6 DISCUSSION
None of the clinical trials that involve cells and biomaterials as treatment of IHD have been successful enough to reach continued clinical evaluation. It seems thereof to be fundamental aspects of knowledge missing, whether being in the disease itself or in the strategy of the therapy. Regardless, both are subjects for further research. In this thesis and discussion, I touch upon some of the possible reasons and strategies that may help in future cell and biomaterial based therapies.
to add other molecules for manipulating cellular phenotypes, while retaining the release mechanism of the capsules by thermo-responsive partial decomposition. The addition of other components able to direct differentiation, maintenance, quiescence and proliferation might therefore be an attractive strategy to tailor cell therapy.
In our Study II (Olesen et al., 2021), we demonstrated an in vitro model that could pinpoint regions of an organ that harbor specific ECM components of importance for cell preservation and theoretically could be used for cell-encapsulation. Extracting niches by dissection of an organ, including isolation of the ECM molecules, or alternatively producing recombinant molecular cocktails, are viable options for producing biomaterial constructs. This advances the possibility to produce artificial stem cell niches or to direct the differentiation and maturation of both exogenously added and endogenous cells in vivo.
6.3 A NICHE IN THE HEART
Regarding the potential generation of artificial niches, understanding the ECM composition and characterizing the cells within niches of tissues are essential for such a purpose. The existence of different niches and stem-/progenitor cells in the heart and also their involvement in regeneration are still extensively debated.
In Study II, we found cells positive for the pericyte marker CD146 in our StEMM model as well as in the native heart, they were detected in the AVJ, and PVN but not to the interstitial valvular root. PDGFR-β was not found in the AVJ, but instead extensively expressed in the interstitial valvular root, and to some extent in the PVN. These findings imply different phenotypes of the pericytes depending on anatomical localization (Litviňuková et al., 2020) and consequently defined by the ECM-composition.
Pericytes and their relationship to MSCs and fibroblasts are still not clearly defined, but a central theory involves the notion that they have the same origin and might even be the same cell with phenotypes based on contextual circumstances (Crisan et al., 2008; Yamazaki and Mukouyama, 2018). However, from the literature it is clear that PDGFR-β is a marker for pericytes, while only a few articles mention subsets of MSCs expressing this receptor (Tokunaga et al., 2008; Wang et al., 2018). Most articles covering MSCs and fibroblasts instead associate them with expression of PDGFR-α, thereby implying the PDGF-receptors as an interesting variable in mural and stromal cell biology and identity.
The cells used in our study (Olesen et al., 2021) characterized as MPCs were
PDGFR-explain their progenitor status and requirements for maintenance and differentiation. EPC markers, like VEGFR-2 (KDR or Flk1) (Friedrich et al., 2006) are known to act as co-receptors with PDGFR and CD146 (Borges, Jan and Ruoslahti, 2000) and determining their expression might aid to verify the progenitor state of the cells. Additionally, not only pericytes express CD146, but also MSCs and endothelial cells (Bardin et al., 2001; Schrage et al., 2008; Leroyer et al., 2019). As such the cells present in the AVJ of the native heart still remain to be determined, as they could be either mesenchymal or endothelial cells. The co-existence of multiple progenitors is also a viable scenario, or perhaps a cell-type that is a progenitor of both mesenchymal and endothelial cells, known as mesoangioblasts (Vodyanik et al., 2010; Chong et al., 2011; Zhang et al., 2018).
6.4 MIMIC A NICHE FOR CULTURE OF CLINICALLY APPLICABLE CELLS Extracellular factors greatly impact cells in vivo, and in particular when expressed within niches that can retain a certain phenotype of interest in favor of tissue regeneration. Although it is clear that not only stemness is important in cell therapy, but also a specific phenotype and response to the pathological process of each individual disease. As MSCs have been shown to exert immunomodulatory functions, the focus has shifted from attempting to integrate them into the target tissue through transplantation, to the use as a means of immunomodulation. This is done by either delivery of cells following mass-expansion to generate efficacious doses, or by extracting the entire, or parts of their secretome. In order to do this, appropriate culture protocols are needed that support not only expansion, but also preserve their inborn phenotype.
