Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Immunol.

Sec. Immunological Tolerance and Regulation

Human amnion epithelial cells induce M2 macrophage polarisation partially via M-CSF secretion but independently of extracellular vesicles in vitro

Provisionally accepted
Louise ZeijlonLouise Zeijlon1Snehil BudhwarSnehil Budhwar1Robert LindauRobert Lindau1Stefan BencinaStefan Bencina2Helen KaipeHelen Kaipe2,3Maria JenmalmMaria Jenmalm1Roberto GramignoliRoberto Gramignoli2,4Johanna RaffetsederJohanna Raffetseder1*
  • 1Department of Biomedical and Clinical Sciences, Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden
  • 2Karolinska Institutet Institutionen for laboratoriemedicin, Huddinge, Sweden
  • 3Karolinska Institutet Avdelningen for Klinisk immunologi & transfusionsmedicin, Karolinska University Hospital, Karolinska Institutet Avdelningen for Klinisk immunologi & transfusionsmedicin, Huddinge, Sweden
  • 4UOSD Cell Therapy Lab, IRCCS Istituto Giannina Gaslini, Genova, Italy

The final, formatted version of the article will be published soon.

Select one of your emails

You have multiple emails registered with Frontiers:

Notify me on publication

Please enter your email address:

If you already have an account, please login

You don't have a Frontiers account ? You can register here

Pregnancy requires major immunomodulatory changes, both systemically and locally, as the maternal immune system needs to be modulated to tolerate the semi-allogeneic foetus. Decidual macrophages and stromal cells, but also foetal tissues are involved in this immune tolerance, for example by inducing M2 macrophages and regulatory T cells. However, it is so far unknown whether foetal membrane cells such as amnion epithelial cells (AECs) can influence human macrophage polarisation. In this study, a human in vitro macrophage assay was employed to demonstrate that conditioned medium (CM) from AECs derived from term placentas induces M2 macrophage polarisation, and to compare AEC culture conditions aiming for efficient M2 polarisation. Macrophage colony-stimulating factor (M-CSF), a well-known M2-inducing cytokine, was found to be secreted by AECs, and M-CSF was partly responsible for the observed M2-polarising effect of AECs. In addition, the M2-polarising effect remained after removal of EVs from AEC-CM, suggesting the involvement of soluble but not of EV-associated mediators. Taken together, this study shows that AECs could play a role in the induction of the vital immunotolerant environment at the foetal-maternal interface. Based on their immunomodulatory effects observed here and in in vivo studies, AECs could be harnessed as cytotherapeutics for inflammatory disorders.

Keywords: amnion epithelial cells, extracellular vesicles, Human macrophage, Immune Regulation, macrophage polarisation, macrophagecolony-stimulating factor, Pregnancy

Received: 13 Oct 2025; Accepted: 02 Jan 2026.

Copyright: © 2026 Zeijlon, Budhwar, Lindau, Bencina, Kaipe, Jenmalm, Gramignoli and Raffetseder. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Johanna Raffetseder

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material