University of Groningen
Regenerative Pharmacology for COPD
Wu, Xinhui
DOI:
10.33612/diss.157528459
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Publication date: 2021
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Wu, X. (2021). Regenerative Pharmacology for COPD. University of Groningen. https://doi.org/10.33612/diss.157528459
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XINHUI WU
Appendix
English summary
Nederlandse samenvatting
Acknowledgement
Curriculum vitae
List of publications
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English summary
Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that result from airway and/or alveolar abnormalities. The main causes of COPD are ageing, tobacco smoke and air pollution resulting in accelerated lung function decline in susceptible individuals. However, the current treatment options can reduce symptoms, but do not reverse or slow down the progression of the disease. Recently, several new methods have been added to the portfolio of the pharmacologist and cell biologist including precision-cut lung slices (PCLS), and lung organoids, which better recapitulate the progenitor cell and its function. Both of these two models are used in this thesis. Furthermore, we unraveled the molecular mechanisms underlying cigarette smoke and air pollution-induced dysfunctional alveolar epithelial repair and discovered several potential promising therapeutic targets that could be beneficial to lung repair in COPD.
In chapter 3, we found that WNT-5A and WNT-5B repress the growth of lung organoid co-cultures of fibroblasts and alveolar epithelial progenitors, of which WNT-5B preferentially restrained both the growth and differentiation of the alveolar progenitors. In addition, we provide evidence that WNT-5A/5B result in the inhibition of WNT/b-catenin signaling in alveolar epithelium. These findings suggest that targeting the imbalance of the canonical and non-canonical WNT signaling pathway in the lung may help restore alveolar repair in COPD.
In chapter 4, the role of Rho-associated coiled-coil-forming protein kinase (ROCK) was studied in lung repair. We identified that a dual pharmacological inhgibitor of ROCK1 and 2 (compound 31) effectively prevents TGF-b-induced fibroblast-to-myofibroblast differentiation and counteracts TGF-b induced growth inhibition of alveolar epithelial progenitors. Additionally, the selective ROCK2 inhibitor (compound A11) does not affect TGF-b effects on extracellular matrix and contractile proteins but does reverse the TGF-b induced organoid growth inhibition. These findings indicate that mesenchymal ROCK1/2 inhibition may be another potential therapeutic target to help promote lung repair in COPD.
In chapter 5, we established a diesel exhaust particle (DEP) exposed organoid model to study the impact of air pollution on defective lung repair. We found that DEP exposure impaired epithelial organoid formation in vitro, which is mediated
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by various molecular signaling pathways involved in the crosstalk between alveolar epithelial progenitors and their fibroblast niche, which can be restored by antioxidants N-acetyl-L-cysteine (NAC) and Mitoquinone (MitoQ).
In chapter 6, we utilized a transcriptomics-guided drug target discovery strategy by analyzing 2 microarray datasets of lung tissues form cigarette smoke (CS)-exposed mice and COPD patients and identified 15 druggable targets expressed in alveolar epithelial progenitors of which we examined the function in CS-exposed lung organoids. We found that among all the drug candidates, PGE2 and PGI2 analogues have the most protective effects against in vivo and in vitro CS(E)-induced damage of alveolar epithelial progenitors. Furthermore, we identified that CS induces a wide range of transcriptional changes, including alterations of circadian clock and cell cycle signaling pathways, which can be counteracted by either misoprostol (PGE2 analogue) or iloprost (PGI2 analogue) treatments. Taken together, we provide several promising therapeutic strategies to specifically address defective lung repair for COPD.
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Nederlandse samenvatting
Chronisch obstructief longlijden (COPD) wordt gekenmerkt door aanhoudende ademhalingsproblemen als gevolg van luchtwegvernauwing die op zijn beurt het gevolg is van afwijkingen aan de luchtweg- en / of alveolaire structuur. De belangrijkste oorzaken van COPD zijn veroudering, tabaksrook en luchtverontreiniging, resulterend in een versnelde achteruitgang van de longfunctie bij daarvoor gevoelige personen. De huidige behandelingsopties kunnen de symptomen wel verminderen, maar de progressie van de ziekte niet omkeren of vertragen. Onlangs zijn verschillende nieuwe methoden toegevoegd aan het portfolio van de farmacoloog en celbioloog, waaronder precies-gesneden longplakjes (PCLS) en longorganoïden, die de voorlopercellen en zijn functie beter recapituleren. Deze twee modellen worden veel gebruikt in dit proefschrift. Tevens hebben we de moleculaire mechanismen ontrafeld die ten grondslag liggen aan sigarettenrook en door luchtvervuiling geïnduceerd disfunctioneel longweefselherstel en ontdekten we verschillende potentieel veelbelovende therapeutische doelwitten die gunstig zouden kunnen zijn voor longherstel bij COPD.