In Study III, we studied the impact of oxygen tension during culture for phenotype preservation of MSCs of different developmental stages.
We found that adult MSCs had an increased glycolytic activity and an unchanged oxidative phosphorylation during hypoxic culture, which support previous notion of a preferred glycolytic activity in adult MSCs (Nuschke et al., 2016). Additionally, MSCs are known to shift in the metabolic ratio between glycolysis and oxidative phosphorylation when they differentiate to chondrocytes, bone and fat (Fig. 16) (Chen et al., 2008; Pattappa et al., 2011;
Tormos et al., 2011; Shum et al., 2016; Salazar-Noratto et al., 2020). Based on this it was suggested that the cells retain their undifferentiated state during the culture. Others have in turn demonstrated an increased proliferation rate and maintained immunomodulatory properties of MSCs during hypoxic cultures (Dos Santos et al., 2010; Roemeling-van Rhijn et al., 2013;
Caroti et al., 2017). In relation to this, hypoxia is a relatively cheap and simple approach and easy to incorporate into good manufacturing practice (GMP) production. Therefore, hypoxic cultures should be considered, validated and used for the expansion of clinically applicable
Figure 16. Metabolism in mesenchymal stem cells and progenitors. (A) Bone marrow mesenchymal stem cells remain quiescent in a hypoxic niche and use glycolysis. (B) Pre-adipocytes upregulate oxidative phosphorylation (OxPhos), and reactive oxygen species (ROS) production from the electron transport chain (ETC) complex III is highly active, to prime adipocyte differentiation. (C) Adipocytes upregulate glycolysis and ATP citrate lyase (ACL), which leads to increased cytosolic acetyl-CoA (Ac-CoA) synthesis and, hence, an increase in histone H3 acetylation (H3ac) and in lipid synthesis. H3ac, in turn, leads to activation of the carbohydrate-responsive element-binding protein (ChREBP) transcription factor to promote GLUT4-mediated glucose uptake and glycolysis in order to generate the acetyl-CoA needed. (D) In osteoblasts, which give rise to bone, OxPhos and O2 consumption are upregulated, but ROS is suppressed via superoxide dismutase (SOD) and catalase (CAT). (E) Glycolysis is further upregulated during chondrogenesis in chondroblasts, which give rise to cartilage. Ng Shyh-Chang, George Q. Daley, Lewis C. Cantley. Development 15 June 2013; 140 (12): 2535–2547 (Shyh-Chang, Daley and Cantley, 2013). Reproduced under terms of COMPANY OF BIOLOGISTS (License ID 1159780-1).
Furthermore, the use of a relevant ECM as a substratum might provide additional improvement for the expansion of MSCs. The general concept of maintaining cell-specific phenotypes was demonstrated back in 2009 by Zhang and co-workers who used decellularized tissues and subsequent culture of their corresponding cell types (Zhang et al., 2009). Later the concept of ECM-substratum was applied on MSCs as well, which could thereby retain their phenotype while proliferating (Lai et al., 2010; Månsson-Broberg et al., 2016). Another study successfully explored 3D-culture of MSCs, which arguably would enhance not only cell-to-cell adhesions but also the ability for the cells to create their own 3D-microenvironment and cell-to-ECM adhesions (Bartosh and Ylostalo, 2019), where both types of adhesions are important for cell-division dynamics (Uroz et al., 2018). Thus incorporating a complex ECM during the expansion of MSCs is another viable option. In combination with a hypoxic environment, this might provide a culture system that supports mass-expansion of MSC for clinical use, by basically mimicking the bone marrow niche.
7 CONCLUSIONS
I. Thermogels can support encapsulation and release of human cells upon exposure to physiological temperatures, while at the same time, provide flexibility in the composition of components.
II. The decellularized heart can be used to create semi-3D anatomical cross-sections as an in situ representation of the ECM, in order to identifiy regions of interest (or cell niches), defined through the combination of cellular and extracellular markers.
