Abstract:
The extracellular matrix (ECM) is a scaffold composed of different proteins in which the cells of living tissues reside. In healthy states, the ECM plays an important role in regulating cellular processes such as apoptosis, proliferation and differentiation, contributing to tissue homeostasis. During events of injury, such as scar tissue formation after myocardial ischemia or fibrotic capsule formation following organ transplantation, the ECM experiences pathological changes which impact the survival of cells and significantly contributes to the severity of the injury. These pathological alterations of the ECM are among the main factors that determine cellular survival in tissues and treatment efficacy. Hence, understanding the roles of the various ECM proteins and elucidating their mechanisms of action in different tissues are of growing interest in the field of tissue engineering and medicine.
In this thesis, the impact of the ECM on cardiovascular and pancreatic tissues was studied. Cardiovascular tissues experience significant impact on native ECM homeostasis during the event of myocardial infarction and reperfusion injury (MI/R). We identified the ECM protein nidogen-1 (NID1) to be highly present during cardiac development. We furthermore showed the positive effect of recombinantly produced NID1 on cellular survival, angiogenesis and prevention of pathological differentiation in vitro. The treatment of mice with NID1 post-MI/R resulted in decreased scar tissue formation, increased revascularization and increased nerval innervation in the infarcted area accompanied by overall improvement in heart function.
ECM alterations in pancreatic tissue are of special interest during the process of isolation and transplantation of hormone-secreting islets of Langerhans to treat diabetes mellitus type 1. We demonstrated that both NID1 and decorin (DCN) co-localize with insulin-producing β-cells within the islets of Langerhans. Treatment of β-cells with NID1 and DCN improved functionality and survival in vitro. Furthermore, we demonstrated that hypoxic conditions significantly impact the ECM and functionality of β-cells, which was rescued upon co-culturing β-cells with endothelial cells in a collagen type 1 gel.
The in vitro models developed in this thesis demonstrate the positive effects of ECM proteins on survival and functionality of cells from different origins and elucidate potential underlying pathways. We furthermore highlight that restoration and recapitulation of native ECM in vitro offers great potential for in vivo translation regarding cellular treatments and therapies.
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