Human amnion epithelial cells (hAECs) promote tissue repair via the modulation of host immune cells. Through the secretion of lipoxins and other mediators, hAECs polarize M1 macrophages to M2 phenotype thereby increasing phagocytosis and promoting resolution of injury. Via numerous soluble mediators such as HLA-G, prostaglandins and IDO, hAECs inhibit T-cell proliferation and likely convert effector T cells to Th2 cells, thereby promoting repair
4.2 Soluble Mediators
Insights into the likely mediators of the reparative properties of hAECs may arise from the observation that while term hAECs are highly effective at preventing bleomycin lung injury, hAECs derived from preterm amnion are not . Preterm hAECs are much more proliferative than term hAECs but, despite extended culture in SAGM, do not switch on surfactant protein expression . Importantly, while term hAECs reduce lung inflammation and fibrosis following bleomycin preterm hAECs do not . Surprisingly, while preterm hAECs were not as effective as term hAECs at inhibiting macrophage recruitment to the injured lung, they did mitigate recruitment somewhat. Whether preterm hAECs can modulate macrophage polarization has not yet been reported. There are likely to be many differences in the factors secreted by preterm and term hAECs that might underlie their differential reparative properties. One possible candidate is HLA-G. HLA-G is a nonclassical immunosuppressive HLA class I molecule . It inhibits the functions of both NK and cytotoxic T cells and induces T regulatory cells (Tregs) [74, 75] (Fig. 19.1). While there are no reports yet that HLA-G mediates the effects of amnion cells, amnion cells do secrete HLA-G  and other placental cells are able to modulate immune cell function via HLA-G . Importantly, preterm hAECs secrete less HLA-G than term hAECs . Whether HLA-G is a key mediator awaits further study.
4.3 Other Mechanisms
In addition to their immunosuppressive activities, hAECs are likely to exert their reparative effects via other mechanisms. For example, hAECs can directly reduce fibroblast proliferation and activation  and amnion stromal cells are able to reverse the myofibroblasts away from profibrotic phenotype . Given the central role that fibroblast play in lung fibrosis these direct effects are likely to be highly beneficial.
It is also possible that hAECs may induce the proliferation of endogenous lung progenitor cells, as has been observed for MSCs . Thus, through the recruitment of host lung progenitor cells hAECs could accelerate repair following injury. Whether hAECs possess such an ability also awaits examination.
hAECs are an abundant and safe source of cells for regenerative medicine. They have proven roles in the prevention and repair of experimental lung injury in both adult and neonatal models and in both acute and chronic injury. While hAECs are certainly able to integrate into injured lung epithelium and differentiate into lung cells, it would appear that they most likely exert their reparative effects via the modulation of host immune cells, particularly host macrophages. There is much yet to be learned about the properties of hAECs and how they might be best used. Given their abundance and safety record, clinical trials of hAECs in lung diseases appear to be relatively straightforward. Hopefully, the next 5 years or so will reveal whether these cells provide us with a whole new therapeutic armamentarium.
The authors acknowledge financial support from the National Health and Medical Research Council (NHMRC) Australia, The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Research Foundation and the Victorian Government’s Operational Infrastructure Support Program.
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