Abstract
Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and enhanced immunosuppressive capacity in vitro. However, this has yet to be examined in ASCs. The present study examined the therapeutic potential of short-term Rapamycin-preconditioned ASCs in the EAE model. Animals were treated at peak disease with control ASCs (EAE-ASCs), Rapa-preconditioned ASCs (EAE-Rapa-ASCs), or vehicle control (EAE). Results show that EAE-ASCs improved clinical disease scores and elevated intact myelin compared to both EAE and EAE-Rapa-ASC animals. These results correlated with augmented CD4+ T helper (Th) and T regulatory (Treg) cell populations in the spinal cord, and increased gene expression of interleukin-10 (IL-10), an anti-inflammatory cytokine. Conversely, EAE-Rapa-ASC mice showed no improvement in clinical disease scores, reduced myelin levels, and significantly less Th and Treg cells in the spinal cord. These findings suggest that short-term Rapamycin preconditioning reduces the therapeutic efficacy of ASCs when applied to late-stage EAE.
Highlights
Multiple sclerosis (MS) is an inflammation-driven autoimmune disease caused by aberrant activation and infiltration of peripheral immune cells into the central nervous system (CNS), and subsequent destruction of myelin-producing oligodendrocytes [1]
We have shown that adipose-derived stem cells (ASCs) suppress proliferation of type 1 T helper (Th1 ) cells, promote T regulatory (Treg ) cells and alternatively-activated macrophages (M2), dampen pro-inflammatory cytokine production, reduce CNS infiltration and demyelinating lesions, and improve overall disease outcomes [10,11,12,13]
Faced with conflicting evidence on the contribution of PGE2 to EAE pathophysiology, and the reported elevation of PGE2 following short-term Rapa in ASCs, the present study investigates the consequences of this preconditioning strategy in the EAE model of CNS inflammation
Summary
Multiple sclerosis (MS) is an inflammation-driven autoimmune disease caused by aberrant activation and infiltration of peripheral immune cells into the central nervous system (CNS), and subsequent destruction of myelin-producing oligodendrocytes [1]. Most evidence of ASC therapy in EAE suggests that their primary benefit derives from their homing to sites of inflammation, modifying innate and adaptive immune cells through paracrine activity, and changing the populations that infiltrate the CNS and determine the course of disease. Translation to human trials faces numerous obstacles due to limited and variable ASC immunosuppression in the post-transplant pathological environment Donor characteristics such as advanced age or obesity status negate the therapeutic effect of ASCs, and strategies to restore their efficacy would reduce donor-to-donor variability and drastically widen the potential donor pool [13,19,20]. Faced with conflicting evidence on the contribution of PGE2 to EAE pathophysiology, and the reported elevation of PGE2 following short-term Rapa in ASCs, the present study investigates the consequences of this preconditioning strategy in the EAE model of CNS inflammation. These findings suggest that further investigation of Rapa-ASCs earlier in EAE may yield greater insight into the dynamic role of PGE2 in disease pathogenesis
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