Development of next generation MSC therapeutics for critical limb ischaemia
Sanz Nogués, Clara
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Cell therapy with mesenchymal stem cells (MSCs) is being explored as a treatment for many ischaemic conditions of unmet medical need, such as critical limb ischaemia. MSC transplantation in humans has occurred in both autologous and allogeneic settings. However, in not all cases has the transplantation of stem cells resulted in successful translation. The field of cell therapy still faces some significant hurdles that need to be overcome before they can be routinely transplanted into patients. Issues of cell delivery and cell retention rates at the target site need to be addressed. Reduced retention of cells at the site of delivery may be due to a variety of factors including the hostile environment to which cells are exposed and, in allogeneic settings, the immune response to cells from an unrelated donor. Here, two possible strategies that aim to protect allogeneic MSC from the host immune system have been investigated. The hypothesis is that suppressing the primary anti-donor immune response to allogeneic MSC or delivering MSCs in a capsule may result in an in vivo persistence of cells, which may enhance the therapeutic outcome. In Chapter 2 I investigated whether SCS-pDADMAC microcapsules supported viability of hMSC and whether these could be used as devices for delivery of angiogenic factors. Results showed a marked reduction of hMSCs viability, which was attributed to impairment in the diffusion of essential macromolecules through the microcapsule membrane. In Chapter 3, I investigated the immunogenicity and efficacy of allogeneic mMSCs transplanted in BALB/c mice with hind limb ischaemia, and whether a short-course of immunosuppression would enhance the therapeutic efficacy of these allogeneic cells. The results showed that transplantation of allogeneic MSC induced a specific anti-donor alloantibody response. Intriguingly, the immunosupression treatment resulted in a diminution of donor-specific antibody production. However, syngenic and allogeneic mMSC transplantation did not result in an enhanced in vivo neovascularization. Furthermore, the immunosuppressive therapy did not improve allogeneic MSC efficacy despite its capacity to diminish anti-donor humoral response.
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