figure layout and design, and provide me very practical feedbacks for the manuscript. They are all incorporated in the two chapters of this thesis. You can always perform the experiment neatly and visualize the data decently. I just feel so comfortable to let you in charge of some of my experiments. I also enjoyed a lot talking with you about the electronics. May you, Suus and your two girls lots of success and happiness.
Dear Nieske, I learned tremendously from you on microglia isolation and library preparation. I am truly impressed that you have worked in our section for more that 40
years (of course, I will never forget your lovely 40-year work anniversary party!). I am impressed even more that after 40 years, you still keep the enthusiasm for the work, and it seems never changed. In the section, you are always there and ready to give me hands when I ask. In private life, you are such an approachable, compassionate and kind person. I enjoyed a lot having conversation with you. I do feel you are the pillar that holds our section. Without you, we cannot work that smoothly and pleasantly in our section. I really wish I could have your spirit in my future career after decades of working. Here, I wish you and Jon ‘gezondheid’ and all the best!
Dear Evelyn, I extremely appreciate the numerous genotyping you did for our Ercc1 mouse line. Thanks for maintaining breeding pairs in the CDP and keeping PCR primers/reagents/consumables well-organized. Whenever I need help from you, you are always there. And you always go with me to the lab, and tell me what did you used, where could I find it and how could I use it. I really appreciate that. Here, I wish your husband, your kids all the very best!
Dear Maaike, thank you very much for developing morphometric pipeline. I am also very grateful for the analyses of RNA-seq and ATAC-seq data of my heterogeneity project, although that part is not included in the thesis. It has been a pleasant experience for me to work together with you. Good luck with your future career and horse riding! Dear Michel, thank you very much for the timely ordering of all the reagents and consumables in our section. I enjoyed the lunch conversation with you. You are funny and versatile (being a photographer, computer engineer and wind surfing athlete). I am also really happy for you that you have found your significant other. I wish you all the best and lots of fun with the wind surfing! Dear Tjalling, thank you for developing morphometric pipeline together with Hilmar and Maaike. Thank you for maintaining all the instruments in the lab. You are the most cheerful and relaxed person I have ever met! I wish you could just keep being yourself, and all the best! Dear Rob, to me, you are the perfect gentleman coming from the classic movies. You always send you sincere greetings to others when you come across someone in the corridor. You always have good conversation with others including me. You are a charming and joyful teacher and professor for me. It even didn’t surprise me that you
Acknowledgements 8 won the best teacher award. All the best with your teaching and lots of fun with your various bikes! Dear Inge Zijdewind, although I haven’t talked to you that much in the past years, I can tell you are kind, warm-hearted and focused. I still remember that you provided Sunlu bed and other stuffs when she first came here. And you are usually the last person who left our floor. I wish you lots of success in your future research, and all the best. Dear Inge Holtman, although we haven’t worked together, I can feel your passion for science in your presentation or during the meetings. Congrats on becoming a junior group leader in our section, and l am looking forward to your exciting research findings in the near future! I would like to thanks all my PhD buddies who are still working in our section: Takuya Oshima, Chairi Misrielal, Nynke Talma, Sharon Eskandar, Marion Wijering, Laura Kracht, Malte Borggrewe, Astrid Alsema, Emma Gerrits, Anneke Miedema, Tiago Medeiros Furquim Mendonça, Roeland Prak and Mirjam Koster. I feel extremely lucky to meet you guys in my limited life. We share so many good memories together. My dear paranymph Takuya, great to meet you in the Netherlands. We did so many things together in the past 3 years, running, training in the gym, basketball, cooking, countless dinners and all kinds of parties. To me, you are a funny, simple (in a good way), easy-going and considerate guy. I just feel comfortable to interact with you. I wish you good luck with the rest of your PhD. I am also curious with your next step after PhD. Hope to meet you in Japan in the future. My dear paranymph Chairi, I am really happy that you would like to be one of my paranymphs. We actually joined the lab around same time. We share the same office for 3 years. I really enjoyed sharing our happiness and troubles with each other. You are a small, sweet and peaceful (without alcohol) girl with big heart. I wish you all the best with your last year of your PhD, and of course also with the life after PhD. My dear roommates Nynke and Sharon, the Karaoke sisters. Together with Chairi, we had so much fun together. I just feel so happy and blessed to know you guys and share the same room with you in the past 3 years. We had our secret office drinking party, non-stop-eating-hotpot nights, dumplings-making dinner, crazy and funny