III. Clinically applicable cells retain stem-like metabolism during culture in hypoxia, which implies the need for oxygen control during culture of MSCs mimicking physoxic conditions.
8 POINTS OF PERSPECTIVE
Taken together, myocardial fibrosis following ischemic heart disease is a complex process. It is however clear that mitochondria, stromal cells and the innate immune system are collectively involved and seemingly key-drivers of the deteriorating development towards fibrosis.
Targeting these parameters by using immunomodulatory cells, muscular progenitors or biomaterials have been and continue to be extensively researched. Even though cells and biomaterials show promise, they are equally unrefined and require technical advances together with an increased fundamental knowledge for their successful applications. Determining cell niches provides an approach that gives great insight to the requirements of cells during culture and engraftment. Providing the extracellular factors associated with a given cell type’s niche might overcome hurdles in expansion of therapeutic cells in vitro, and in the delivery and engraftment in vivo.
9 ACKNOWLEDGEMENTS
Even though I started my PhD in 2017, I have people to thank for back from ten years to now.
I could never in words say thank you enough, but I hope some words of appreciation will do!
=)
Thank you Karl-Henrik Grinnemo for giving me the opportunity to engage in a PhD in your lab. At the time, I never thought I would get the chance, but you gave me it and I am extremely grateful for it! You supported me throughout the years. Always with quick specific feedback and optimism! We do not always agree with each other, but you always make sure that by the end of the day we always try to make it work, and that is something I appreciate, and respect a lot, about you.
Andreas Tilevik, thank you for being my co-supervisor and giving me all the support that you did. I especially enjoyed our time we spent in the office programming, discussing and chatting.
Most fun and memorable was our trip to Japan for the conference, thank you!
Cecilia Österholm, thank you for being my co-supervisor. Whenever I needed your support I always got it, and I should probably have asked for more help than I did from you! You are always considerate, supportive, fair and on point. You are an amazing researcher, and an even better person. Thank you for everything!
Wing Cheung Mak, thank you for being my co-supervisor! We worked together before my PhD, when I was research assistant. Already then you were supervising me, but you were also being a great friend! You helped me when I was having though times and I cannot be more grateful for that. Thank you so much! And thank you to Cheung Kwan Yee (Queenie) for being a great friend and office mate during the times at LiU. Hopefully we all soon we get to have more dinners, BBQs and nice discussions about everything!
Magnus Fagerlind, thank you for being my co-supervisor. You are honest, engaged and you always gives realistic expectations on my projects. We did not get to do much in the lab or analysis together, but I hope we get to do so in the future!
And also, thank you to Yuji Teramura for kindly accepting to be my Opponent for my dissertation, and to Elmir Omerovic, Anna Falk and Cecilia Götherström for being in the Examination Board. And thank you to Elmir for good discussions during my halftime seminar.
Thank you to all in Kalle’s Lab and people at Uppsala University, Surgical Sciences; Elizabeth Ståhle, Ulrika Felldin, Sergey Rodin, Sandeep Kadekar, Johan Wedin, Oscar Simonsson.
Thank you as well to Sandeep Kadekar, you are experienced and have so much to share, and on top of that extremely kind and helpful. I loved all our discussions about life, research, and training. Thank you for being my co-worker and friend!
And thank you to Johan Wedin, although we only had time to talk when meeting outside office-hours at the animal house, or lab-dinner, it would have been nice to have worked more with you.
Thank you to previous and new members of Kalle’s group, Carl Granath, Marie Löfling, Karin Ljung, Ivana Bulatovic, Ida Hafstrand, Amanda Nordlander, Felix Grinnemo and Ken Braesch.
I had a great time with you Carl Granath, and I really wished we would have continued the whole PhD together! You are a critical thinker, sincere, honest and reliable and a great person!
It was always fun spending time in the lab with you. You taught me dissection and suturing, and then tried to teach me something about music and musicians =) I enjoyed all discussions with you, especially about common interests like games, movies and martial arts =) Thank you!
