Although most tissues in the human body have self-renewal capabilities, there are defects, e.g. caused by trauma or disease, which are beyond regenerative potential. Tissue engineering offers a possibility to heal such defects without the necessity of finding a suitable graft donor. While a number of in vivo studies concerning tissue engineering for tissues replacement have been successfully performed, a need occurred to introduce vascular networks in newly formed tissues in order to guarantee their survival and correct functionality. Therefore, tissue engineering of blood vessels and capillaries is a widely investigated aspect necessary for various applications. This thesis describes the in vitro and in vivo biological evaluation of the potential of human mesenchymal stromal cells (hMSC) to differentiate towards endothelial-like cells (EL-MSC). The success of regenerative strategies where EL-MSCs are applied relies on the following requirements: the differentiation protocol should be simple and robust, the issue of donor-related variability needs to be addressed, clinically approved ways of delivery must to be provided and finally, the usefulness of EL-MSCs in certain applications ought to be proven. Since hMSCs are already widely used in various therapies, EL-MSCs are likely to fulfil all these requirements. Chapter 1 summarizes the content of this thesis. In chapter 2, a general review of literature is given, with the particular emphasis on emerging strategies for blood ves- sel engineering. Various cell types, biomaterials and approaches to generate functional vessels are described. Chapter 3 contains the evaluation of hMSC endothelial differen- tiation. The robustness of the presented protocol is assessed in chapter 4 together with the estimation of hMSC in vitro expansion potential when endothelial differentiation is required. Several molecular markers are also suggested for predicting whether cells obtained from a particular donor can be used in therapies that require EL-MSC appli- cation. Chapters 5 and 6 contain the description of two potential strategies to deliver EL-MSC for vascularization purposes. Modular tissue engineering approaches based on collagen modules and injectable in-situ-forming dextran-based hydrogel applica- tions are presented. Two strategies are described to improve biological performance of EL-MSCs: creation of 3-dimensional structures allowing for easier vessel in-growth and alternatively, applying growth factor stimulation to induce angiogenesis from host vessels. The potential applications of EL-MSCs for tissue engineering purposes are described in chapter 7 and 8. In chapter 7 the beneficial influence of EL-MSCs on bone formation is presented while chapter 8 shows how EL-MSCs can be used for improving vascularization of islets of Langerhans. Finally, chapter 9 summarizes and discusses all the results presented in this thesis. Overall, this thesis presents a multifactorial approach towards improving vascularization of both in vitro and in vivo engineered tissues and also suggests future developments and applications of endothelial-like cells derived from MSCs.
|Award date||10 Apr 2014|
|Place of Publication||Enschede|
|Publication status||Published - 10 Apr 2014|