gaming/drinking nights. And for Nynke and Sharon, we did skydiving and Texel trip together. I really appreciated that small break during that time. Nynke, you are such an optimistic, easy-going, and open-minded girl. I am truly believed that your life won’t be boring since you just can find so many things to enrich your life like climbing, swimming, and pole dancing. I wish you could keep enjoying the life as you do now, and best of the luck for your future. Sharon, you are such a funny, energetic and thoughtful girl. You can easily notice whether there is something wrong with someone and are willing to cheer him/her up. You always have a good taste and choice for the gift. I wish you all the best and have a bright future. Dear Marion, we shared so many memories together. We had hotpot, Chinese cuisine, Japanese curry rice (with Seigen, also pass my thanks to Seigen), dumplings-making dinner, gaming nights and all kinds of parties together. I was super moved that you guys secretly made a balloon with my pictures and brought a cake to celebrate my 30th birthday. You are such an easy-going, delightful and considerate girl. I wish you good luck with the work and all the best! Dear Laura, we spent more than 4 years together! We joined lots of courses together and worked on Ercc1 project and MIA model for some time. I am truly impressed by your dedication to work and your objective interpretation of the results. In private life, you are such an easy-going, calm and unprejudiced girl. You are open-minded and can accept the differences. I really enjoyed the pizza, sushi, hotpot at your place. And of course, the conversation as well. I wish you and Soeren all the best! Dear Malte, you are an organized, calm but also funny non-typical German. I am quite impressed by how professional you are being a PhD researcher. Also, I enjoyed quite a lot having random talk with you. I wish you and me both can grow more hair, haha, just kidding. I learned that you haven’t decided to stay in academia or not yet. But I am truly believed that you will have many successes in either case. Dear Astrid, you are so kind, peaceful and considerate. Remember? We won the best costume during the Halloween party! I really enjoyed our skydiving trip to Texel and amazing food and wine we had in Porto. You have very good talent in pooling also. I wish you all the best in the future. And, I hope you get your driver license soon.
Acknowledgements 8 Dear Emma, you are funny, dedicated and proactive. We worked extensively on the nuclei project. Actually, I somehow feel that I have watched you grow, since you also have done your internship in our lab. It really impressed me how fast you could switch from Bachelor student to PhD researcher. Now, you prove yourself to be an expert on singe-cell/nucleus RNA-seq. I wish you lots of success in your projects, and all the best. Dear Anneke, you are easy-going, kind and organized. Together with Astrid, we won the best costume during the Halloween party! It was a good memory. It is a pity that I cannot attend your wedding with Niels due to the corona. But I wish you all the best and may you have a great wedding.
Dear Tiago, you are smart, cheerful and dedicated. In my opinion, your scientific attainments have made you quite outstanding in your peers. And I truly think this is because of your enthusiasm and dedication for your research. Without doubts, I think you will have lots of success in your research. At the same time, I wish you have a wonderful life in the Netherlands. Dear Roeland, you are such an easy-going, peaceful and kind guy. After years, I realized the ‘’go! go! go! go!” sound is from you. Now, I really miss that. And, I am impressed how fast you can run. I wish you all the luck and happiness in your future work and life. Dear Mirjam, I am happy for you that you have gotten the PhD position after doing internship in our section. Wish you lots of success in your PhD journey. I also would like to thanks all the PhD buddies who previously worked in our section for your kind help and company: Xiaoming Zhang, Claudio Tiecher, Qiong Jiang,
Javier Gustavo Villamil Ortiz, Marissa Dubbelaar, Mengfei Cai, Lu Sun, Leroy Schreuder, Clarissa Haas, Zhuoran Yin, Jaime Mondragon, Coren Grit, Koen van Zomeren, Arun Thiruvalluvan, and Alain Dekker. Dear Xiaoming, you are both a teacher and a friend to me. I learned tremendously from you when I worked together with you. You are organized, peaceful and focused. I am amazed that how well you can arrange your work and private life. I have been to your place several times. And, I am glad to meet Ping and your mom and your lovely two kids Dongdong and Ruirui there. I still missed the steamed bun from you mom. I wish you
lots of success as a postdoc and for your future career. Also, I wish your wife Ping, your kids and your other families all the very best! Dear Claudio, I am super super happy to know you in the Netherlands. You are such a cheerful, friendly, considerate and relaxed guy. I am really happy to be able to visit your home Caldonazzo during Christmas. It was a good memory for me. Now, I really miss the amazing food, grappa, all types of wine and your warm-hearted families. In the past 4 years, we ran together, we played basketball together, we played Mahjong together, and we had numerous dinners and drinks together. I just want you know that I feel so lucky and happy to be your friend. I wish you, Roos, and your families all the very best. Please do visit me when you have time, I will be more than happy to hang out with you in China. Dear Jade, you are an energetic, cheerful and hardworking guy. We worked together on the single-cell RNA-seq for my heterogeneity project. We shared our troubles and concerns about the experiments, and helped each other a lot during the 2 years you worked here. In private life, we had lots of dinners and drinks at your place, played basketball together many times, and had numerous dinners together in the UMCG. I wish you all the best and lots of happiness with your girlfriend.