In hoofdstuk 3 hebben we vastgesteld dat WNT-5A en WNT-5B de groei van longorganoïde co-culturen van fibroblasten en alveolaire epitheliale voorlopers onderdrukken, waarbij WNT-5B zowel de groei als de differentiatie van de alveolaire voorlopers beperkt. Daarnaast leveren we bewijs dat WNT-5A / 5B resulteert in de remming van WNT / b-catenine-signalering in alveolair epitheel. Deze bevindingen suggereren dat het aanpakken van de onbalans van de canonieke en niet-canonieke WNT-signaleringsroute in de long kan helpen bij het herstel van alveolair herstel bij COPD.
In hoofdstuk 4 werd de rol van Rho-geassocieerde coiled-coil-vormende proteïne kinase (ROCK) bestudeerd bij longweefselherstel. We vonden dat de dubbele farmacologische remming van ROCK1 en 2 (farmacon 31) TGF-b-geïnduceerde fibroblast-myofibroblast-differentiatie effectief voorkomt en TGF-b-geïnduceerde groeiremming van alveolaire epitheliale voorlopers tegengaat. Bovendien heeft de selectieve ROCK2-remmer (farmacon A11) geen invloed op de TGF-b-effecten op extracellulaire matrix en contractiele eiwitten, maar keert deze de door TGF-b geïnduceerde organoïde groeiremming wel om. Deze bevindingen geven aan dat mesenchymale ROCK1 / 2-remming een ander potentieel therapeutisch doelwit kan zijn om longherstel bij COPD te bevorderen.
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In hoofdstuk 5 hebben we een organoïdemodel ontwikkeld dat is blootgesteld aan dieseluitlaatdeeltjes (DEP) om de impact van luchtvervuiling op defect longweefselherstel te bestuderen. We ontdekten dat DEP-blootstelling de vorming van epitheliale organoïden in vitro verstoorde, wat wordt verklaard door verschillende moleculaire signaalroutes die betrokken zijn bij de communicatie tussen alveolaire epitheliale voorlopers en de fibroblasten, die hun niche vormen. Deze verstoorde communicatie kan worden hersteld door antioxidanten N-acetyl-L-cysteïne (NAC) en mitochinon. (MitoQ). Samengevat, kan het benaderen van de defecte mesenchymale-epitheliale signalering geïnduceerd door DEP-blootstelling helpen bij longweefselherstel bij COPD.
In hoofdstuk 6 hebben we een transcriptomics-geleide ontdekkingsstrategie voor nieuwe geneesmiddelen gebruikt door 2 microarray datasets van longweefsels van aan sigarettenrook (CS) blootgestelde muizen en van COPD-patiënten te analyseren en 15 mogelijke targets geïdentificeerd in alveolaire epitheliale voorlopers in CS-blootgestelde longorganoïden. We ontdekten dat van alle kandidaat-geneesmiddelen, PGE2- en PGI2-analoga de meeste beschermende effecten hebben tegen in vivo en in vitro CS (E) -geïnduceerde schade van alveolaire epitheliale voorlopers. Bovendien hebben we vastgesteld dat CS een breed scala aan transcriptionele veranderingen induceert, inclusief veranderingen in de circadiane klok en in signaleringsroutes betrokken bij de celcyclus. Beide processen kunnen worden tegengegaan door zowel misoprostol (PGE2-analoog) als door iloprost (PGI2-analoog) behandeling. Samengevat bieden deze bevindingen verschillende veelbelovende therapeutische strategieën om op specifieke wijze defect longweefselherstel bij COPD aan te pakken.
