Lung and brain injury that occurs during the perinatal period leads to lifelong disability and is often driven and/or exacerbated by inflammation. Human amniotic epithelial cells (hAEC), which demonstrate immunomodulatory, anti-fibrotic, and regenerative capabilities, are being explored as a therapeutic candidate for perinatal injury. However, limitations regarding scalable manufacturing, storage, transport, and dose-related toxicity have impeded clinical translation. Isolated therapeutic extracellular vesicles (EVs) from stem and stem-like cells are thought to be key paracrine mediators of therapeutic efficacy. The unique characteristics of EVs suggest that they potentially circumvent the limitations of traditional cell-based therapies. However, given the novelty of EVs as a therapeutic, recommendations around ideal methods of production, isolation, storage, and delivery have not yet been created by regulatory agencies. In this concise review, we discuss the pertinence and limitations of cell-based therapeutics in perinatal medicine. We also review the preclinical evidence supporting the use of therapeutic EVs for perinatal therapy. Further, we summarize the arising considerations regarding adequate cell source, biodistribution, isolation and storage methods, and regulatory roadblocks for the development of therapeutic EVs.

In animal experimental models the administration of stem cells into the spleen should ensure high effectiveness of their implantation in the liver due to a direct vascular connection between the two organs. The aim of this study was to update the methods of experimental intrasplenic cell transplantation using human amniotic epithelial cells (hAECs) which are promising cells in the treatment of liver diseases. BALB/c mice were administered intrasplenically with 0.5, 1, and 2 million hAECs by direct bolus injection (400 µl/min) and via a subcutaneous splenic port by fast (20 μl/min) and slow (10 μl/min) infusion. The port was prepared by translocating the spleen to the skin pocket. The spleen, liver, and lungs were collected at 3 h, 6 h, and 24 h after the administration of cells. The distribution of hAECs, histopathological changes in the organs, complete blood count, and biochemical markers of liver damage were assessed. It has been shown that the method of intrasplenic cell administration affects the degree of liver damage. The largest number of mice showing significant liver damage was observed after direct administration and the lowest after slow administration through a port. Liver damage increased with the number of administered cells, which, paradoxically, resulted in increased liver colonization efficiency. It was concluded that the administration of 1 × 106 hAECs by slow infusion via a subcutaneous splenic port reduces the incidence of complications at the expense of a slight decrease in the effectiveness of implantation of the transplanted cells in the liver.

The route of administration of implanted cells may affect the outcome of cell therapy by directing cell migration to the damaged site. However, the question of the relationship between the route of administration, the efficacy of colonisation of a given organ, and the efficacy of cell therapy has not been resolved. The aim of the study was to localise transplanted intravenously and intraperitoneally human amniotic epithelial cells (hAECs) in the tissues of mice, both healthy and injured, in an animal experimental model of acute liver failure (ALF). Mice intoxicated with D-Galactosamine (D-GalN) at a dose of 150 mg/100 g body weight received D-GalN alone or with a single dose of hAECs administered by different routes. Subsequently, at 6, 24, and 72 h after D-GaIN administration and at 3, 21, and 69 h after hAEC administration, lungs, spleen, liver, and blood were collected from recipient mice. The degree of liver damage and regeneration was assessed based on biochemical blood parameters, histopathological evaluation (H&E staining), and immunodetection of proliferating (Ki67+) and apoptotic (Casp+) cells. The biodistribution of the administered cells was based on immunohistochemistry and the identification of human DNA. It has been shown that after intravenous administration, in both healthy and intoxicated mice, most of the transplanted hAECs were found in the lungs, while after intraperitoneal administration, they were found in the liver. We concluded that a large number of hAECs implanted in the lungs following intravenous administration can exert a therapeutic effect on the damaged liver, while the regenerative effect of intraperitoneally injected hAECs on the liver was very limited due to the relatively lower efficiency of cell engraftment.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by immune dysregulation. Restoration of the balance between regulatory T (Tregs) and T helper 17 (Th17) cells improves UC symptoms. Human amniotic epithelial cells (hAECs) have emerged as a promising therapeutic option for UC because of their immunomodulatory properties. In this study, we aimed to optimize and maximize the therapeutic potential of hAECs by pre-treating them with tumor necrosis factor (TNF)-α and interferon (IFN)-γ (pre-hAECs) for UC treatment. We evaluated the efficacy of hAECs and pre-hAECs in treating dextran sulfate sodium (DSS)-induced colitis mice. Compared to hAECs, pre-hAECs were found to be more effective in alleviating colitis in acute DSS mouse models than in the controls. Additionally, pre-hAEC treatment significantly reduced weight loss, shortened the colon length, decreased the disease activity index, and effectively maintained the recovery of colon epithelial cells. Furthermore, pre-hAEC treatment significantly inhibited the production of pro-inflammatory cytokines, such as interleukin (IL)-1β and TNF-α, and promoted the expression of anti-inflammatory cytokines, such as IL-10. Both in vivo and in vitro studies revealed that pre-treatment with hAECs significantly increased the number of Treg cells, decreased the numbers of Th1, Th2, and Th17 cells, and regulated the balance of Th17/Treg cells. In conclusion, our results revealed that hAECs pre-treated with TNF-α and IFN-γ were highly effective in treating UC, suggesting their potential as therapeutic candidates for UC immunotherapy.