Dear Javier, you are funny, easy-going and uninhibited. Although you have left our section, you funny stories still here vividly in our mind. I enjoyed a lot our special greeting way in the corridor. I am really happy that you can find a postdoc position in Nijmegen and you can be together with Caroline. I wish you all the best. Dear Marissa, we worked together on postmortem delay project and Ercc1 project. Thanks for all the analyses you did for these two projects. You are friendly and kind. I enjoyed a lot the gaming nights and your birthday parties at your place. I wish you have lots of success as a postdoc in Germany, and all the best. Dear Mengfei (Freeman), you are focused, self-disciplined and with good nature. I am really happy to hear that you are doing pretty well in Nijmegen. You impressed me with your dedication to work as well as your persistence for running. With these qualities, I fully believe that you will get your PhD degree decently, and I wish you all the best after that.
Acknowledgements
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Dear Lu Sun, you are friendly and optimistic. I am really happy for you that you have already gotten a position. Although we haven’t worked together, but I can tell you have a really good attitude toward science. I hope everything is going well for you in Göttingen, and all the best.
Dear Leroy, you are funny, easy-going and self-disciplined. I really admire your enthusiasm for training. We had lots of conversations which I really enjoyed in the lab or bar. The joke you played on Jade just stuck in my mind. It was really a good one. I wish you all the best for your future career and life. Dear Clarissa, you are warm-hearted, friendly and passionate. I really appreciate your helps when I first joined the lab. I hope you best of the luck as a postdoc in US, and all the best. Dear Zhuoran, you are peaceful, kind and dedicated. I always feel delightful to talk to you. You provided me many useful suggestions at the beginning of my PhD. I wish you and your families all the best! Dear Jaime, you are focused and learned. I really enjoyed our basketball time. I wish you lots of success in your future career, and all the best. I wish all the master students I knew from our section good luck: Jiawei Yu, Marijn Riemsma, Beau Elting, Armin Dedic, Eline Sportel, Anna Pijnacker, Raquel Flores, Ieva Rybakovaite, Tegan Otto, Tanja Grabietz, Iris Gorter and Jafta Stomp.
I would like to thanks the colleagues in our department who helped me, gave me constructive suggestions on projects, or accompanied me: Harrie Kampinga, Wia
Baron, Jody de Jong, Jacomien Jongsma, Wendy Oost, Pauline van Schaik, Qinghong Li, Yue Sun, Rianne Gorter, Dennis Lentferink and Inge Werkman.
