Human ESC-Derived MSCs Outperform Bone Marrow MSCs in the Treatment of an EAE Model of Multiple Sclerosis

Abstract

SummaryCurrent therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.

Stem Cell Therapy Versus T Lymphocytes: Friend or Foe?

“…(A): It is hypothesized that factors released by short-lived therapeutic stem cells include LIF, or closely related cytokines that signal through the LIF-receptor "gp190": increased Treg cells will sustain therapeutic benefit in an antigen-specific manner by further release of LIF [9]. This hypothesis is in accord with the recent reports (a) that short-lived stem cell grafts give rise to long-term benefits and (b) that hBM-MSC release IL-6 and are less efficacious compared to hES-MSC in reducing symptoms of EAE [1]. Notably, hBM-MSC-by releasing IL-6-may support TH17-driven immunity.…”

“…Given the recent findings that transplanted therapeutic stem cells may die within days of implantation, soluble factors are now thought to play a key role in the outcome of stem cell therapies [1,2]. This brings focus on pivotal immune regulatory switches within the host and is especially relevant where the source of therapeutic stem cell influences therapeutic efficacy.…”

“…This brings focus on pivotal immune regulatory switches within the host and is especially relevant where the source of therapeutic stem cell influences therapeutic efficacy. By comparing human bone-marrow-derived mesenchymal stem cells (hBM-MSC) versus human embryonic stem cell-derived MSC (hESC-MSC) in experimental autoimmune encephalitis (EAE)-a mouse model of multiple sclerosis (MS)-Wang et al [1] discovered that hBM-MSC failed to match hES-MSC in efficacy, identifying release of interleukin-6 (IL-6) by the hBM-MSC as a possible reason. This is important, first because-in T-lymphocyte maturation -IL-6 promotes differentiation of the inflammatory Th17 effector cell lineage [3]; and second because Th17 cells are key mediators of the autoimmune disease process [4].…”

Stem Cell Therapy: A Promising Therapeutic Approach for Multiple Sclerosis

“…Transplanted neural precursors migrated into the host white matter; however, differentiation into mature oligodendrocytes and remyelination were insignificant (3). In the EAE model of MS, the therapeutic effect of hES-MSCs, including reduction of clinical symptoms and prevention of neuronal demyelination, was significantly higher than BMMSCs (98). Transplantation of ESCs in adult rat spinal cord had the ability to survive, migrate, and differentiate into mature myelin-producing cells in areas of demyelination (99).…”

Effect of Secreted Molecules of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells on Acute Hepatic Failure Model

“…To date, human ESCMSCs have been used to treat various animal models such as inflammatory bowel disease [11], fistulizing Crohn's disease [12] and experimental autoimmune encephalitis [13]. However, no report has discussed the use of human ESC-MSC-CM in hepatocytes both in vitro and in an ALF mouse model.…”