The placenta and the extraembryonic tissues represent a valuable source of cells for regenerative medicine. In particular, the amniotic membrane possesses cells with stem cells characteristics that have attracted research attention. Human amniotic epithelial cells (hAECs) have unique and desirable features that position them over other stem cells, not only because of the unlimited potential supplied of, the easy access to placental tissues, and the minimal ethical and legal barriers associated, but also due to the embryonic stem cells markers expression and their ability to differentiate into the three germ layers. In addition, they are non-tumorigenic and have immunomodulatory and anti-inflammatory properties. Hepatic failure is one of the major causes of morbidity and mortality worldwide. Organ transplantation is the best way to treat acute and chronic liver failure, but there are several associated obstacles. Stem cells have been highlighted as alternative hepatocytes source because of their potential for hepatogenic differentiation. HAECs, in particular, have some properties that make them suitable for hepatocyte differentiation. In this work, we review the general characteristics of the epithelial stem cells isolated from human amniotic membrane as well as their ability to differentiate to hepatic cells. We also revise their regenerative properties, with the focus on their potential application in the liver disease treatment.

Stem cell engraftment is currently a promising approach for type 1 diabetes mellitus (T1DM) treatment. In our previous study, engraftment of a combination of human amniotic epithelial cells (hAECs) and hyaluronic acid (HA) showed potent anti-diabetic effect in streptozotocin (STZ)-induced T1DM mice via tail vein injection. Here, we adopted a different route of stem cell delivery, that is via pancreatic subcapsular transplantation. This combined local engraftment of hAECs and HA in STZ-induced T1DM rats showed potent anti-diabetic activity, leading to stronger hypoglycaemia, more intact islet structure and increased number of insulin-positive cells compared with those with hAECs or insulin treatments. Engraftment of hAECs alone increased the proportion of Th1 and T-reg cells and decreased the proportion of Th2 and Th17 cells to protect islet β cells in STZ-induced T1DM rats, whereas the combined engraftment of hAECs and HA showed more potent regulatory capacity, considerably decreased the level of TNF-α and IL-17 and increased the level of TGF-β1 compared with those by other treatments. The potent synergistic effect of HA contributed to the recovery of immune balance in the diabetic rat model, thereby suggesting a new strategy for effective treatment of T1DM.

The induction of feto-maternal tolerance, fetal non-immunogenicity, and the regulation of mother\'s immune system are essential variables in a successful pregnancy. Fetal membranes have been used as a source of stem cells and biological components in recent decades. Human amniotic epithelial cells (hAEC) have stem/progenitor characteristics like those found in the amniotic membrane. Based on their immunomodulatory capabilities, recent studies have focused on the experimental and therapeutic applications of hAECs in allograft transplantation, autoimmune disorders, and gynecological problems such as recurrent spontaneous abortion (RSA), recurrent implantation failure (RIF), and premature ovarian failure (POF). This review discusses some of the immunomodulatory features and therapeutic potential of hAECs in preventing infertility, miscarriage, and implantation failure by controlling the maternal immune system.

Human amniotic epithelial cells (hAECs), which are a type of placental stem cell, express stem cell marker genes and are capable of differentiating into all three germ layers under appropriate culture conditions. hAECs are known to undergo TGF-β-dependent epithelial-mesenchymal transition (EMT); however, the impact of EMT on the stemness or differentiation of hAECs has not yet been determined. Here, we first confirmed that hAECs undergo EMT immediately after starting primary culture. Comprehensive transcriptome analysis using RNA-seq revealed that inhibition of TGF-β-dependent EMT maintained the expression of stemness-related genes, including NANOG and POU5F1, in hAECs. Moreover, the maintenance of stemness did not affect the nontumorigenic characteristics of hAECs. We showed for the first time that TGF-β-dependent EMT negatively affected the stemness of hAECs, providing novel insight into cellular processes of placental stem cells.

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UNASSIGNED: Parkinson\'s disease (PD) a neurodegenerative disorder for which no preventive or long term effective treatment strategies are available. Epidemiological studies have failed to identify specific environmental, dietary or lifestyle factors for PD. However oxidative stress in the substantia nigra (SN) and Corpus striatum is the most broadly accepted hypothesis for the etiopathology of PD. Many experiments state the notion that augmentation of neurotrophic factors and glial cell-derived neurotrophic factors, could prevent or halt the progress of neurodegeneration in PD.
UNASSIGNED: The present study was designed to assess the motor behaviour with apomorphine injection and level of enzymatic and non-enzymatic antioxidants after transplantation of Human Amniotic Epithelial (HAE) cells in 2,4,5 trihydroxyphenylethylamine (6-OHDA) lesioned striatum in rats.
UNASSIGNED: Human Amniotic Epithelial (HAE) cells ameliorated 6-OHDA induced changes in rotational behaviour and modulated the antioxidants. 6-OHDA induced neurotoxicity by the generation of free radicals was pronounced by indication of increased Lipid peroxidation (LPO) levels and decrease in antioxidants level. The present result suggest that increased free radicals and the decrease in the antioxidant defence system possibly lead to structural and functional alterations in membrane-related events and play significant role of the 6-OHDA induced neurotoxicity. In HAE cells transplanted animals the level of LPO was significantly reduced in striatum (36%) and moderately reduced (20%) in midbrain of the 6-OHDA lesioned animals.
UNASSIGNED: These alterations were found to be recovered after the HAE cells graft during long term. The 6-OHDA induced neurotoxicity by the generation of free radicals was pronounced by indication of the increased LPO level, decrease in antioxidants and alteration in the dopamine and its metabolites.