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Acknowledgement
I can almost see it. That dream I’m dreaming, but there’s a voice inside my head saying: “You’ll never reach it!” Every step I’m taking, every move I make feels, lost with no direction. My faith is shaking, but I gotta keep trying, keep my head held high. (Climb, Miley Cyrus)
This is the song called ‘climb’, which I heard first during an NBA match online in a summer day of 2016. I remembered in that season of game, my favorite team, the Golden State Warriors lost their championship. Similarly, I lost my scholarship application to support my PhD study in the Netherlands. After rounds of arguments and disappointments, I finally persuaded my parents and received my financial support from them, and I can come to the Netherlands. Reinoud, you are the reason at that time to make me insist. When I check back on my email box, I can’t believe over 50 emails and 10 skype meetings are there just to discuss my application for this PhD position. It is a very correct decision (see this thesis). There is no single moment I regret but appreciate that I made this decision. You deserved the best PhD supervisor award! The longer I work with you, the more I learn from you, and the learning process seems endless, both in science and as a person. You never blame or judge, but always encourage and support. You are a great person, and also an excellent scientist. Without your support and training, I won’t have received so many scientific achievements to shine myself in academia. Amazingly, your gift is unlimited. As a good “actor”, dressed in a skirt, acting as a stewardess helped me to stop calling you Prof. dr. Reinoud Gosens but your voornaam. The second big decision I made is to extend my “stay”, and I strongly believe it is also a correct one. Luckily, I received this honor to work with you for another 3.5 years as a postdoctoral researcher. As our collaboration is continued, I hope you could witness my growth again.
Martina, you are a “superwoman”! As the super chair of the department, you are
always taking care of us by sending lots of super interesting cards and flowers, though your handwriting is super difficult to read. The super memorable talk we had was the second dinner at Lung Science Congress 2020 in Estoril. The conversations at that night comforted me just as the seafood comforted my belly, and the sea wind blowed out my sad emotions. Thanks for your support and all advices to the project! Also, thanks for awarding me ‘MF selfie queen’ and joined me with all the funny pictures.
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Loes, I still remember our first meet, which was in a skype meeting together with
Reinoud. You were holding an “Aquilo” mug in your hands and smiled to me, which indicated my close collaboration with Aquilo started. I really appreciate your feedbacks and suggestions on the projects, particularly to all my writings. You could always bring up a different angle to trigger me thinking, and I benefited a lot. I also remembered my first time holding a Dutch baby in my arms, though I confused the differences between Eva and Sepp when they were born not too long. They are so lovely, and I still should visit Luuk.
Amalia, you are a “workaholic”, but it made a great you, as a smart and successful
scientist. Also, it created many chances for us to have small talks in the hallway, in the kitchen and even in front of the elevators after working hours. I enjoyed all these small talks about life, about science. It is a pity that we didn’t have a real collaborative project to work together, but I do appreciate your feedbacks and suggestions. Thanks for inviting me to give a talk for FIGON, which was the last oral talk I gave in my PhD and I really enjoyed it. Please forward my thank to Chris as well for helping me hanging on the curtain rod. I owe you a big Chinese dinner.
Barbro, I heard many compliments of you from Shanshan before you joined
our department, and I was so curious about you. Thanks for inviting me to the collaborative projects and I enjoyed working with you. Besides, I didn’t expect you are such a humorous lady and I like your jokes when we are discussing science. My sincere gratitude to the members of my reading committee, Prof. dr. Irene
Heijnk, Prof. dr. Pieter Hiemstra, and Prof. dr. Phil Hansbro. Thanks for reading my
thesis and I hope we will have a lively discussion during my defense.
My sincere gratitude to Prof. dr. Melanie Königshoff, Prof. dr. Aleksey Matveyenko,
dr. Thomas Conlon, and dr. Ali Önder Yildirim. Thanks for contributing to my
research project and it was an honor to work with so many experts in my project. My sincere gratitude to GRIAC as well. This excellent platform gave me so many chances to learn from each other, and the interdisciplinary communications are very helpful for my own research. I also made friends here, Hataitip, Zhijun, Qing, and
Khosbayar, thanks for spending time together within and outside GRIAC meetings! Prof. dr. Huib Kerstjens, thanks for your interest in my projects and thanks for taking
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well as the small chats afterwards. Prof. dr. Janette Burgess, thanks for inviting me to join the Jilin delegation visit and provided me a chance to be a bridge between GRIAC and the scientists from my hometown.
My sincere gratitude to Dr. Jill Johnson, Prof. dr. Marco Harmsen and Prof. dr. Andries van der Meer accepted my application for the post doc position before I complete this thesis. I am appreciated to join this new team and look forward to our collaborations.
Method of the Year 2017: Organoids.
This mini lung companied me throughout my PhD research. I am proud that the MF organoid team started from JP and me, and now is attracting more teammates.
