Human Amnion Epithelial Cells Prevent Bleomycin-Induced Lung Injury and Preserve Lung Function

Abstract

Human amnion epithelial cells (hAECs) have attracted recent attention as a promising source of cells for regenerative therapies, with reports that cells derived from human term amnion possess multipotent differentiation ability, low immunogenicity, and anti-inflammatory properties. Specifically, in animal models of lung disease characterized by significant loss of lung tissue secondary to chronic inflammation and fibrosis, the transplantation of hAECs has been shown to reduce both inflammation and subsequent fibrosis. To further explore the mechanisms by which hAECs reduce pulmonary fibrosis and enhance lung regeneration, we utilized a bleomycin-induced model of pulmonary fibrosis and investigated the ability of hAECs to reduce fibrosis and thereby improve pulmonary function. We aimed to determine if hAECs, injected into the peritoneal cavity could migrate to the lung, engraft, and form functional lung epithelium, and whether hAECs could modulate the inflammatory environment in the bleomycin-injured lung. We demonstrated that, compared to bleomycin alone, IP administration of hAECs 24 h after bleomcyin, decreased gene expression of the proinflammatory cytokines TNF-α, TGF-β, IFN-γ, and IL-6 and decreased subsequent pulmonary fibrosis with less pulmonary collagen deposition, reduced levels of α-smooth muscle actin and decreased inflammatory cell infiltrate. We also showed that hAECs are able to prevent a decline in pulmonary function associated with bleomycin-induced lung damage. We were unable to detect any significant engraftment of hAECs in injured, or uninjured, lung after administration. The findings from this study support the further investigation of hAECs as a potential cell therapy for inflammatory and fibrogenic diseases.

Human Amnion Epithelial Cells do Not Abrogate Pulmonary Fibrosis in Mice with Impaired Macrophage Function

“…Rather, we suggest that the hAECs mised mice have shown that both hAECs (31) and amniotic fluid-derived cells (6) are able to integrate into the primarily exert their effects by reducing acute inflammation, both leukocyte infiltration and cytokine responses, host epithelium and differentiate in vivo into lung epithelial cells following bleomycin lung injury (6), we and thereby mitigating subsequent pulmonary fibrosis. A wide array of inflammatory and fibrotic signaling have not been able to show this in immune competent mice in either a previous study (33) or in this current pathways are activated by bleomycin, including key players in lung injury such as TGF-β (2), the inflammastudy. Acknowledging that FACS analysis, one of the approaches we use for cell detection, excludes dead cells some (12,30,46), and inflammatory cytokines such as…”

“…With this in mind, there has been recent interest which hAECs exert their effects in this model of lung injury remain uncertain. In particular, it is not clear in the reparative/regenerative potential of cell-based whether hAECs exert their effects via differentiating and fibrosis maximum at day 14 following bleomycin treatment (33). Body weight, core temperature, and into lung epithelial cells in vivo, as we have shown occurs in immune-compromised mice (31), or whether basal lung function were recorded prior to commencement of experiments and at days 3, 7, and 14. the principle mechanism is via modulation of the host response to injury.…”

“…of lung function in Sftpc +/+ mice, but not in Sftpc −/− mice. and has a lower level of sensitivity compared to other techniques (33), in this study we utilized both FACS We were unable to demonstrate any integration or differentiation of hAECs into the lungs of either mouse analysis and immunohistochemistry to identify CFSElabeled cells in host tissue. As before, we were unable strain.…”

“…Importantly, these protective and reparative effects are associated often associated with significant side effects. Accordingly, there is an increasingly urgent need for the develwith mitigation of the loss of lung function induced by bleomycin (33). However, the precise mechanism(s) by opment of novel, effective treatments of chronic lung disease.…”

“…Body weight, core temperature, and into lung epithelial cells in vivo, as we have shown occurs in immune-compromised mice (31), or whether basal lung function were recorded prior to commencement of experiments and at days 3, 7, and 14. the principle mechanism is via modulation of the host response to injury. Based on a study undertaken in Bleomycin Induction of Pulmonary Fibrosis immune-competent mice where we observed no in vivo differentiation of hAECs and yet mitigation of lung Intranasal administration of bleomycin to rodents is considered a useful model for the histological changes injury, we have recently suggested that the latter is the more likely mechanism (33).…”