Using a variety of relevant preclinical mouse models, this thesis not only showed several ways to improve antibody-based cancer immunotherapy but also demonstrates the importance of the choice of... Show moreUsing a variety of relevant preclinical mouse models, this thesis not only showed several ways to improve antibody-based cancer immunotherapy but also demonstrates the importance of the choice of the model for the translational relevance of the preclinical observations. Show less
Autosomal Dominant Polycystic Kidney Disease (ADPKD) progression involves a complex interaction of different molecular pathways, ultimately leading to cyst growth and loss of kidney function. The... Show moreAutosomal Dominant Polycystic Kidney Disease (ADPKD) progression involves a complex interaction of different molecular pathways, ultimately leading to cyst growth and loss of kidney function. The exact mechanism behind cyst formation is still not clearly understood. Moreover, we know some of the molecular pathways involved in cyst initiation and progression, but we do not know at which stage of the disease they play a role. In this thesis, we investigated the molecular pathways involved in renal injury-repair mechanisms and ADPKD. According to the currently available literature, injury-repair and ADPKD are two extremely intertwined mechanisms, which not only are characterised by activation of similar molecular pathways but are also able to influence each other. In fact, injury is able to accelerate cyst formation and progression, and cyst growth can cause injury to the surrounding tissue. Thus, the introduction of injury in the context of ADPKD can help to characterize the steps of disease progression, particularly in the early phases of cyst initiation, and direct future research to new possible therapeutic targets. Show less
Schwach, V.; Fernandes, M.G.; Maas, S.; Gerhardt, S.; Tsonaka, R.; Weerd, L. van der; ... ; Salvatori, D.C.F. 2020
Aims Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human... Show moreAims Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.Methods and results CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.Conclusion Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs. Show less
