Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases

Abstract

Immune-mediated inflammatory diseases (IMIDs) encompass several entities such as "classic" autoimmune disorders or immune-mediated diseases with autoinflammatory characteristics. Adult stem cells including mesenchymal stem cells (MSCs) are by far the most commonly used type in clinical practice. However, due to the possible side effects of MSC-based treatments, there is an increase in interest in the MSC-secretome (containing large extracellular vesicles, microvesicles, and exosomes) as an alternative therapeutic option in IMIDs. A wide spectrum of MSC-secretome-related biological activities has been proven thus far including anti-inflammatory, anti-apoptotic, and immunomodulatory properties. In comparison with MSCs, the secretome is less immunogenic but exerts similar biological actions, so it can be considered as an ideal cell-free therapeutic alternative. Additionally, since the composition of the MSC-secretome can be engineered, for a future perspective, it could also be viewed as part of a potential delivery system within nanomedicine, allowing us to specifically target dysfunctional cells or tissues. Although many encouraging results from pre-clinical studies have recently been obtained that strongly support the application of the MSC-secretome in IMIDs, human studies with MSC-secretome administration are still in their infancy. This article reviews the immunomodulatory effects of the MSC-secretome in IMIDs and provides insight into the interpretation of its beneficial biological actions.

Keywords: autoimmune diseases; exosomes; extracellular vesicles; immune-mediated inflammatory diseases; mesenchymal stem cell-derived secretome.

Figure 1

The secretome is defined as the set of substances released from the cell (e.g., mesenchymal stem cells—MSCs) to their surroundings with a wide spectrum of biological action. The figure represents the components, their origin, size, and characteristic surface markers. (RNA: ribonucleic acid; miRNA: micro-RNA; circRNA: circular-RNA; lncRNA: long non-coding-RNA; DNA: deoxyribonucleic acid; TS101: tumor susceptibility 101; ESCORT3: endosomal sorting complex required for transport-3; CD40L: CD40 ligand; ARF: ADP-ribosylation factor; VAMP3: vesicle-associated membrane protein 3; ANX: Annexin; PS: phosphatidylserine; TS: thrombospondin).

Figure 2

The beneficial immunomodulatory effects of the MSC-secretome. The diagram illustrates how MSC-secretome components contribute to the amelioration of inflammation. (IL: interleukin; pKNOX1: PBX/knotted 1 homeobox 1; TLR: Toll-like receptor; PI3K: phosphatidylinositol 3-kinase; NFkB: nuclear factor kB; TGF: transforming growth factor; Treg: regulatory T cell; Th1: type 1 helper T cell).

Figure 3

The modes and biological effects of MSC-secretome manipulation. Methods marked with green and green arrows favor the appearance of the MSC2 immunosuppressive phenotype. The method marked in red and the red arrow promote the MSC1 proinflammatory phenotype (TLR: Toll-like receptor; poly (I:C): polyinosinic:polycytidylic acid; 3D: 3 dimensional; MSC: mesenchymal stem cell; IFN: interferon; TNF: tumor necrosis factor; IL: interleukin; LPS: lipopolysaccharide; CXCL: C-X-C motif chemokine ligand; TGF: transforming growth factor; PGE: prostaglandin E; IDO: indolamin-2,3-dioxigenase).

Figure 4

The anti-inflammatory and immunomodulatory effects of the MSC-secretome in rheumatoid arthritis. The figure depicts how components of the MSC-secretome contribute to the amelioration of disease activity. (RA-FLS: rheumatoid arthritis fibroblast-like synoviocyte; MMP: matrix metalloproteinase; HDAC4: histone deacetylase 4; RANKL: receptor activator of nuclear factor kappa-B ligand; OPG: osteoprotegerin; CCL2: C–C motif chemokine ligand 2; CXCL12: C-X-C motif chemokine ligand 12).

Figure 5

The potential modes of beneficial action of the MSC-secretome in type 1 diabetes mellitus (T1DM). The figure shows how MSC-secretome contributes to the restoration of immune dysregulation in T1DM (IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; TGF: transforming growth factor; Treg: regulatory T cell; Th1/Th17: type 1/type 17 helper T cell).