Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Abstract

Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4 (LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085–1095

Amniotic MSCs reduce pulmonary fibrosis by hampering lung B-cell recruitment, retention, and maturation

“…In agreement with ours and others' previous studies performed in bleomycin-induced and in other models of fibrosis, [7][8][9][10]18,24 In addition, the presence of lymphoid aggregates has been described in the lungs of mice challenged with bleomycin, 40 of mice genetically modified (CCR7−/− mice) showing an impaired homing of Treg cells, 41 and of mice with rheumatoid arthritis-related interstitial lung disease. 42 Here, we also detected intrapulmonary aggregates composed of T and B lymphocytes in bleomycin-instilled animals and we demonstrated that hAMSC treatment inhibited the formation and expansion of these aggregates.…”

“…There is growing evidence suggesting a mechanistic link between inflammation, which endures to the end stage of IPF, and the development and progression of fibrosis. [1][2][3][4] Interestingly, we and others have reported that cells derived from the amniotic membrane of human term placenta, such as amniotic epithelial cells and amniotic mesenchymal stromal cells (hAMSCs) [5][6][7][8][9][10] and related secretome, [11][12][13] can prevent and reduce the progression of pulmonary fibrosis when injected in bleomycin-instilled rodents, a model which closely resembles human IPF. 14 Amniotic cells and their secreted factors possess in vitro and in vivo immune-modulatory properties.…”

First-In-Human Administration of Allogeneic Amnion Cells in Premature Infants With Bronchopulmonary Dysplasia: A Safety Study

“…Median (range) Apgar score at 5 minutes of life was 6 (0-9). The first three infants were dependent on invasive mechanical ventilation with a median mean airway pressure of 18 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) Table 1.…”

“…Similar to MSCs, the major mechanism of hAEC action appears to be via modulation of host immune cell responses to injury achieved through paracrine factors such as lipid‐based mediators and the release of extracellular vesicles . In the Pneumostem trial, the tracheal aspirate fluid of MSC‐treated infants had reduced levels of matrix metalloproteinase‐9, interleukins ‐6 and ‐8, tumor necrosis factor α, and transforming growth factor β compared with the matched comparison group .…”

A Pilot Study Evaluating the Safety of Intravenously Administered Human Amnion Epithelial Cells for the Treatment of Hepatic Fibrosis

“…These include the potential for genomic instability ( Wang et al, 2013 ) and cellular senescence ( Schellenberg et al, 2011 ) seen with passaged MSCs and as such, we have ventured into alternatives such as human amnion epithelial cells (hAECs), which have similarly potent anti-inflammatory and anti-fibrotic properties ( Manuelpillai et al, 2010 , 2012 ; Murphy et al, 2010a , 2011 ; Hodges et al, 2012 ; Hodge et al, 2014 ; Tan et al, 2016 ). Specifically, hAECs appear to influence inflammation and fibrosis by interacting with a multitude of cell types including fibroblasts ( Vosdoganes et al, 2012 ), neutrophils ( Tan et al, 2016 ), and macrophages ( Manuelpillai et al, 2012 ; Tan et al, 2014 ). These outcomes appear to be independent of significant cell engraftment, but are instead indicative of a paracrine effect, similar to what has been previously reported in MSCs.…”