Extracellular Vesicles Released from Human Umbilical Cord-Derived Mesenchymal Stromal Cells Prevent Life-Threatening Acute Graft-Versus-Host Disease in a Mouse Model of Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Mesenchymal stromal cells (MSCs) are attractive agents for the prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, safety concerns remain about their clinical application. In this study, we explored whether extracellular vesicles released from human umbilical cord-derived MSCs (hUC-MSC-EVs) could prevent aGVHD in a mouse model of allo-HSCT. hUC-MSC-EVs were intravenously administered to recipient mice on days 0 and 7 after allo-HSCT, and the prophylactic effects of hUC-MSC-EVs were assessed by observing the in vivo manifestations of aGVHD, histologic changes in target organs, and recipient mouse survival. We evaluated the effects of hUC-MSC-EVs on immune cells and inflammatory cytokines by flow cytometry and ProcartaPlex™ Multiplex Immunoassays, respectively. The in vitro effects of hUC-MSC-EVs were determined by mitogen-induced proliferation assays. hUC-MSC-EVs alleviated the in vivo manifestations of aGVHD and the associated histologic changes and significantly reduced the mortality of the recipient mice. Recipients treated with hUC-MSC-EVs had significantly lower frequencies and absolute numbers of CD3CD8 T cells; reduced serum levels of IL-2, TNF-α, and IFN-γ; a higher ratio of CD3CD4 and CD3CD8 T cells; and higher serum levels of IL-10. An in vitro experiment demonstrated that hUC-MSC-EVs inhibited the mitogen-induced proliferation of splenocytes in a dose-dependent manner, and the cytokine changes were similar to those observed in vivo. This study indicated that hUC-MSC-EVs can prevent life-threatening aGVHD by modulating immune responses. These data provide the first evidence that hUC-MSC-EVs represent an ideal alternative in the prophylaxis of aGVHD after allo-HSCT.

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…On the one hand, SC-EVs have been reported to induce the immune response of T helper type 1 (Th1) conversion to T helper type 2 (Th2). For example, SC-EVs drove the shift from Th1 toward Th2 cells and reestablished Th1/Th2 homeostasis by downregulating pro-inflammatory TNF-α and INF-γ and upregulating anti-inflammatory IL-10 or IL-4 (29,44,51,74,76) ( Table 1). Moreover, SC-EVs could also regulate Th2 immune response toward Th1.…”

Potential roles of extracellular vesicles in the pathophysiology, diagnosis, and treatment of autoimmune diseases

“…The EVs isolated from patient serum contains three miRNAs (miR-423, miR-199, miR-93), which may be related to the incidence and severity of GVHD [68]; and the expression of CD146, CD31, and CD140-α on EVs surface, is also closely related to the onset of the disease [69]. Traditional MSCs therapy after replacement with EVs for GVHD also showed ideal results, suggesting that MSCs-derived EVs are potential for cell-free therapy for GVHD [58,70]. Kordelas L et al used MSCs-derived EVs instead of MSCs in the patient with GVHD, and the promising results were obtained.…”

Mesenchymal Stem Cell Derived Extracellular Vesicles: A Role in Hematopoietic Transplantation?

“…Wang et al instead showed that UCB-MSC-EVs could prevent aGvHD in a mouse model of allo-HSCT by modulating immune responses [10]. The study demonstrated that UCB-MSC-EVs reduce in vivo manifestations of aGvHD, attenuate the associated histological changes, and prolong mice survival.…”

“…The study demonstrated that UCB-MSC-EVs reduce in vivo manifestations of aGvHD, attenuate the associated histological changes, and prolong mice survival. In fact, in recipient mice a significant decrease of frequency and the absolute number of CD3 + CD8 + T-cells and an increased ratio of CD3 + CD4 + to CD3 + CD8 + T-cells were found [10]. Finally, as reported by Kordelas et al [121], in vitro and in vivo experiments confirmed the decreased levels of different inflammatory cytokines, including IL-2, TNF-α, and IFN-γ, and an increase of anti-inflammatory cytokines, such as IL-10 (Figure 1) [10].…”

“…Interestingly, recent studies have demonstrated that MSCs release extracellular vesicles (EVs) and have shown that MSC-EVs have similar functions to those of MSCs; as a consequence, MSC-EVs are widely studied as potential therapeutic agents in various diseases [7,8]. In vitro and in vivo studies indicate that MSC-EVs therapy appears to hold substantial promise, particularly in the treatment of immune-based disorders, including complications of allo-HSCT [9,10]. In this article, we will review the characteristics of MSCs and MSC-EVs and their therapeutic role in allo-HSCT and GvHD.…”