JP, you are the person I ‘love’ the most and also ‘hate’ the most at the beginning of
my PhD. Your charming British accent and ‘harry potter’ looking is very attractive as I am a big fan of Harry Potter series. However, I never forgot how hard you trained me to be more independent by saying ‘be creative’. It was frustrating sometimes but indeed helpful. You are a very smart scientist but also an excellent guitar player. The MF band was alive for a while and I enjoyed our performances. Rosa, thanks for coming back to the department for your PhD study after your internship with me, Lars and JP. I enjoyed the team atmosphere very much when you were doing the internship. Now, you are a great player in the team and thanks for taking over chairing the organoid club. Manon, you are a very skillful and trustworthy person. I really appreciated working together with you. Thanks for sharing technique experience and correcting my mistakes. Vicky, I really like the Dolmadakia you made, and it became my favorite Greek dish. Thanks for helping to optimize the organoid method, and I appreciate to work with you as you always made everything neat and efficient. Fransien, I’m glad that you threw out the unclear conversation when you joined the team, and I enjoyed working with you for the RNAseq set ups. I hope you are enjoying the second baby coming. Habibie, you are such a kind guy that are very modest and considerate. I’m glad that you added me to your project to help and we will share more contacts soon in the office. Luke, welcome back to the department and organoid team, what a surprise! Thanks for taking care my PC and look forward to our new starts. Chiara, my cute Italian girl! It feels great to share similar hobbies and tastes with an Italian girl in the world. Do you remember the tinder story? Thanks for coming back and let’ revive the team spirit as well as MF band together! Furthermore, I am grateful to the helps given by my master students
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Lars, Angela and Valliant. Thank you for contributing to the projects, and I enjoyed
the working atmospheres we spent together.
Super girls: you are stronger than you believe. You have greater powers than you know (wonder woman).
Inge, we started our PhD more or less at the same time together with Mariska, and
luckily, I could witness almost the whole process of your PhD. It was never easy, and I could see your improvements day by day. I’m really proud of you! It is grateful to have you as my music buddy. Though we never collaborated on one project, we did give many musical performances, and whenever I heard the melody of crzardas, I think of you. Friends are the best drugs to treat sadness, and so does music. I hope you are enjoying your new job and new life with Gerke together in Utrecht.
Pien, you are so energetic, optimistic, clever and Dutch! It seems you always ask me
“sharp” but interesting questions, and these always trigger me to check whether we are living in the same world. Whenever we started a chat, you could always surprise me with lots of stories that I never experienced before. I like those moments spent with you. the ERS seminar journey to Berlin was fantastic and it was a pity that we didn’t make the trip to ATS together. Ayha, my shy, soft, and brave Indonesian girl. I like all the small talks, lunch meetings, hangouts with you. We always shared our adventurous stories in the Netherlands, and since we both grew up within the Asian culture, we could always understand each other better. Thanks for listening, encouraging and supports. Isabella, thanks for your company at the lung science congress in Estoril, 2020. Your Portuguese is really good. ☺Thanks for studying together with me on how do dilute DEP and look forward to your promotion.
Melissa, I was attracted by your charming personality since your internship in the
department and it was great to have you again around to work with. I like your jokes, your smiles and your muscles! Angie, you worked so hard and still working very hard after your promotion. You are a very confident and clever girl. I like your company and you discovered my talent as a photographer. Asmaa, you are a great lady that can always take care your career as well as your family simultaneously. Whenever I sneaked in your office, we cannot stop chatting with everything. Communications (gossiping) are always important ☺. Marina Rezende, thanks for your trust and choosing me as your paranymph was a bit unexpected. You are a tough and strong girl. Your hard-working and persistence made you and deserve respects! I hope you are enjoying life in Brazil and look forward to meeting you again in life.
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Eline, thanks for sharing your experience on PCLS studies, and the experience on
how to manage projects. I still remembered the re-union in the pub after your promotion, and your words encouraged me a lot when I got lost with my future.
Birgit, my smart, strong and lovely German girl! You always work hard, play hard
and drink hard! It was so much fun to have you in the super girls’ group and thanks for treating us in Bonn! We should organize the re-union more often! Bing, thanks for carrying me to the house agency to check in my life in Groningen on my day arrival. Haoxiao, thanks for inviting me a dinner at your place in Groningen, and also shared life experience and working experience to me. Congrats on the second princess coming to your family. Xuelin, thanks for trusting me and invited me as your paranymph. Though your stay in Groningen was short, but I enjoyed walking with you and sharing stories about life. Susan, you always made me believe you are my roomies as well since you always showed up in our office ☺. It was pleasant to spend time together and I like those stories shared on Instagram.
