Distinct Immunomodulatory and Migratory Mechanisms Underpin the Therapeutic Potential of Human Mesenchymal Stem Cells in Autoimmune Demyelination

Abstract

Mesenchymal stem cells (MSCs) are efficacious in a variety of intractable diseases. While bone marrow (BM)-derived MSCs (BM-MSCs) have been widely investigated, MSCs from other tissue sources have also been shown to be effective in several autoimmune and inflammatory disorders. In the present study, we simultaneously assessed the therapeutic efficacy of human BM-MSCs, as well as MSCs isolated from adipose tissue (Ad-MSCs) and umbilical cord Wharton's jelly (UC-MSCs), in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Prior to in vivo experiments, we characterized the phenotype and function of all three MSC types. We show that BM-MSCs were more efficient at suppressing the in vitro proliferation of mitogen or antigen-stimulated T-cell responses compared to Ad-MSCs and UC-MSCs. Notably BM-MSCs induced the differential expression of cytokines from normal and stimulated T-cells. Paradoxically, intravenous transplantation of BM-MSCs into C57Bl/6 mice with chronic progressive EAE had a negligible effect on the disease course, even when multiple MSC injections were administered over a number of time points. In contrast, Ad-MSCs had the most significant impact on clinical and pathological disease outcomes in chronic progressive and relapsing-remitting EAE models. In vivo tracking studies revealed that Ad-MSCs were able to migrate to the central nervous system (CNS), a property that most likely correlated with their broader expression of homing molecules, while BM-MSCs were not detected in this anatomic region. Collectively, this comparative investigation demonstrates that transplanted Ad-MSCs play a significant role in tissue repair processes by virtue of their ability to suppress inflammation coupled with their enhanced ability to home to the injured CNS. Given the access and relatively ease for harvesting adipose tissue, these data further implicate Ad-MSCs as a cell therapeutic that may be used to treat MS patients.

Distinct In Vitro Properties of Embryonic and Extraembryonic Fibroblast-Like Cells are Reflected in their in Vivo Behavior following Grafting in the Adult Mouse Brain

“…Further research will have to address this topic. Of note, a recently published study also attributed distinct immunomodulatory and migratory mechanisms to human mesenchymal cells derived from different tissues (15,20). Third, while mEF cultures are responsive to LPS/IFN-g signaling, mFMSC cultures are unresponsive, at least with regard to TNF-a production.…”

Transplantation of umbilical cord and bone marrow-derived mesenchymal stem cells in a patient with relapsing-remitting multiple sclerosis

“…However, pre-clinical evidence suggests that other sources of MSC such as adipose or umbilical cell-derived MSC (hUC-MSCs) may actually be more efficacious and suitable for clinical translation. 8,9 We report a patient treated with hUC-MSC infusions as well as BM-MSCs over a 4 y period.…”

Bone Marrow Mesenchymal Stromal Cells Isolated from Multiple Sclerosis Patients have Distinct Gene Expression Profile and Decreased Suppressive Function Compared with Healthy Counterparts

“…The administration of MSCs in mice with experimental autoimmune encephalomyelitis (EAE) suppressed specific T-cell proliferation; decreased interferon-g (IFN-g), tumor necrosis factor (TNF), and IL-17 secretion; shifted the cytokine profile to a Th2 polarization; and increased the number of regulatory T-cells (2,20,41,58). In addition, MSCs migrated to the demyelinated areas, where they diminished cellular infiltrate, stimulated proliferation of oligodendrocytes and astrocytes through the release of soluble factors, mainly HGF (1,2), and decreased demyelinated areas and clinical EAE disability scores (27,34,59,60).…”