Despite optimal medical treatment and advanced revascularization strategies, a growing number of patients suffer from severe coronary artery disease not amenable to conventional treatment... Show more Despite optimal medical treatment and advanced revascularization strategies, a growing number of patients suffer from severe coronary artery disease not amenable to conventional treatment options. Bone marrow cell injection has emerged as a new potential therapeutic option for these patients. As preclinical studies provided evidence for improvement in myocardial perfusion and function after transplantation of cells, cell therapy was introduced in the clinical setting. As initial studies demonstrated promising results, intramyocardial injection of autologous bone marrow-derived mononuclear cells emerged as a new therapeutic option for patients with severe coronary artery disease. Although studies demonstrated safety and feasibility of the approach, the overall effect of bone marrow cell treatment has shown moderately positive but variable effects. However, many questions remain whether there are certain factors, such as patient specific characteristics, that influence treatment outcome. Therefore, in the current thesis, the efficacy of bone marrow cell injection was investigated in a large refractory angina patient population with chronic myocardial ischemia to further evaluate treatment effect during short and long term follow-up. In addition, the safety and effect of autologous mesenchymal stem cells injection, a specific bone marrow-derived cell type, in patients shorty after acute myocardial infarction was evaluated. Show less
This thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific... Show moreThis thesis focuses on the potential of cell-based therapy in ischemic heart disease and the role of the inflammatory response after myocardial infarction (MI). Chapter 2 reviews the specific myocardial inflammatory events that occur following MI and explores the potential role of cell therapy, in specific of the mesenchymal stromal cell (MSC), to positively influence this process. In chapter 3 we studied the usefulness of a clinically relevant transient ischemia MI model in immunodeficient mice to investigate the potential of human stem cell therapy and compared this to the commonly used animal MI model via permanent ischemia. Next, in chapter 4 we aimed to extend our previous research regarding the positive therapeutic effects of MSC therapy after MI by injecting MSCs stimulated with the pro-inflammatory cytokine interferon-γ, since pro-inflammatory priming has shown additional beneficial effects in several experimental disease models. Chapter 5 evaluates the short-term effect of human cardiomyocyte progenitor cell infusion on cardiac function in an animal MI model. Chapter 6 discusses the effect of diet-induced hypercholesterolemia on both cardiac function and inflammation after myocardial ischemia-reperfusion injury. Finally, chapter 7 provides an overview of the results described in this thesis, and discusses future perspectives. Show less
Locher, H.; Saadah, N.; Groot, S. de; Groot, J.C.M.J. de; Frijns, J.H.M.; Huisman, M.A. 2015
Once prostate cancer has spread to the skeleton, patients cannot be cured from their disease. Identification of the cell(s) of origin of prostate cancer as well as the neoplastic cell(s) involved... Show moreOnce prostate cancer has spread to the skeleton, patients cannot be cured from their disease. Identification of the cell(s) of origin of prostate cancer as well as the neoplastic cell(s) involved in the formation of distant metastases is, therefore, fundamental to understanding of carcinogenesis and metastasis. The functional identification of metastasis-initiating cells is a prerequisite for properly targeted therapy of metastatic disease in advanced prostate cancer. In chapter 2 of this thesis, the possible use of aldehyde dehydrogenase (ALDH) as marker for the identification and isolation of tumor-initiating and metastasis-initiating cells in prostate cancer is studied. In chapter 3, the functional role of a single ALDH isoform (ALDH7A1) in metastatic prostate cancer is investigated by knockdown studies in vitro and in vivo. In chapter 4, the functional involvement of _v integrins in the formation of a metastatic stem/progenitor prostate cancer phenotype is studied. Subsequently, in chapter 5, the targeting of integrins by a novel non-peptide integrin antagonist is evaluated in vitro and in preclinical models of prostate cancer progression and metastasis. Finally, general conclusions and discussions are described in chapter 6. Show less
Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic... Show moreHematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal antigens. MSCs have the capacity to differentiate into a wide variety of distinct cell lineages and to suppress immune responses in vitro and in vivo. The main goal of this thesis was to study the safety, feasibility, and applicability of stem cell therapy in IBD. Chapter 2 concludes that autologous HSCT appears to be safe and can be an alternative strategy for Crohn__s disease patients with severe and therapy resistant disease. Data from the phase I study described in Chapter 3 demonstrates that MSCs isolated from Crohn__s disease patients have similar characteristics compared to MSCs from healthy donors and that administration of autologous bone marrow derived MSCs appears to be safe and feasible in the treatment of refractory Crohn__s disease. Chapter 4 shows that MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. Chapter 5 demonstrates that IFN-_ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo. Show less
The aim of this thesis was to unravel the role of the humoral immune system in rheumatoid arthritis patients by employing new immunosuppressive strategies, i.e. specific B-cell depletion with... Show moreThe aim of this thesis was to unravel the role of the humoral immune system in rheumatoid arthritis patients by employing new immunosuppressive strategies, i.e. specific B-cell depletion with Rituximab and non-specific lymfoablative treatment with high dose chemotherapy and hematopoeietic stem cell transplantation. This thesis evaluates the clinical benefit of these strategies as well as the immunological changes that coincide with clinical improvement. By combining clinical outcome with immunological parameters of the humoral immune system, these studies provide a unique approach to investigatepathologic mechanisms in rheumatoid arthritis. Show less
Injection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were... Show moreInjection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were investigated. The first is to induce cardiomyogenic differentiation by genetically engineering cells to express the transcription factor myocardin (a regulator of cardiomyocyte differentiation). We found that overexpression of myocardin induces a large part of the cardiac muscle gene expression program in various non-muscle cells. Forced expression of myocardin enables cardiac infarction scar fibroblasts to conduct a cardiac action potential, and injection of myocardin-transduced MSCs resulted in greater preservation of cardiac function and reduced detrimental remodeling compared to untreated MSCs in a mouse model of myocardial infarction. Indicating that overexpression of myocardin endows cells with several beneficial properties of cardiomyocytes. We hypothesized that myocardial regeneration might be enhanced by including novel cell types with supportive functions in cell therapy strategies. We found that the mesothelial cells of the human epicardium, like embryonic epicardium-derived cells (EPDCs) can form fibroblasts and smooth muscle cells. Indicating that EPDCs from human adults recapitulate at least part of the differentiation potential of their embryonic counterparts, which form various essential supportive cell types during heart development. Show less
