Fig 2
![Model of wound healing and fibrosis, modified from [40].](profile/Antonietta_Silini/publication/233998881/figure/fig1/AS:339935073718272@1458058245482/Fig-2-Model-of-wound-healing-and-fibrosis-modified-from-40.png)
Model of wound healing and fibrosis, modified from [40].
Source publication
![Fig. (2). Model of wound healing and fibrosis, modified from [40].](profile/Antonietta_Silini/publication/233998881/figure/fig1/AS:339935073718272@1458058245482/Fig-2-Model-of-wound-healing-and-fibrosis-modified-from-40_Q320.jpg)
Inflammation is a complex defense mechanism characterized by leukocyte migration from the vasculature into damaged tissues and subsequent deposition of extracellular matrix resulting in tissue repair. The inflammatory process is generally categorized into an acute, rapid response, and a persistent but slowly evolving chronic condition, which may pr...
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The human placenta has long been the subject of scientific interest due to the important roles which it performs during pregnancy in sustaining the fetus and maintaining fetomaternal tolerance. More recently, however, researchers have begun to investigate the possibility that the placenta’s utility may extend beyond fetal development to act as a so...
Liver fibrosis is the most common outcome of chronic liver diseases, and its progression to cirrhosis can only be effectively treated with liver transplantation. The amniotic membrane (AM) has been studied as an alternative therapy for fibrosis diseases mainly for its favorable properties, including anti-inflammatory, anti-scaring and immunomodulat...
Introduction: Unexplained Recurrent Spontaneous Abortion (URSA) is the most common immunological complication during pregnancy. It has been found that the cells such as human amnion epithelial cells (hAECs) have the potency to modulate immune responses in vitro and in vivo. In the present study, we assessed the immunomodulatory effect of hAECs on N...
Citations
... Experimental and clinical data support the role of MMPs in HCC tumor metastasis, invasion, and neo-angiogenesis, rendering MMPs ideal targets for HCC therapy (Scheau et al. 2019;Overall and López-Otín 2002). Moreover, the hAM displays anticancer, anti-inflammatory, and immunomodulatory properties (Niknejad et al. 2016;Carbone et al. 2014;Silini et al. 2013;Chen et al. 2021;Jirsova and Jones 2017;Kogan et al. 2018). Yet, the underlying molecular mechanisms for these effects are still questionable and not well elucidated (Jafari et al. 2021a;Dhiman et al. 2021). ...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Current therapeutic approaches suffer significant side effects and lack of clear understanding of their molecular targets. Recent studies reported the anticancer effects, immunomodulatory properties, and antiangiogenic effects of the human amniotic membrane (hAM). hAM is a transparent protective membrane that surrounds the fetus. Preclinical studies showed pro-apoptotic and antiproliferative properties of hAM treatment on cancer cells. Herein, we present the latest findings of the application of the hAM in combating HCC tumorigenesis and the underlying molecular pathogenies and the role of transforming growth factor-beta (TGFβ), P53, WNT/beta-catenin, and PI3K/AKT pathways. The emerging clinical applications of hAM in cancer therapy provide evidence for its diverse and unique features and suitability for the management of a wide range of pathological conditions.
... In conclusion, the adhesion of epithelial stem cells on a GOfunctionalized surface might overall constitute a tailored microenvironment useful to face the inflammatory phase of the regenerative process. Indeed, GO promoting the shift of AECs towards the mesenchymal phenotype potentiates both their anti-fibrotic [62][63][64] and pro-regenerative actions [4,36,40,65]. In fact, AECs due to EMT enhance cell migration and the secretion of inflammatory mediators, thereby increasing the recruitment of other immune cells. ...
The application of biomaterials on immune regenerative strategies to deal with unsolved pathologies is getting attention in the field of tissue engineering. In this context, graphene oxide (GO) has been proposed as an immune-mimetic material largely used for developing stem cell-based regenerative therapies, since it has shown to influence stem cell behavior and modulate their immune response. Similarly, amniotic epithelial stem cells (AECs) are getting an increasing clinical interest as source of stem cells due to their great plasticity and immunomodulatory paracrine activities, even though GO bio-mimetic effects still remain unknown. To this aim, GO-functionalized glass coverslips have been used for AECs culture. The results demonstrated how GO-coating is able to induce and accelerate the Epithelial-Mesenchymal Transition (EMT), in a process mediated by the intracellular activation of TGFβ1-SMAD2/3 signaling pathway. The trans-differentiation towards mesenchymal phenotype provides AECs of migratory ability and substantially changes the pattern of cytokines secretion upon inflammatory stimulus. Indeed, GO-exposed AECs enhance their pro-inflammatory interleukins production thus inducing a more efficient activation of macrophages and, at the same time, by slightly reducing their inhibitory action on peripheral blood mononuclear cells proliferation. Therefore, the adhesion of AECs on GO-functionalized surfaces might contribute to the generation of a tailored microenvironment useful to face both the phases of the inflammation, thereby fostering the regenerative process.
