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Stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs) are able to repair/replace damaged or degenerative tissues and improve functional recovery in experimental model and clinical trials. However, there are still many limitations and unresolved problems regarding stem cell therapy in terms of ethical barriers, immune rejection, tumorigenicity, and cell sources. By reviewing recent literatures and our related works, human amnion-derived stem cells (hADSCs) including human amniotic mesenchymal stem cells (hAMSCs) and human amniotic epithelial stem cells (hAESCs) have shown considerable advantages over other stem cells. In this review, we first described the biological characteristics and advantages of hADSCs, especially for their high pluripotency and immunomodulatory effects. Then, we summarized the therapeutic applications and recent progresses of hADSCs in treating various diseases for preclinical research and clinical trials. In addition, the possible mechanisms and the challenges of hADSCs applications have been also discussed. Finally, we highlighted the properties of hADSCs as a promising source of stem cells for cell therapy and regenerative medicine and pointed out the perspectives for the directions of hADSCs applications clinically.

Cell therapy with a variety of stem populations is increasingly being investigated as a promising regenerative strategy for cardiovascular (CV) diseases. Their combination with adequate scaffolds represents an improved therapeutic approach. Recently, several biomaterials were investigated as scaffolds for CV tissue repair, with decellularized extracellular matrices (dECMs) arousing increasing interest for cardiac tissue engineering applications. The aim of this study was to analyze whether dECMs support the cardiac differentiation of CardiopoieticAF stem cells. These perinatal stem cells, which can be easily isolated without ethical or safety limitations, display a high cardiac differentiative potential. Differentiation was previously achieved by culturing them on Matrigel, but this 3D scaffold is not transplantable. The identification of a new transplantable scaffold able to support CardiopoieticAF stem cell cardiac differentiation is pivotal prior to encouraging translation of in vitro studies in animal model preclinical investigations. Our data demonstrated that decellularized extracellular matrices already used in cardiac surgery (the porcine CorTMPATCH and the equine MatrixPatchTM) can efficiently support the proliferation and cardiac differentiation of CardiopoieticAF stem cells and represent a useful cellular scaffold to be transplanted with stem cells in animal hosts.

Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells.

Human amniotic epithelial cells (hAECs) are non-immunogenic epithelial cells that can develop into cells of all three germline lineages. However, a refined clinically reliable method is required to optimize the preparation and banking procedures of hAECs for their successful translation into clinical studies. With the goal of establishing standardized clinically applicable hAECs cultured cells, we described the use of a powerful epithelial cell culture technique, termed C onditionally R eprogrammed Cells (CRC) for ex vivo expansion of hAECs. The well-established CRC culture method uses a Rho kinase inhibitor (Y-27632) and J2 mouse fibroblast feeder cells to drive the indefinite proliferation of all known epithelial cell types. In this study, we used an optimized CRC protocol to successfully culture hAECs in a CRC medium supplemented with xenogen-free human serum. We established that hAECs thrive under the CRC conditions for over 5 passages while still expressing pluripotent stem markers (OCT-4, SOX-2 and NANOG) and non-immunogenic markers (CD80, CD86 and HLA-G) suggesting that even late-passage hAECs retain their privileged phenotype. The hAECs-CRC cells were infected with a puromycin-selectable lentivirus expressing luciferase and GFP (green fluorescent protein) and stably selected with puromycin. The hAECs expressing GFP were injected subcutaneously into the flanks of Athymic and C57BL6 mice to check the tolerability and stability of cells against the immune system. Chemiluminescence imaging confirmed the presence and viability of cells at days 2, 5, and 42 without acute inflammation or any tumor formation. Collectively, these data indicate that the CRC approach offers a novel solution to expanding hAECs in humanized conditions for future clinical uses, while retaining their primary phenotype. Graphical abstract

Carnosic acid (CA) is a phenolic diterpene widely distributed in herbal plants, rosemary and sage. Although its medicinal properties, such as antioxidant, antimicrobial, and neuroprotective effects, have been well-documented, its relevant biochemical processes and molecular targets have not been fully explored yet. In the present study, we conducted an untargeted whole-genome transcriptomics analysis to investigate CA-induced early biological and molecular events in human amniotic epithelial stem cells (hAESCs) with the aim of exploring its multiple tissue-specific functionalities and potential molecular targets. We found that seven days of CA treatment in hAESCs could induce mesoderm-lineage-specific differentiation. Tissue enrichment analysis revealed that CA significantly enriched lateral plate mesoderm-originated cardiovascular and adipose tissues. Further tissue-specific PPI analysis and kinase and transcription factor enrichment analyses identified potential upstream regulators and molecular targets of CA in a tissue-specific manner. Gene ontology enrichment analyses revealed the metabolic, antioxidant, and antifibrotic activities of CA. Altogether, our comprehensive whole-genome transcriptomics analyses offer a thorough understanding of the possible underlying molecular mechanism of CA.

Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell‐derived mesenchymal stem cells (PSC‐MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC‐MSCs (ES‐MSCs from embryonic stem cells) to fetal MSCs (AF‐MSCs from the amniotic fluid), demonstrating that ES‐MSCs have a superior neuroprotective potential over AF‐MSCs in the mouse brain following hypoxia‐ischemia. Further, we demonstrate that nuclear factor (NF)‐κB‐stimulated interleukin (IL)‐13 production contributes to an increased in vitro anti‐inflammatory potential of ES‐MSC‐conditioned medium (CM) over AF‐MSC‐CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell‐derived MSCs (iMSCs) exhibit many similarities to ES‐MSCs, including enhanced NF‐κB signaling and IL‐13 production in comparison to AF‐MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES‐MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic‐ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439–449 We hypothesize that the increased nuclear factor (NF)‐κB activation and, therefore, higher levels of interleukin (IL)‐13 production observed in pluripotent stem cell‐derived mesenchymal stem cells contributes to the increased anti‐inflammatory potential of these cells compared with other types of mesenchymal stem cells.

