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Mesenchymal stromal cells and hematopoietic stem cell transplantation; from bench to bedside.

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Carlijn Voermans



Mesenchymal stromal cells (MSC) can be obtained from various tissues in our body, e.g. in the bone marrow were they support hematopoiesis. Transplantation of cultured MSC is promising and is increasingly applied for various purposes, for instance after hematopoietic stem cell transplantation or to repair large bone fractions. This research was aimed to unravel the mechanism of immunomodulation, migration and hematopoietic support of MSC with the ultimate goal to improve MSC for clinical application. Currently MSC are always culture expanded ex vivo before application. Once applied intravenously MSC should go on their way to tissue were they are needed (migration and homing), however, only a small percentage of the cells arrives at the desired destiny. With respect to migration we have now evidence that specifically in human MSCs the form of the nucleus is irregularly shaped and even prone to wrinkling. Nuclear wrinkling is already present at passage 1 after culturing of human MSCs from bone marrow aspirates and occurs irrespective of the culture passage, demonstrating that it is an intrinsic property of the cells. Besides we demonstrate that cultured MSCs show an imbalance in communication between the nucleus and the actin cytoskeleton, and may explain their low migration capacity. Our findings reveal that strategies aimed at restoring the nuclear envelope might improve MSC-based cellular therapies.
With respect to immunomodulation, we systematically analyzed whether different sources, culture and stimulation conditions could improve immunosuppressive potential of culture expanded MSC. We here show that the use of different MSC sources, culture- or stimulation methods could not further enhance the suppressive capacities of MSCs.
Interestingly we confirm that EVs are interesting candidates to replace MSC cellular therapy. Furthermore our research demonstrated that stimulation of MSC with IFN-y enhances the immunomodulation capacity, but inhibits the hematopoietic support of MSC.
For MSC and innate Iymphoid cells (ILC) has been described that they could have a protective role in graft versus host disease. Within this project we have also studies to what respect these two cell-types could interact. We demonstrate that MSC not only enhance the proliferation of ILC but also influence the cytokine production of ILC and via this pathway possibly can contribute in the treatment of graft versus host disease.
Neuroblastoma (NBL) is an embryonic tumor of neuroectodermal origin and accounts for 15% of all cancer-related deaths in children. About 50% of the patients present with bone marrow (BM) metastases at diagnosis. High-risk patients are treated by a multimodality approach, including chemotherapy, autologous stem cell transplantation (ASCT) and immunotherapy. Despite this intensive treatment, relapse frequently occurs and long-term survival of patients with high-risk neuroblastoma remains less than 40%. The main site of disease dissemination and relapse is bone marrow (BM). We aimed to evaluate the feasibility of stem cell apheresis and study hematological reconstitution after autologous stem cell transplantation (ASCT) in high risk-NBL patients and compare with children treated with chemotherapy only. Our results show that it is feasible to harvest sufficient amount of blood stem and progenitor cells. Moreover the white blood cell recovery is comparable but the recovery of the platelets remains behind. Further research learned that the transplanted blood stem and progenitor cells are less viable in the HR group and contained less cells expressing CD62L (L-selectin), a marker associated with rapid platelet recovery. However the delayed recovery of the platelets could also be related to the changed composition of the micro-environment of the bone-marrow. The bone marrow niche is composed among others of MSC. There is increasing evidence that tumor cells can alter their environment and make that insensitive to chemotherapy or that (recovery of) hematopoiesis such as platelet production is hampered. It is currently unknown whether MSC also play a role in metastasis or recurrence of neuroblastoma. We now have evidence that BM residing neuroblastoma cells alter the composition of the MSC population. Our current research is aimed at this latter aspect.

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