Human placental stem cells induce a novel multiple myeloid cell-driven immunosuppressive program that ameliorates proinflammatory CNS pathology

Sarlus, H.; Guo, Y.; Bencina, S.; Zhu, K.; Joshua, V.; Virgilio, G. A.; Cheng, Y.; Lin, J.; Min, J. H.; Cuesta, I. B.; Suerth, V.; Alonso, P. T.; Thomas, O. G.; Rykaczewska, U.; Cacais, A. O. G.; Jagodic, M.; Gramignoli, R.; Harris, R. A.

doi:10.1101/2025.06.14.659704

bioRxiv · 10.1101/2025.06.14.659704

Human placental stem cells induce a novel multiple myeloid cell-driven immunosuppressive program that ameliorates proinflammatory CNS pathology

Sarlus, H.·Guo, Y.·Bencina, S.·Zhu, K.·Joshua, V.·Virgilio, G. A.·Cheng, Y.·Lin, J.·Min, J. H.·Cuesta, I. B.·Suerth, V.·Alonso, P. T.·Thomas, O. G.·Rykaczewska, U.·Cacais, A. O. G.·Jagodic, M.·Gramignoli, R.·Harris, R. A.

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Abstract

Despite a growing interest in Amniotic Epithelial Cell (AEC)-based therapies, the immune responses triggered by AEC transplantation in vivo remain poorly characterized. In particular, how direct exposure to AECs within the central nervous system (CNS) shapes the local immune environment is currently unknown. Herein we describe a novel CNS- specific immunoregulatory pathway induced by intracisternal delivery of human AECs. Local immune responses induced by AECs in the brain led to recruitment of immunosuppressive Arginase 1+ (ARG1+) macrophages and a novel population of myeloid-derived suppressor cells with eosinophilic characteristics, which we term Eo- MDSCs. We further demonstrate that Eo-MDSCs produce Maresin 2 (MaR2), a specialized pro-resolving mediator (SPM) involved in the resolution of inflammation. In a mouse model of Multiple Sclerosis (MS), treatment of established disease with AECs induced immunological responses that resulted in reduced numbers of pathogenic macrophages and T helper (TH)17 cells, increased anti-inflammatory T cell subsets, and enhanced myelin phagocytosis, all of which led to functional recovery. These findings suggest that AEC therapy has the potential to target CNS-intrinsic inflammatory processes in MS, providing a strong rationale for translation into the clinic.

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Sarlus, H., Guo, Y., Bencina, S., Zhu, K., Joshua, V., Virgilio, G. A., Cheng, Y., Lin, J., Min, J. H., Cuesta, I. B., Suerth, V., Alonso, P. T., Thomas, O. G., Rykaczewska, U., Cacais, A. O. G., Jagodic, M., Gramignoli, R., Harris, R. A.. 2025-06-15. Human placental stem cells induce a novel multiple myeloid cell-driven immunosuppressive program that ameliorates proinflammatory CNS pathology. https://doi.org/10.1101/2025.06.14.659704

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