The strength of the team is each individual member. The strength of each member is the team.
I would like to thank all the MF family members, Annet, Jacques, Zaid, Sara, Nshunge,
Gwenda, Anienke, Marina de Jager, for spending those lovely time together with
lab outings, retreats and vrijmebo. Guilherme, it was great to meet you again at ERS last year in Madrid. It feels so amazing to hangout and enjoyed a beer with people after a whole day congress program. Look forward to your coming back to Groningen. Janneke, thanks for organizing general things for us and I really enjoyed hearing your laughs whenever I passed by your office or the kitchen. Happiness is a good virus to spread. I hope you are enjoying your retirement. Brenda, thanks for joining us and take over the complex work to make our working environment nice.
Hoeke, thanks for answering all my questions about WNT. As another “Wnt-er”
came, we could celebrate our birthdays together again. Marina Trombetta Lima,
Alejandro, Dan, Tong, Yuequ, I’m happy to meet you guys at the last phase of my
PhD, and I hope we could create more good memories together in the future! Lung time no see, Karen and Denise! It’s unbelievable we became friends from the lung science course with Mariska together. I really appreciated NRS created the chances. It feels so fantastic to meet friends at conferences, and thanks for all the companies with lung science! Denise, thanks for your company in Madrid 2020!
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We spend so much great time together during ERS congress as well as the following travelling! I like traveling with you and look forward to our next trip!
There are friends, there is family, and then there are friends that become family.
There are 3 VIPs that are more than a colleague, a roomie, and they are my family. The moment I am writing down these acknowledgements, we have been apart geographically, but our relationships not. Caro, I can’t find a second person as unique as you are. You talk to your PC, you dislike Chinese medicine but like acupunctures, and you can easily recognize my bad energy and sadness. Whatever topic we ever started, you will lead it psychologically, physiologically, and “zan” (禅). You are a great influencer to me. You told me how to do meditation, you told me how to balance life, you taught me to accept, to face fear, to refuse and what’s more important, is to be happy. I really appreciated that I could feel the supportive energy from you whenever I needed. Sophie, you are a naughty girl, a great teammate, a good cappuccino company, a bridge, and a Bos. Tank for being my strong assistant in all my projects and I like working with you, and we created our own working pattern. Tank for being my sister, and laugh, cry, gossip as well as be childish together with me. Tank for introducing me to your family, and I like all three lovely girls. Tank for tasting all the Chinese foods either made or recommended by me and I strongly believed you and Claudia should learn Chinese as both of you are talented. I am glad to make you be a paranymph for the 10th time and you will receive a big gift
after finishing your job. Don’t blame Reinoud on my moving, as I promise it will only make us closer. Are you ready to team up with me again for another adventure and witness my growth? Mariska, my personal consultant, my M, my friend, my sister and my energy rescuer. It’s unbelievable that you sometimes know me better than I do. It’s unbelievable that we finished our PhD togethers now and I am extremely proud of you. I know how hard your PhD journey was even to the last minute. It’s unbelievable that you are the mommy of Bernd and I became his aunt. Time flies, but since you appeared in my life, you never left. I am really appreciated to have met you at the beginning of my PhD, and you solved my insecurity and helped me to feel at home quickly and you became a ‘necessity’ of my life. The adventures in the U.S. is definitely the most unforgettable time in my life and we had our first argument/fight in San Francisco, which made us cried one after one on the street. Until then, I clearly noticed that you are so important to me and you are not only a close friend, but already became my family. The biggest acknowledgement I will do is to try my best to keep “bothering” you as much as I can and as long as I can ☺!
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Caelan, I appreciate your company at Esdoornlaan as my close neighbor and thanks
for taking care of me. You are a smart and kind man and I believe you will have a bright future. I enjoyed talking with you and all the trips we had together.
