Mechanisms utilized by feline adipose-derived mesenchymal stem cells to inhibit T lymphocyte proliferation

Abstract

Background: Feline adipose-derived mesenchymal stem cells (ASCs) have been successfully used in clinical trials for the treatment of immune-mediated diseases with T cell dysregulation. However, the immunomodulatory pathways utilized by feline ASCs to suppress T cell activation have not been fully determined. We investigated the mechanisms used by feline ASCs to inhibit T cell proliferation, including the soluble factors and the cell-cell contact ligands responsible for ASC-T cell interaction. Methods: The immunomodulatory activity of feline ASCs was evaluated via cell cycle analysis and in vitro mixed leukocyte reaction using specific immunomodulatory inhibitors. Cell-cell interactions were assessed with static adhesion assays, also with inhibitors. Results: Feline ASCs decrease T cell proliferation by causing cell cycle arrest in G0-G1. Blocking prostaglandin (PGE 2), but not IDO, partially restored lymphocyte proliferation. Although PDL-1 and CD137L are both expressed on activated feline ASCs, only the interaction of intercellular adhesion molecule 1 (ICAM-1, CD54) with its ligand, lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18), was responsible for ASC-T cell adhesion. Blocking this interaction reduced cell-cell adhesion and mediator (IFN-γ) secretion and signaling. Conclusions: Feline ASCs utilize PGE 2 and ICAM-1/LFA-1 ligand interaction to inhibit T cell proliferation with a resultant cell cycle arrest in G0-G1. These data further elucidate the mechanisms by which feline ASCs interact with T cells, help define appropriate T cell-mediated disease targets in cats that may be amenable to ASC therapy, and may also inform potential translational models for human diseases.

Pre-conditioning of Equine Bone Marrow-Derived Mesenchymal Stromal Cells Increases Their Immunomodulatory Capacity

“…Similar to what was described earlier for equine BM-derived MSCs, our results show that cyclooxygenase (COX) pharmacological inhibition restores the proliferation of lymphocytes in co-culture with MSCs (45,46). Since PGE 2 was identified as a molecule secreted in the culture media of human MSCs (61), it has been described as a major mediator of MSCs modulatory effects in several species (11,37,53,62), not only inhibiting lymphocyte proliferation, but also inhibiting the expression of co-stimulatory molecules by antigen presenting cells (APCs), thus limiting their capacity to activate T cells. Additionally, MSCs produce PGE 2 in sufficient quantity to be able to reprogram macrophages, thus inhibiting production of TNF-α and IL-6 and increasing the secretion of IL-10 (63, 64).…”

“…Multiple soluble mediators have been described as relevant in the inhibitory effect of MSCs on lymphocyte proliferation (33). Although precise mechanisms seem to be speciesdependent, prostaglandin E 2 (PGE 2 ) secretion, indoleamine 2,3dioxygenase (IDO) activity and nitric oxide (NO) production seem to be the most common events across species (34)(35)(36)(37). Although there is sufficient evidence on the in vitro modulatory effect of MSCs on the immune response, there are disparate results between the beneficial effect of MSCs in preclinical models and their actual use in clinical diseases related to the immune system (38,39).…”

Placenta-derived multipotent mesenchymal stromal cells: a promising potential cell-based therapy for canine inflammatory brain disease

“…It has also been shown that blockade of ICAM-1 and VCAM-1 ablates MSC-mediated immunosuppression which highlights the potential mechanistic role of adhesion molecules by MSCs [ 60 ]. The role of ICAM-1/LFA ligand has been shown to play a critical role in feline ASC-mediated immunosuppression through induction of G0-G1 cell cycle arrest [ 61 ]. Feline ASCs also induce cell cycle arrest by utilizing PGE 2 which is comparable to our findings in dog MSCs, suggesting ICAM-1 may also play a significant role in canine MSC mediated immunosuppression.…”

Isolation and Characterization of Feline Wharton’s Jelly-Derived Mesenchymal Stem Cells

“…There are several reports using feline stem cells in therapeutic studies in cats. The stem cells used in most cases have been shown to originate from feline adipose tissue [ 16 , 17 , 18 , 19 , 50 , 51 ]. With regard to potential therapeutic uses, there is a need for a source of stem cells of established diversity.…”