From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

Abstract

Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L₁ expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.

Keywords: diabetes mellitus; immunogenicity; immunomodulation; insulin-producing cells; mesenchymal stem cells.

Figure 1

GAD65 Expression: GAD65 converts glutamic acid into GABA, which takes part in β-cell proliferation and regeneration and glucose homeostasis. (A) Human islets: Positive staining for insulin (Green). (B) Human islets: Positive staining for GAD65 (Red). (C) Human islets: Electronic merging revealed the presence of GAD65 within the majority of insulin-producing cells (Yellow). (D) MSC-derived IPCs: Positive staining for insulin (Green). (E) MSC-derived IPCs: Positive staining for GAD65 (Red). (F) MSC-derived IPCs: Electronic merging revealed the presence of GAD65 within the majority of insulin-producing cell (Yellow). (G) Negative staining for GAD65 in undifferentiated MSCs.

Figure 2

MSC-Mediated Immunomodulation: Under inflammatory conditions, MSCs exert their immunomodulatory effect via cell-to-cell contact and/or the release of soluble factors. In addition to contact-dependent inhibition, MSCs suppress T cell proliferation by secreting IDO, NO and TGF-β. MSCs also modulate naïve T cells to generate Tregs through cell-to-cell contact, as well as via TGF-β and PGE2. B cell proliferation and antibody production is inhibited by IDO and PD-L₁. Through direct interactions, MSCs also promote the generation of IL-10-producing Bregs. MSCs affect the innate immune system and suppress NK cell proliferation and cytokine secretion, a process mediated by IDO and PGE2. MSCs also inhibit the differentiation of monocytes into DCs via the release of IL-6 and IL-10. Additionally, MSCs can drive DCs towards an IL-10-producing tolerogenic phenotype through the activation of Notch signalling. MSCs also direct macrophages towards an anti-inflammatory phenotype (M2) via the action of IL-10. IL-10 production from via different pathways triggers the generation of Tregs.