文佳，珊珊，感恩与你们相遇、相知。你们鉴证了我的成长，陪伴了我的成长！那一年的大加纳利之行， 终身难忘！每年的圣诞市场之约伴随着我们的分道扬镳可能越来越难了，但是一起吐槽博士生活的苦与 乐，一起分享美食，一起喝酒的日子是我在格罗宁根最难忘的日子。感恩这一旅途有你们的陪伴，对我来 说意义非。在我最伤心脆弱的时候，谢谢你们收留了我，开导我，安慰我，最终成就了我的成长。 刘静，你就像一个小精灵，带我看到了一个不一样的世界。谢谢你带我去体验生活的各种可能性，谢谢你 让我在你身上学到了快乐和坚持。少敏，你的出现很“戏剧“，你的人生可能更”戏剧“。但都不影响你 做一个有主见、坚强、聪明又独立的女孩！谢谢你对我无微不至的关心与操心，还兼顾我的心理健康！坚 持做自己很难得，也很重要。小宇， 锅包肉哥哥，谢谢你让我感受到了家乡的味道！你的苦口婆心，你的 善良，让我感受到了满满的家乡情。春立，欣欣，璐璐，谢谢你们在我初来乍到的时候，在生活上对我满 满的照顾跟关心！谢谢陪我一起练舞蹈的小伙伴雪莱，映秋，与其，青青，小阿陈，晓燕！在你们身上我 看到了女博士的万千可能性，也谢谢你们挖掘了我的可能性！ 马冠群，感谢你对我的各种“嫌弃跟批评“。忠言逆耳，都是促进我成长的动力。谢谢你收留我，把我 从红楼带到89号公馆，彻底改变了我的生活状态。随着对你了解的增多，我竟发现一个小公主住在你这 个“爷们儿”的外表下。谢谢你在寒冷的冬夜骑车去接我回家，谢谢你大半夜陪我去处理朋友的危机！生 活继续，友情继续，韩国游约起来！庞明德，超级爱干净，爱喝酒，住在我隔壁的小屁孩貌似长大了。你 的入住，让整个89号公馆热闹了起来，谢谢你带来的欢声笑语，还有公馆的保留剧目，不知道何时再能 看到了。阿庆，认识你之后让我对上海人的性格有了鲜活的理解。谢谢你在生活中对我们的照顾。阿毅 哥，谢谢你的各种盛情款待，让枯燥的疫情生活有了趣味。 史丰田，我的小王子，小粉丝，小猪的疯狂迷恋者。谢谢你的出现，让有些灰暗的生活再次亮了起来。 尽管我们认识的时间很短，但熟悉以后总感觉我们上辈子是一家人。就如我在你23岁生日那天写道的一 样，我期待文艺片变成剧情片的那一天，希望我有幸可以继续一路鉴定这一变化的发生。我的开心果，祝 你顺利毕业，希望明年的这个时候，我们相约日本！ 彭逸清，沉稳的你，幼稚的你，幽默的你，“十三点”的你，都是一个懂得生活、明白自己要什么的人。 遇见你，我的生活发生了翻天覆地的变化。三年有余的相伴，五味陈杂。你让我变成了更好的我自己。慢 慢地我才明白你对我的关心，鼓励跟支持像润物细无声的雨帘，是需要用心去体会的。疫情期间的朝夕相 处，让我更加珍惜这场相遇与相知。谢谢你的照顾与包容！分别在即，纵有万般不舍，愿未来可期，你我 都好。
196 最后，我想感谢我的爸爸妈妈跟家人。我来自一个非典型的中国家庭，爸爸妈妈十分独立跟开明。从小到 现在，我们三个人总是分居三城，聚少离多，这也成就了我从小独立的性格。很遗憾因为疫情的原因，你 们无法出席我的毕业答辩。老爸，你是我的山，我的肩膀，我的一切！你总是一个人为这个家默默付出， 默默支持我，鼓励我，宠着我，爱着我，希望我少吃苦，多享福。可没曾想我就是一个闲不下来的小孩， 总想去外面的世界走走看看闯闯。你是一个会生活的人，是一个聪明有担当的男人，好多事情我长大以后 才发现与明白，你的好，可能妈妈都没有发现，但我发现了。感恩做你的女儿。老妈，我的女王，我的老 师，我们的冯导儿。你的独立自强，你的韧性与坚强深深地影响着我。在别人眼中你是个女王，其实在你 的内心里也渴望被照顾跟宠爱。你很少跟我分享工作的事情，可能在你眼里我还是个小朋友，但我想这是 你想保护我的方式。你总是希望我少走弯路，但是我十分明白吃苦才能成长的道理。感谢你从小对这个家 的付出，是时候好好享受生活了！希望你跟爸爸不要再分居两地，而是一起挽手开心幸福地享受余生！ 谢谢舅舅，从小对我的关心跟照顾，无论生日还是节日，你的红包从未缺席过。谢谢舅妈总是用各种好吃 的“填喂”我，乐观的你是家里的开心果！谢谢爷爷（在天上看着我）、奶奶，大姑，老姑对我的照顾跟 关心！我不是一个经常出现在家庭聚会的孩子，但是你们从未离开过我的生活，还要谢谢你们在我背井离 乡时帮我照顾爸爸妈妈！谢谢佳佳，我聪明伶利，漂亮可爱的老妹。每次放假回去，都很享受跟你腻在一 起的日子，离开的时候很想把你打包带走。谢谢老哥，每次都是以最热烈的方式迎接我回家！如果我没有 坚持健身，你的重量压在身上，我可能真的承受不住这份爱。你最聪明的决定就是把我朋友娶回家！看着 你跟欣卓还有宝贝们的幸福生活，总是很羡慕，希望疫情快快结束，跟你们早日相聚！
There’s always going to be another mountain. I’m always going to make it move. Always going to be an uphill battle. Sometimes I’m going to lose. It isn’t about how fast I get there It isn’t about what is waiting on the other side. It’s the climb. (Climb, Miley Cyrus)
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Curriculum vitae
The author of this thesis was born in Changchun, China, on the 8th of March in 1990.
