Human amnion favours tissue repair by inducing the M1-to-M2 switch and enhancing M2 macrophage features.

Marta Magatti,Ornella Parolini,Mario Delgado,Maddalena Caruso,Silvia De Munari,Marta Caro,Elsa Vertua,Antonietta Silini

doi:10.1002/term.2193

Abstract

Human amniotic mesenchymal cells (hAMTCs) possess interesting immunomodulatory properties, making them attractive candidates for regenerative medicine applications. Recent in vivo reports argue in favour of an important role for macrophages as targets of hAMTC‐mediated suppression of inflammation and the enhancement of tissue repair. However, a comprehensive study of the effects of hAMTCs and their conditioned medium (CM) on human macrophage differentiation and function is unavailable. In the present study we found that hAMTCs and CM induce the differentiation of myeloid cells (U937 and monocytes) towards macrophages. We then investigated their effects on monocytes differentiated toward pro‐inflammatory M1 and anti‐inflammatory M2 macrophages. Monocytes treated under M1 conditions in the presence of hAMTCs or CMs shifted towards M2‐like macrophages, which expressed CD14, CD209, CD23, CD163 and PM‐2 K, possessed higher phagocytic activity and produced higher IL‐10 and lower pro‐inflammatory cytokines. They were also poor T cell stimulators and Th1 inducers, while they were able to increase activated and naïve suppressive Treg subsets. We show that prostaglandins, and not IL‐6, play a role in determining the M2 activation status. Instead, monocytes treated under M2 conditions in the presence of hAMTCs or CM retained M2‐like features, but with an enhanced anti‐inflammatory profile, having a reduced expression of the co‐stimulatory molecule CD80, reduced phagocytosis activity and decreased the secretion of inflammatory chemokines. Importantly, we provide evidence that macrophages re‐educated by CM improve tissue regeneration/repair in wound‐healing models. In conclusion, we identified new cell targets of hAMTCs and their bioactive factors and here provide insight into the beneficial effects observed when these cells are used in therapeutic approaches in vivo. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

Highlights

In recent years, increasing evidence has demonstrated that cells isolated from the amniotic membrane of human term placenta possess interesting immunomodulatory properties that make them an attractive tool for the cellular treatment of immune-related disorders
It is noteworthy that U937 cells co-cultured in transwell with Human amniotic mesenchymal cells (hAMTCs) or exposed to conditioned medium (CM) had increased expression of the macrophage-associated markers CD11b, CD11c, CD23, CD86 and CD14, indicating that hAMTCs and CM induced macrophage-like differentiation of U937 cells
Similar to phorbol 12-myristate 13-acetate (PMA) treatment, hAMTCs and CM did not affect the expression of other markers, such as CD1a, CD197, CD80, CD209 or CD163

Summary

Introduction

In recent years, increasing evidence has demonstrated that cells isolated from the amniotic membrane of human term placenta possess interesting immunomodulatory properties that make them an attractive tool for the cellular treatment of immune-related disorders. We and others have demonstrated that human amniotic mesenchymal cells (hAMSCs) and epithelial cells (hAECs), as well as conditioned medium (CM) derived from their culture, possess anti-inflammatory and anti-proliferative properties that affect cells of the innate and adaptive immune systems (Parolini et al, 2011). These properties include the in vitro ability to suppress T cell proliferation (Li et al, 2005; Wolbank et al, 2007; Magatti et al, 2008; Rossi et al, 2012; Pianta et al, 2015). Dendritic cell differentiation was blocked at the monocyte level, but skewed toward macrophage-like cells (Magatti et al, 2015)

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