Thank you to the department of Molecular Medicine and Surgery for all the support! Thank you to prefect Anders Franco-Cereceda for all your support. Thank you to all the administrational staff for the all the work, it has been some extra for sure and I appreciate all of it! So, thank you Ann-Britt Wikström, Britt-Marie Witasp, Therese Kindåker, Chatrin Lindahl. And also Susanne Forsberg booking the dissertation room on a pressing schedule!
Special thanks to my friends and colleagues at Flemingsberg. Special thanks to Rui He, Wenyi Zhang, Xinyuan Liu, Qiang Wang, Xuan Li, Ying Zhao and Paulina Ljung for all the time we had, you made the time at Flemingsberg fun and I will never forget it, even though mostly involving food or tea! Thanks for always putting a smile on my face! And also for trying to teach me some Chinese, I am still learning slowly.
Thank you as well Ying Zhao for the help with the IVIS machine. And also Thank you to Kathrin Reiser, Nicolas Tadif (Nico), Amo Saini, Anton Törnqvist Andrén and Cecilia Ström (Cissi).
And to others at Karolinska Institutet;
Thank you to Ewa Ellis for letting me work in the lab, and to Helene Johansson for letting me in =)
Thank you again to Vladana, and Masataka Kinjo, Thorsten Wohland for Summer Workshop in Hokkaido. Thank you to Akira Kitamura, Sho Oasa, Fusako Gan, Xioali Sun and all from Hokkaido Summer Institute 2019.
Thank you to everyone at University of Skövde for the support throughout all the years, both during my undergraduate and graduate studies. Special thanks to Erik Gustafsson and Henrik Thilander for the great evening courses in Viral and Bacterial Pathogenesis and Forensic Science! Thank you to my old class-mates and friends, Amanda Svensson, Kitt Cheung, Sofie Johansson, Erik Svanström, Kalle Backlöf, and Lina Backlöf. You all made the University studies a million times better!
Thank you Mikael Ejdebäck, for your support. Thank you to fellow PhD-students, Marcus Johansson, Heléne Lindholm, Matthew Herring, Simon Keane, Maria Araceli Diaz Cruz, Henrik de Werde, Tejaswi Badam.
Thank you Jane Synnergren, Ferenc Szekeres, Zelmina Lubovac, Diana Tilevik, Anna-Karin Pernestig, Helena Enroth, Sanja Jurcevic and Patric Nilsson.
And to others at Uppsala University;
Jöns Hilborn, thank you for everything! You have supported me in so many ways and to extent that I cannot be more grateful for. I do not only look up to you as a researcher, but also as a person! I also appreciate all the spontaneous talks with you! =)
Jan Bohlin, thank you for being you! You are always helpful, cheerful and you look at life in a good way! You helped us getting settled in the lab when moving to Uppsala, and you have always taken your time to help, or to just enjoy a good talk =)
Thank you to everyone in Jön’s lab, current and previous members and associates of Polymer chemistry; Shujiang Wang, Liyang Shi, Hannah Pohlit, Ganesh Nawale, Patrick Shakari, Ken Braesch, Norein Norein, Jenny Rosenquist, Murtaza Sharq, Ann Van de Ven, Francesca Spagnuolo, Prithwiraj Mandal, Samah Abousharieha, Matilde Folkesson, Christos Leliopoulos, Martina Paetsch, Adriana Saldivar, Mahsa Jamadi, Shima Tavakoli, Lisa Höglund, Matteo Iannacchero, Sibel Özcan, Yange Fan, Maruthi Paidikondala, Rohith Parvathaneni, Nithiyanandan Krishnan, Vignesh Kumar Rangasami, Sujit Kootala, Juan Ramón, Orpita Majumdar, Emil Gustafsson and PIs Tim Bowden, Oommen Varghese, Ayan Samanta. And thank you to collaborators, Katarina Le Blanc, Oommen Podiyan,
Special thanks to Thomas Schiffer at KI, not only for running the Oroboros measurements, but because I had some of the best times working with you. Interesting, fun and sincere conversations all though and through, and just great to be around. Was fun and nice to hear stories from the Åstrand lab as well, unfortunately I just missed you when I was there!
