Mesenchymal stem cells (MSC) represent multipotent stromal cell populations, capable of differentiating into bone, cartilage and adipose cells. In addition to regenerative properties, MSC’s possess immunomodulatory properties. Feline adipose-derived mesenchymal stem cells (ASC) have previously been used in clinical trials, with varying success, for the treatment of immune-mediated diseases involving T lymphocyte dysregulation, including: chronic enteropathy, chronic kidney disease, and feline asthma. To date, ASC’s have been most successfully applied to the treatment of feline chronic gingivostomatitis (FCGS), a painful and debilitating oral inflammatory condition of cats.
ASC’s can modulate T lymphocyte function, suppress T lymphocyte proliferation, and decrease T lymphocyte viability. However, the mechanisms utilized by ASCs to effect T lymphocyte modulation are not yet fully elucidated. Several methods have been hypothesized, including: induction of apoptosis, cell cycle arrest, induction of phenotype switch to regulatory T cells, or decreasing T lymphocyte activation. These functions may be performed by soluble factors, or direct cell-to-cell contact.
The objective of the present experimental study was to investigate and define the mechanisms by which T cell inhibition is achieved by ASC’s, focusing on both soluble mediators and direct cell contact ligands. To accomplish this, ASC’s were isolated from subcutaneous feline adipose tissue, and obtained surgically from specific pathogen-free (SPF) cats or from client-owned cats undergoing clinical trials at the UC Davis William R. Pritchard Veterinary Medical Teaching Hospital Regenerative Medicine Laboratory. Cells were then cultured and expanded according to previously established protocols, and evaluated via cell cycle analysis and in vitro mixed leukocyte reactions using specific immunomodulatory inhibitors. Cell-to-cell interactions were assessed using static adhesion assays and specific inhibitors.
Data generated from the present study indicate that feline ASC’s decrease T-cell proliferation as well as the secretion of pro-inflammatory cytokines (most notably TNF-⍺). These actions are accomplished both with soluble factors and direct cell-to-cell contact. Firstly, results indicated that ASCs achieved T lymphocyte immunomodulation by inducing cell cycle arrest at G0-G1 in activated lymphocytes. Moreover, findings suggested that PGE2 is a primary soluble factor partially responsible for the inhibition of T lymphocyte proliferation. Lastly, results indicated that interactions of intracellular adhesion molecule ICAM-1 with its ligand were crucial for ASC-T lymphocyte adhesion, and the authors speculate that these molecules may be involved in contact-dependant immunomodulation by ASC’s.
Overall, the results of the present study indicate that feline ASC’s utilize PGE2 and ICAM-1 to inhibit T-cell proliferation, with resultant cell cycle arrest of T lymphocytes in G0-G1. These results suggest that ASC’s may be appropriate for use in therapeutic trials for both CD4+- and CD8+-mediated immune-mediated diseases. In conclusion, the findings of the present study may assist in defining appropriate T lymphocyte-mediated disease targets in cats that may be amenable to ASC therapy, and may inform potential translational models for immune-mediated inflammatory diseases in other species. (HM)