hAEC are highly abundant and easily harvested from term delivered amnion membranes typically yielding over 1506106 cells/ membrane and thereby minimizing the need for expensive and time consuming cell expansion. hAEC are derived from embryonic epiblast cells prior to gastrulation and possess some features of their founder pluripotent stem cells including the ability to differentiate into multiple lineages derived from the primary germ layers. Importantly, like other fetalderived placental cells that evade maternal immune recognition and secrete factors known to dampen maternal immune responses against the fetal semi-allograft, hAEC have also been shown to have low immunogenicity and the capacity to modulate innate and adaptive immune cell responses. Collectively, these features make hAEC an attractive source of cells for potential therapeutic applications. While we have shown ameliorative effects of hAEC transplantation on hepatic fibrosis, our study and others investigating stem cells were carried out predominantly in models of acute or short-term inflammation in which primarily mild fibrosis was evident. Therefore, the effects of cellular therapy in models of chronic inflammation with well established fibrosis, which better reflect the clinical problem of advanced liver disease and cirrhosis, remain uncertain. Furthermore, there is no data on the efficacy of an additional cell dose or the generation of antibodies against the transplanted cells which may influence the timing and donor selection for subsequent treatments. Thus, using mice chronically injured with long-term CCl4 treatment, hAEC on host T cells and anti-hAEC antibody generation. In order to gain an SP600125 understanding of potential anti-fibrotic mechanisms, we studied the effects of hAEC transplantation on hepatic macrophages that play a pivotal role in mediating fibrogenesis and fibrosis resolution. In this study we have shown that intravenously delivered human AEC engraft in injured livers of immunocompetent mice and lead to significant changes in hepatic macrophage numbers and phenotype and significantly reduce the extent of established fibrosis. hAEC engraftment was demonstrated by the presence of intact human IMM protein and HLA-G positive cells up to four weeks post transplantation. Similar outcomes showing grafted hAEC remaining several weeks after transplantation have also been reported in immunocompetent animals with brain, spinal cord and lung injury. Low levels of HLA Class IA expression, lack of co-stimulatory molecules CD80/86 and secreted factors such as TGF-b and IL-6 from hAEC that can suppress T cell expansion may have limited the surveillance of the engrafted cells by host T cells. However, anti-human antibodies were generated against the transplanted hAEC and it would be important to identify the antigens responsible, immunoglobulin sub-classes and the survival of hAEC following multiple infusions. Further, chemokines and adhesion molecules that regulate migration of intravenously infused hAEC to injury sites and subsequent engraftment remain uncertain.