A frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous... Show moreA frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous discharge from the fistula causing skin irritation. Nowadays, a wide range of medical and surgical therapies for perianal fistulizing CD is available. However, achieving complete fistula healing is often a long process preceded by multiple relapses during the treatment. Currently, mesenchymal stromal cells (MSCs) have gained much interest as a potential therapeutic option for inflammatory disorders, including fistulizing CD, because they possess immunosuppressive and tissue regenerative properties. We performed a clinical trial evaluating MSCs as a treatment for perianal fistulas. Local administration of MSCs additional to a standardized surgical treatment was safe and feasible and resulted in a higher percentage of healed fistulas compared to placebo. In addition, several experimental studies were performed to unravel the mechanism of action of MSCs. The role of the time of MSC administration, disease severity, prestimulation of MSCs with inflammatory cytokines, migration of MSCs and the formation of spheroid-like structures are described in this thesis. 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
Hommes, D.W.; Duijvestein, M.; Zelinkova, Z.; Stokkers, P.C.F.; Holsbergen-de Ley, M.; Stoker, J.; ... ; Kersten, M.J. 2011
