Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients

Abstract

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c + dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c + DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c + DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c + DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c + DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…The metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) overexpression promotes DC-SIGN expression by functioning as an miR155-5p sponge in the DC cytoplasm, which derives DC to Tol-DC with low expression of costimulatory molecules and high IL-10 secretion, protecting mice from acute rejection after cardiac transplantation ( 71 ). Apart from these, some biological interventions have also been used to induce Tol-DC, such as mesenchymal stem cells (MSCs) ( 72 ), induced pluripotent stem cells (iPSCs) ( 73 ), and recombinant Schistosoma mansoni antigens ( 32 ). Cai et al generated Tol-DC from murine iPSCs and injected these Tol-DC 7 days before transplantation into the recipients, resulting in a decreased expression of perforin/granzyme B, increased secretion of TGF-β, and proliferation of CTLA4 + GITR + Treg in mice with prolonged cardiac graft survival ( 73 ).…”

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury

“…Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are characterized by their abilities of selfrenewal, differentiation, immunomodulatory and trophic support [1][2][3], which endows them with enormous potential to treat multiple human diseases, including graftversus-host disease, systemic lupus erythematosus, Crohn's disease, cardiovascular and kidney diseases [3][4][5]. However, safety issues regarding MSC-based therapy, such as embolism, immunogenicity, and potential risk of proliferation, are main concerns for their usage [6][7][8][9].…”

Deconstructing transcriptional variations and their effects on immunomodulatory function among human mesenchymal stromal cells

“…Activated MSCs produce chemokines CCL5, CXCL9, CXCL10, and CXCL11, which could recruit T cells to the proximity of MSCs and suppress the proliferation and activity of T cells in their vicinity by expressing tryptophan catabolism rate-limiting enzyme IDO1 through metabolite kynurenic acid and/or by expression the immune checkpoint protein CD274 through cell-to-cell interaction [ 1 , 84 , 85 ]. In addition, a recent study demonstrated that MSCs might utilize IFNγ-FLT3L-FLT3 axis to suppress inflammation in lupus through upregulating tolerogenic DCs [ 86 ]. Different groups of MSCs should deploy shared regulation networks to exert immunosuppressive function upon IFNγ licensing, including JAT-STAT, NF-kappaB, IL-12/IL23, response to interferon, immune response, antigen and protein degradation, extrinsic apoptosis pathway, and complement system signaling pathways, which could form a regulatory network to orchestrate MSC immunomodulatory function (Fig.…”