I would like to acknowledge all the organizations that provide me the platform and/or financially support me to do research in the Netherlands. China Scholarship Council
(CSC) and UMCG for the joint scholarship. BCN and GSMS for funding my courses,
conferences, and thesis printing. Central Animal Facility (CDP) for approving my IvD and taking care of my animals. I would like to thank Klaas Sjollema from the UMCG
Microscopy and Imaging Center (UMIC) for training me on the SP8 microscope. Thanks Nancy Halsema and Jennefer Beenen from Eriba for helping me with RNA-seq. Special thanks to Johan Teunis, Geert Mesander, Theo Bijma and Wayel Abdulahad from The Flow Cytometry Unit (FCU) for the technical support. I think FCU is the third most familiar facility in UMCG for me apart from my lab and CDP. You guys have always been supportive and helpful to me. Dear Johan, you are funny, kind and easy-going. I enjoyed a lot talking with you about electronics and gaming. I wish you all the best. Dear
Geert, you are focused, peaceful and versatile. I am so happy that we have done
paragliding with you. I wish you every success and happiness. Dear Theo, you are calm, funny and with good nature. I wish you and your daughters all the best. I would like to thanks my friends whom I have met during my stay in the Netherlands. Yingying Cong, Yi Yu, Chenglong Deng, Yanxi Zhang, Xin Zhao, Bin Jiang, Changsen Leng, Yingying Cui, Peng Wang, Yuanke Liang, Hongping Wan, Xinghong Zhao, Min Zhang, Congying Xia, Xiu Jia, Yang Liu, Yuchen Du, Jie Ma, Kaisheng Zheng, Miaozheng Huang, Daozheng Yang, Lin Zhou, Cong Duan, Yi Zhang, Xingdong Zhou, Xiaoyan Wang, Xiaoxiang Ren, Qian Wang, Yi Wu, Yue Sun, Jiacong Wei, Shang Li, Fan Liu, Chunli Kong, Shuxian Hu, Yingqiu Wu, Chao Guo, Ting Huang, Tingli Mo, Qi Xu, Runlei Ma, Ge Sun, Canxia Shi, Mengfan Zhang, Weiteng Guo, Zhibo Li, Yanyan Liu, Peijia Jiang, William Kure, Zeus Tlaltecutli Dominguez Vega… Thank
you all for becoming a part of my life.
Dear Yingying Cong, you are cheerful, funny and passionate. I am really happy to know you in the Netherlands. We had so much fun together. We went to Switzerland, Iceland, Strasbourg, Bergen op zoom, Walibi, and had numerous dinners, parties and BBQ together. It is also a pleasure for me to meet Yue Gu via you. I wish both of you lots of success in your future career, and all the best. Dear Yi Yu, my ‘laotie’. You are peaceful, dedicated and considerate. I enjoyed a lot the days we travelled together, skiing, and lots of hotpot we had. I hope everything is going well for the last part of you PhD. And I wish you and your girlfriend Tingting Zheng all the best.
Acknowledgements 8 Dear Chenglong Deng and Yanxi Zhang. I am glad to meet you two in the Netherlands. We all love electronics. It was a good memory for me to go to MediaMarkt with three of us every now and then. I hope you both good luck and all the best. Dear Xin Zhao, it is always delightful to talk with you about random stuff. I hope you every success, and I hope I can meet you in China once we have time. Dear Bin Jiang, you are energetic, passionate and easy-going. I am always happy to hang out with you in parties, bars and horse riding. Glad that you are now settled and have a baby. Wish you and your families all the best. Dear Changsen Leng& Yingying Cui, great to know you couple here, I wish you all the best for your new jobs in Guangzhou. Dear Peng Wang, I wish you all the best for your job in Ningxia. Dear Yuanke Liang, greet to meet you in Groningen. I wish everything is going well for your new job in Shantou, and all the best. Dear Hongping Wan and Min Zhang, we arrived in Groningen at the same day in 2016. Now, 4 years have passed, I am super happy we are still in touch. I wish you both all the best. Yang Heng
