Abstract
Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed tissue, proinflammatory lymphocytes such as IL-17-producing T helper cells (Th17) may interact with the stromal microenvironment, including MSCs. In this context, MSCs may encounter different levels of T cells as well as specific inflammatory signals. Uncovering the cellular and molecular changes during this interplay is central for developing an efficient and safe immunotherapeutic tool. To this end, an in vitro human model of cocultures of FSK-MSCs and T cells was established. These cocultures were performed at different cell ratios in the presence of an inflammatory setting. After confirming that FSK-MSCs respond to ISCT criteria by showing a typical phenotype and multilineage potential, we evaluated by flow cytometry the expression of Th17 cell markers IL-17A, IL23 receptor and RORγt within the lymphocyte population. We also measured 15 human Th17 pathway-related cytokines. Regardless of the T cell/MSC ratio, we observed a significant increase in IL-17A expression associated with an increase in IL-23 receptor expression. Furthermore, we observed substantial modulation of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40, and TNF-α secretion. These findings suggest that FSK-MSCs are receptive to their environment and modulate the T cell response accordingly. The changes within the secretome of the stromal and immune environment are likely relevant for the therapeutic effect of MSCs. FSK-MSCs represent a valuable cellular product for immunotherapeutic purposes that needs to be further clarified and developed.
Highlights
Stromal/stem cells have been the focus of intense research, introducing new possibilities for the treatment of various diseases
The properties of isolated FSK-Mesenchymal stromal/stem cells (MSCs) were characterized according to the criteria of the International Society for Cellular Therapy (ISCT)
Our data showed that RORγt expression levels were significantly decreased regardless of the MSC:T cell ratio with or without inflammation, suggesting that FSK-MSCs may oppose and reduce Th17 differentiation. The latter results seem to be specific to FSK-MSCs since we previously showed that coculture of T cells and stromal/stem cells originating from marrow and adipose tissues constantly increased
Summary
Stromal/stem cells have been the focus of intense research, introducing new possibilities for the treatment of various diseases. One of the main features of stromal/stem cell therapy is the induction of a proregenerative and tolerogenic microenvironment to promote graft acceptance and tissue repair [1]. Mesenchymal stromal/stem cells (MSCs) have attracted much interest in the fields of immunotherapy and regenerative medicine [2]. Communication between stromal and immune cells is essential to maintain tissue homeostasis and promote tissue repair. The implantation of stem cells within a milieu of inflammation will establish immediate crosstalk among stem cells, microenvironmental molecules, and resident and infiltrating immune cells [3]. MSCs show tropism toward damaged and inflamed tissues, where they exert their beneficial effects by both direct and indirect mechanisms. MSCs have the capacity to actively sense their local molecular and cellular environment and respond by properly adjusting their regulatory machinery [2]
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