One of the main causes of acute respiratory distress syndrome in coronavirus disease 2019 (COVID‐19) is cytokine storm, although the exact cause is still unknown. Umbilical cord mesenchymal stromal cells (UC‐MSCs) influence proinflammatory T‐helper 2 (Th2) cells to shift to an anti‐inflammatory agent. To investigate efficacy of UC‐MSC administration as adjuvant therapy in critically ill patients with COVID‐19, we conducted a double‐blind, multicentered, randomized controlled trial at four COVID‐19 referral hospitals in Jakarta, Indonesia. This study included 40 randomly allocated critically ill patients with COVID‐19; 20 patients received an intravenous infusion of 1 × 106/kg body weight UC‐MSCs in 100 ml saline (0.9%) solution (SS) and 20 patients received 100 ml 0.9% SS as the control group. All patients received standard therapy. The primary outcome was measured by survival rate and/or length of ventilator usage. The secondary outcome was measured by clinical and laboratory improvement, with serious adverse events. Our study showed the survival rate in the UC‐MSCs group was 2.5 times higher than that in the control group (P = .047), which is 10 patients and 4 patients in the UC‐MSCs and control groups, respectively. In patients with comorbidities, UC‐MSC administration increased the survival rate by 4.5 times compared with controls. The length of stay in the intensive care unit and ventilator usage were not statistically significant, and no adverse events were reported. The application of infusion UC‐MSCs significantly decreased interleukin 6 in the recovered patients (P = .023). Therefore, application of intravenous UC‐MSCs as adjuvant treatment for critically ill patients with COVID‐19 increases the survival rate by modulating the immune system toward an anti‐inflammatory state. Acute respiratory distress syndrome in COVID‐19 patients is caused by a cytokine strom. Umbilical cord mesenchymal stromal cell (UC‐MSC) influence proinflammatory Th2 cells to shift to an anti‐inflammatory agent. An UC‐MSC infusion was given for the experimental group, and normal saline for the control group. Our result showed 2.5 times significantly higher survival rate in the experimental group that achieved by modulating the immune system toward anti‐inflammatory state.

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation, severe scarring, and stem cell senescence. Stem cell‐based therapies modulate inflammatory and fibrogenic pathways by release of soluble factors. Stem cell‐derived extracellular vesicles should be explored as a potential therapy for IPF. Human amnion epithelial cell‐derived exosomes (hAEC Exo) were isolated and compared against human lung fibroblasts exosomes. hAEC Exo were assessed as a potential therapy for lung fibrosis. Exosomes were isolated and evaluated for their protein and miRNA cargo. Direct effects of hAEC Exo on immune cell function, including macrophage polarization, phagocytosis, neutrophil myeloperoxidase activity and T cell proliferation and uptake, were measured. Their impact on immune response, histological outcomes, and bronchioalveolar stem cell (BASC) response was assessed in vivo following bleomycin challenge in young and aged mice. hAEC Exo carry protein cargo enriched for MAPK signaling pathways, apoptotic and developmental biology pathways and miRNA enriched for PI3K‐Akt, Ras, Hippo, TGFβ, and focal adhesion pathways. hAEC Exo polarized and increased macrophage phagocytosis, reduced neutrophil myeloperoxidases, and suppressed T cell proliferation directly. Intranasal instillation of 10 μg hAEC Exo 1 day following bleomycin challenge reduced lung inflammation, while treatment at day 7 improved tissue‐to‐airspace ratio and reduced fibrosis. Administration of hAEC Exo coincided with the proliferation of BASC. These effects were reproducible in bleomycin‐challenged aged mice. The paracrine effects of hAECs can be largely attributed to their exosomes and exploitation of hAEC Exo as a therapy for IPF should be explored further. Stem Cells Translational Medicine 2018;7:180–196 Human amnion epithelial cells (hAECs) possess potent reparative and regenerative properties, especially in experimental models of lung fibrosis. It is now evident that these mechanism may be attributed to secretory factors released by hAECs termed exosomes. These hAEC Exo can be isolated with high purity through differential ultracentrifugation. Transmission electron microscopy shows exosomes of typical cup‐shaped morphology, intracellular and outward budding vesicles from hAECs (Scale bar = 100 nm). Administration of 10 μg of hAEC Exo into bleomycin challenged mice ameliorated fibroblast activated αSMA positive cells (Scale bar = 50 μm) and increased lung progenitor cell renewal seen through expression of CC10+/SPC+ dual positive staining for bronchioalveolar stem cells (Scale bar = 50 μm).

Regenerative, cell‐based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta‐analysis summarized the effect of cell‐based interventions in DKD animal models and treatment‐related factors modifying outcomes. Electronic databases were searched for original investigations applying cell‐based therapy in diabetic animals with kidney endpoints (January 1998‐May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random‐effects models. Subgroup analyses tested treatment‐related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non‐MSC (15%), and cell‐derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell‐based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial‐mesenchymal‐transition, oxidative stress). Preconditioning, xenotransplantation, and disease‐source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell‐based interventions in diabetic animals improved kidney function and reduced injury with treatment‐related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD. Cell‐based therapies improve diabetic kidney repair: a systematic review and meta‐analysis.