中文致谢 在这里，我要感谢我母校北京协和医学院，药物研究所的老师们一路以来对我的帮助。他们 是苑玉和研究员，陈乃宏研究员，胡金凤老师，楚世峰老师，张钊老师，王真真老师。同时， 我也要感谢求学道路上遇到的师兄师姐师弟师妹以及同学对我的帮助和陪伴，他们是杨鹏飞， 周恒，温志霖，牟正，高岩，夏聪媛，张帅，张美金，温璐，张秋双，邵千航，艾启迪，黄 菊阳，马寅仲，李建平，闫加庆，左玮，王莹莹，娄玉霞，任倩…以及一起来到欧洲求学的李 波和尹森。 我要感谢，一直以来陪伴我的，天津中医药大学的同学们。他们是龚剑波，李浩，刘小平， 王兴路。我想和龚剑波和李浩说，十分庆幸和开心，在认识 11 年以后，即使远隔重洋，我们 还能一起愉快的打 dota。 我要感谢我的爷爷奶奶，我的大爷大娘，老叔老婶，以及我可爱的弟弟衡宇，衡威。感谢我 的姥姥姥爷，大姨大姨夫，老姨老姨夫及其家人。以及我在天津求学期间，照顾我的老爷爷 老奶奶，大姑，老叔老婶。同样，感谢大家族里面其他亲人一路以来对我的照顾。 亲爱的爸爸妈妈，我难以想象，在我成长的过程中，你们为我付出了多少心血。可能真的只 有我有了孩子那一天，我才能完全并且真切地感受到。我十分庆幸和感恩我们是一家人。虽 然物质上我们不是很富有，但是我们过得很踏实，很平安。我从你们身上学到了要脚踏实地， 要善良。亲爱的衡远，我的弟弟。自从上高中以来，我和你相处的时间就没那么多了。我现 在有时候很怀念我们小时候一起打闹的日子。我很高兴你成功找到了工作，也在很认真地， 踏实地，一步一步走向更好的生活。希望以后，我能多陪陪你们，一起健健康康，快快乐乐 地生活下去。 衡洋
Curriculum vitae 8 Curriculum vitae Yang Heng PERSONAL INFORMATION Name Yang Heng Sex Male Date of birth September 9th, 1990 Place of birth Chengde, Hebei, China EDUCATION AND PROFESSIONAL EXPERIENCE Nov. 2016-present University Medical Center Groningen, Groningen, The Netherlands PhD candidate in Neuroscience PhD thesis: Innate immune memory and transcriptional profiling of microglia Promoters: Prof. dr. Bart J.L. Eggen and Prof. dr. Jon D. Laman Co-promoter: Dr. Susanne M. Kooistra Sep.2013-Jul.2016 Peking Union Medical College, Beijing, China Master degree in Pharmacology
Master project: The neuroprotective effects of Ginsenoside Rg1 in the MPTP-probenecid-induced parkinsonism in mice
Supervisor: Prof. dr. Yuhe Yuan
Sep.2009-Jul.2013 Tianjin University of Traditional Chinese Medicine, Tianjin, China
Bachelor of Pharmacy in Chinese Medicine
Bachelor project: Synergistic protective effects of tetramethylpyrazine and coumarins extracts of Radix Angeliea dahurica against cerebral ischemic reperfusion injury induced by transient focal ischemia
PUBLICATIONS
• Heng Y, Zhang XM, Borggrewe M, van Weering HRJ, Brummer ML, Nijboer TW, Joosten LAB, Netea
MG, Boddeke EWGM, Laman JD, Eggen BJL. Systemic administration of β-glucan induces immune training in microglia. (Submitted)
• Heng Y, Dubbelaar ML, Boddeke EWGM, Eggen BJL (2020) The effects of post-mortem delay on
mouse and human microglia gene expression. Glia 10.1002/glia.23948 (co-first author)
• Heng Y, Zhang XM, Kooistra SM, van Weering HRJ, Brummer ML, Gerrits E, Wesseling EM, Brouwer N,
Nijboer TW, Dubbelaar ML, Boddeke EWGM, Eggen BJL (2020) Intrinsic DNA damage repair deficiency results in progressive microglia loss and replacement. Glia 10.1002/glia.23925 (co-first author) • Heng Y, Gerrits E., Boddeke, EWGM, Eggen BJL (2020) Transcriptional profiling of microglia; current state of the art and future perspectives. Glia 68(4), 740-755 (co-first author) • Heng Y, Eggen, BJL, Boddeke, EWGM, Kooistra SM (2017) Mouse models of central nervous system ageing. Drug Discovery Today: Disease Models 25-26, 21-34 (review)
• Zhang QS, Heng Y, Mou Z, Huang JY, Yuan YH, Chen NH (2017) Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease. Acta pharmacologica Sinica 38, 1317-1328 • Zhang QS, Heng Y, Yuan YH, Chen NH (2017) Pathological alpha-synuclein exacerbates the
progression of Parkinson's disease through microglial activation. Toxicology letters 265, 30-37 (Review)
• Heng Y, Zhang QS, Mu Z, Hu JF, Yuan YH, Chen NH (2016) Ginsenoside Rg1 attenuates motor
impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting alpha-synuclein abnormalities in the substantia nigra. Toxicology letters 243, 7-21