She started her bachelor’s in Animal science at Yanbian University, China, in the summer of 2009. In 2010, she had her first overseas study as an exchange student in Animal biotechnology in Chonbuk National University, South Korea. After the exchange life, she went back to China and finished her bachelor in 2013. In the same year, she started her Master’s in Animal Reproduction at Jilin University, China. At there, she studied the role of FAT1-mediated apoptotic pathways in porcine cumulus cells (supervised by Prof. dr. Jiabao Zhang) and abstained the master’s degree by 2016 summer. In November 2016, she initiated her PhD study at the department of Molecular Pharmacology, University of Groningen, under the supervision of Prof. dr. Reinoud Gosens and Prof. dr. Martina Schmidt. Her research focused on the mechanisms of defective lung repair in COPD and discovering novel regenerative therapeutic strategies/targets. The results of her PhD study are presented in this thesis. In 2017, she received the scholarship from China Scholarship Council (CSC) and in 2018, she received a project grant from Noordelijke CARA Stichting (NCS). Furthermore, she presented in many congresses and received awards/fellowships including NRS Young Investigator Travel Grant (2018), ATS International trainee scholarship (2018), Longfonds Travel Grant (2018), ERS Young Scientist Sponsorship (2020). In the last year of her PhD, Xinhui successfully applied for a post doc position supported by Longfonds at the University of Groningen and Aston University.
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List of publications
X. Wu, van Dijk, E.M., Ng-Blichfeldt, J.-P., Bos, I.S.T., Ciminieri, C., Königshoff, M.,
Kistemaker, L.E., Gosens, R. Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors. Cells 2019, 8, 1147.
X. Wu, E.M. Dijk, S. Bos, L.E.M. Kistemaker, R. Gosens. Mouse Lung Tissue Slice
Culture. Methods Molecular Biology, Vol.1940. 2019
John-Poul Ng-Blichfeldt, Tristan de Jong, Rosa K. Kortekaas, Xinhui Wu, Michael Lindner, Victor Guryev, Pieter S. Hiemstra, Jan Stolk5, Melanie Königshoff, Reinoud Gosens. TGF-β activation impairs fibroblast ability to support adult lung epithelial progenitor cell orgaoid formation. Am J Physiol Lung Cell Mol Physiol. 2019 Apr 10.
X. Wu, Fu Y, Sun X, Liu C, et al.: The possible FAT1-mediated apoptotic pathways in
porcine cumulus cells. Cell Biol Int. 2017 Jan; 41(1):24-32.
Published abstracts:
Xinhui Wu, Sophie Bos, Lars Verkleij, Angela D’Ambrosi, Martina Schmidt, Loes Kiestemaker, Reinoud Gosens, PGE2 and PGI2 restore defective lung epithelial progenitors induced by cigarette smoke. European Respiratory Journal 2020 56: 4785;
Xinhui Wu, Sophie Bos, Martina Schmidt, Loes Kistemaker, Reinoud Gosens, Cigarette smoke and diesel particles repress functional responses in lung epithelial progenitors, European Respiratory Journal 2019 54: PA2437
