B Lymphocytes as Targets of the Immunomodulatory Properties of Human Amniotic Mesenchymal Stromal Cells.

Marta Magatti,Antonietta Rosa Silini,Ornella Parolini,Elsa Vertua,Alice Masserdotti,Francesca Romana Stefani,Patrizia Bonassi Signoroni

doi:10.3389/fimmu.2020.01156

Abstract

Mesenchymal stromal cells (MSC) from the amniotic membrane of human term placenta (hAMSC), and the conditioned medium generated from their culture (CM-hAMSC) offer significant tools for their use in regenerative medicine mainly due to their immunomodulatory properties. Interestingly, hAMSC and their CM have been successfully exploited in preclinical disease models of inflammatory and autoimmune diseases where depletion or modulation of B cells have been indicated as an effective treatment, such as inflammatory bowel disease, lung fibrosis, would healing, collagen-induced arthritis, and multiple sclerosis. While the interactions between hAMSC or CM-hAMSC and T lymphocytes, monocytes, dendritic cells, and macrophages has been extensively explored, how they affect B lymphocytes remains unclear. Considering that B cells are key players in the adaptive immune response and are a central component of different diseases, in this study we investigated the in vitro properties of hAMSC and CM-hAMSC on B cells. We provide evidence that both hAMSC and CM-hAMSC strongly suppressed CpG-activated B-cell proliferation. Moreover, CM-hAMSC blocked B-cell differentiation, with an increase of the proportion of mature B cells, and a reduction of antibody secreting cell formation. We observed the strong inhibition of B cell terminal differentiation into CD138+ plasma cells, as further shown by a significant decrease of the expression of interferon regulatory factor 4 (IRF-4), PR/SET domain 1(PRDM1), and X-box binding protein 1 (XBP-1) genes. Our results point out that the mechanism by which CM-hAMSC impacts B cell proliferation and differentiation is mediated by secreted factors, and prostanoids are partially involved in these actions. Factors contained in the CM-hAMSC decreased the CpG-uptake sensors (CD205, CD14, and TLR9), suggesting that B cell stimulation was affected early on. CM-hAMSC also decreased the expression of interleukin-1 receptor-associated kinase (IRAK)-4, consequently inhibiting the entire CpG-induced downstream signaling pathway. Overall, these findings add insight into the mechanism of action of hAMSC and CM-hAMSC and are useful to better design their potential therapeutic application in B-cell mediated diseases.

Highlights

Mesenchymal stromal cells (MSC) from the amniotic membrane of human term placenta, and the conditioned medium generated from their culture (CM-human amniotic mesenchymal stromal cells (hAMSC)) possess the ability to modulate inflammation [1]
Similar results were obtained with purified B-cells (Figure 1B), indicating that inhibition of proliferation is exerted directly by hAMSC and CM-hAMSC on B cells and is likely not mediated by a third-party subset
The present study provides the first evidence that both MSC from the amniotic membrane and the conditioned medium generated from their culture (CM-hAMSC), strongly suppress Bcell proliferation and differentiation, with an increase of mature B cells and a reduction of antibody-secreting cells (ASC) formation, abrogating their terminal maturation into plasma cells

Summary

Introduction

Mesenchymal stromal cells (MSC) from the amniotic membrane of human term placenta (hAMSC), and the conditioned medium generated from their culture (CM-hAMSC) possess the ability to modulate inflammation [1]. We and others have demonstrated that hAMSC and CM-hAMSC suppress the in vitro proliferation, inflammatory cytokine production, and functions of T lymphocytes [16, 17], monocytes [10], dendritic cells [18], macrophages [10], and natural killer cells [19], and are able to induce a phenotype and functional switch of monocytes toward macrophages with anti-inflammatory pro-regenerative M2-like features [10, 17], and support the expansion of regulatory T cells [16, 17] These in vitro immunomodulatory actions have been confirmed in preclinical studies [4, 11, 13].

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Results

Conclusion