Thank you to Tomoko Akiyama for tea, tips and for practicing Japanese.
Thank you to MedBioInfo for providing training in bioinformatics, I appreciate the research school alot! Thank you Samuel Florence as director, Arne Elofsson, Lars Arvestad, Lukas Käll, Carsten Daub and my MedBioInfo mentor Zelmina. All members, extra thank you to Markus Johansson, Qingyang Xiao, Isak Johansson-Åkhe, Linnea Thörnqvist, Gad Hatem, Gustavo Jeuken, Samuel Backmans, Evgeny Akkuratov, Emmy Borgmästars, Daniel Rivas, Joana Costeira-Paulo, John Lamb, Max Karlsson, Ludvig Bergenstråhle and Carmen Fourier
A big Thank You to May Griffith for introducing me to regenerative medicine and giving me immense amount of support!
Thank you to Griffith’s previous group-members, Mirazul Islam, Brice Magne, Diana Atanasova, Chyan-Jang Lee, Maxim Gerasimov, Hirak Patra, Elle Edin and Fiona Simpson. Thank you to previous collaborators Emilio Alarcon for teaching me electrospinning. Thank you to Malcom Latorre for also teaching me electrospinning =) and being great support and for the many interesting discussions and ideas! Also thank you Kimberly Merret for support during TFF of collagen.
And to others at Linköping University;
Big thank you to Monika Kozak Ljunggren and Erland Ljunggren for being amazing people! Thank you as well to Anna Weinhofer, Hanna Gällström, Eva Åström, Peter Pålsson, Ing-Marie Ahl and Per Fagerholm.
I also want to thank my host lab during my masters at The Swedish School of Sport and Health Sciences (GIH), PI Eva Blomstrand, and my lab-supervisors William Apro and Marcus Moberg, I enjoyed my time in the lab while learning a lot! It definitely helped me during my PhD-studies, thank you! Also thank you to Marjan Pontén and Björn Ekblom.
Other than pure research I have interest in training, language and culture. I would therefore like to express further appreciation to everyone outside of my research field, for making life more fun.
Thank you to my teachers at Dalarna University for teaching me Japanese, Rieko Hattori and Masako Thor. Thank you to my class-mates, André Andersson, Malin Almgren, Emmy Holmström, Jim A Marshall, Sanne Enebrant, Pontus Svensson and Madeleine Gustafsson.
And thank you to my teachers at Dalarna University teaching Chinese, Chonghui Li, Lung-Lung Hu and Wei Hing Rosenkvist and thank you to my class-mates.
Thank you to everyone in Stockholms Wushu Akademi, special thanks to Da Sifu Louis Linn, for bringing Kung Fu to Sweden back in the 70s, and for still today continuing to practice and teach. Thank you to Sifu Lainy Linn, and Lao Shih Dennis Guerrero, Lao Shih Paulina Wysotzky Davegårdh and Zhu Jiao John Gullborn.
Thank you to everyone at Skövde Wushu, special thanks to Sifu Peter Renström, Lao Shih Jani Minkkinen, Lao Shih Thomas Thörnquist, Lao Shih Ola Thörnquist, Stefan Hanna, Marcus Johansson, Tim Haglund, Alexander Frejd, Linus Sjöholm and to all others active and non-active =)
Also thank you to Skövde Kraftsport.
Thank you to my closest friends Tobias Andersson and Martin Johansson. You are always there for me, and I cannot thank you enough for all the years you have given me laughter, support, encouragement and motivation. I could never have asked for better friends.
Thank you to my family, parents Gunnar Nilsson and Pia Olesen, sisters Tanja, Zelina and Eija, and my brother Charlie. I could never have done a PhD or even study without your support and encouragement. And thank you to my nephew Liam and nieces Sonja and Julia for bringing “some” extra joy into life.
Love you all!
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