Multilineage-differentiating stress-enduring (MUSE) cells improve pancreatic islet transplantation in murine models of autoimmune diabetes

GIMENO, ML; PERONE MJ; FUERTES FLORENCIA; MARINA ERDOCIA

WOODS HOLE

Conferencia; 9th Aquatic Models of Human Disease Conference (MBL); 2018

MBL

A particular population of pluripotent stem cells has been isolated from human adult dermal fibroblasts and bone marrow stromal cells, and has been termed MUSE cells. We recently described the cellular and molecular characteristics of MUSE cells derived from human subcutaneous adipose tissue (AT) lipoaspirates. MUSE-AT cells isolated under severe stress conditions expressed pluripotency stem cell markers and differentiated into the three germ lineages. A distinguishable characteristic of MUSE-AT cells, important for their potential therapeutic use, is their limited proliferation rate and inability to form teratomas when injected into immunodeficient mice. Using LPS-stimulated macrophages and antigen-specific-challenged T cell assays, we demonstrated that MUSE-AT cells display anti-inflammatory activities down-regulating the secretion of pro-inflammatory cytokines, such as IFN-γ and TNF-α. We showed that MUSE-AT cells spontaneously gain TGF-β1 expression over time in culture which, in a pSMAD2-dependent manner, might prove pivotal in their observed immunoregulatory activity through decreased expression of T-box transcription factor in T cells (Gimeno et al., 2017).Type 1 diabetes (T1D) is a T cell mediated autoimmune disease in which there is insufficient β-cell mass to maintain normoglycemia. Transplantation of pancreatic islets is a clinical option in T1D patients suffering impaired awareness of hypoglycemia and severe hypoglycemic events. However, the need of multiple cadaveric donors as well as, the control of immune responses responsible for allogeneic-rejection has not been resolved yet. Several experimental studies demonstrated that transplanted islets have inadequate blood vessel density leading to a hypoxic and undernourished microenvironment that causes impaired function and gradual islet death. Recently we demostraded that: MUSE-AT cells spontaneously express IL-37, VEGF and CD31 (factors involved in endothelial cells growth and tissue vascularization), and murine islets co-cultured for several days with MUSE-AT cells retain their intact morphology like freshly isolated islets, while islets cultured alone (as controls) become amorphous with loss of their featured morphology. Our general objective is to improve the outcome of allogeneic islets transplantation using MUSE-AT cells at the site of engraftment. This therapeutic approach applied in murine models of autoimmune diabetes highlights the promise of improving islets engraftment, reducing the number of donors and the risk of side effects.