... There are five main groups of hormones: auxins, gibberellins, cytokinins, ethylene, and abscisic acid [67]. ...
For over a century, the scientific community has had a comprehensive understanding of how rhizobia can promote the growth of legumes by forming nitrogen fixing nodules. Despite this knowledge, the interaction of rhizobia with non-legumes has remained largely ignored as a subject of study until more recent decades. In the last few years, research has shown that rhizobia can also associate with non-legume roots, which ultimately leads to the stimulation of growth through diverse direct and indirect mechanisms. For example, rhizobia can enhance growth through phytohormones production, the improvement of plant nutrient uptake, such as the solubilization of precipitated phosphorus, the production of siderophores to address iron needs, and also the reduction of ethylene levels through the ACC deaminase enzyme to cope with drought stress. Additionally, rhizobia can improve, indirectly, non-legume growth through biocontrol of pathogens and the induction of systemic resistance in the host plant. It can also increase root adherence to soil by releasing exopolysaccharides, which regulate water and soil nutrient movement. The objective of this review is to assess and analyze the existing knowledge and information regarding the mechanisms through which rhizobia promote the growth of non-legumes. By conducting a comprehensive analysis of these findings, we aim to gain new insights into the development of Rhizobium/non-legume interactions.
... We presumed that a healthy human umbilical cord would be a promising biomaterial for tissue-engineered cartilage. The antiinflammatory, antioxidant, anti-fibrotic and proangiogenesis capabilities of the human umbilical cord tissue (hUCT) are well established to be important natural wound healing processes of wounded tissues 9,25,26,36,41 . Low immunogenicity of placental tissues permits allogeneic use of placental transplants without donor and recipient matching 1,16 . ...
Human placental tissues are used as raw materials for applications in regenerative medicine. The extracellular matrix scaffolds which are abundant in collagen, glycosaminoglycans, proteoglycans, growth factors and cytokines are effective in accelerating the healing process. In this study, the processed umbilical cord was assessed for morphological and functional characteristics to assess its competence for regenerative properties in wound healing. The histological analysis of the umbilical cord was assessed with hematoxylin and eosin and immunohistochemistry for type-IV collagen. Physical properties such as ball burst, thickness and moisture were examined. ELISA and multiplex assays were performed to estimate the growth factors and cytokines. Anti-inflammatory properties were assessed using RAW 264.7 cell line. Further, functional aspects were determined through cell proliferation, cell migration and tube formation studies. Histological results revealed the scaffold had retained its structural features like an amnion layer with epithelial cells and sparsely distributed stromal cells in Wharton jelly. Physical properties were consistently maintained across the tissues. Functional analysis showed reduced macrophage proliferation, increased cell proliferation and cell migration validating its efficacy towards wound healing. Altogether data suggest that the umbilical cord is an effective remedial biological cover for wound healing applications with therapeutic potential for tissue repair and regeneration.
... O mecanismo mais aceito, por meio do qual a MA manifesta essas propriedades, é pela liberação de fatores solúveis produzidos pelas células, que ficam também armazenados no estroma da MA. Dessa forma, esses produtos atuariam de modo parácrino no tecido, diminuindo a expressão de citocinas pró inflamatórias e pró fibróticas, aumentando as citocinas anti-inflamatórias, promovendo, assim, um ambiente tissular propício ao reparo tecidual (Manuelpillai et al., 2011;Silini et al., 2013). ...
... The anti-inflammatory properties of PnD make them highly attractive for treating inflammatory, autoimmune, and degenerative diseases (Silini et al., 2013;Cargnoni et al., 2021;Yang et al., 2021). Inflammation is the body's defense mechanism to harmful stimuli, such as pathogens or damaged tissues. ...
Perinatal derivatives (PnD) are birth-associated tissues, such as placenta, umbilical cord, amniotic and chorionic membrane, and thereof-derived cells as well as secretomes. PnD play an increasing therapeutic role with beneficial effects on the treatment of various diseases. The aim of this review is to elucidate the modes of action of non-hematopoietic PnD on inflammation, angiogenesis and wound healing. We describe the source and type of PnD with a special focus on their effects on inflammation and immune response, on vascular function as well as on cutaneous and oral wound healing, which is a complex process that comprises hemostasis, inflammation, proliferation (including epithelialization, angiogenesis), and remodeling. We further evaluate the different in vitro assays currently used for assessing selected functional and therapeutic PnD properties. This review is a joint effort from the COST SPRINT Action (CA17116) with the intention to promote PnD into the clinics. It is part of a quadrinomial series on functional assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer activities, anti-inflammation, wound healing, angiogenesis, and regeneration.
... They appear to minimise any local inflammatory response in an injured or early osteoarthritic joint through the prevention of T-lymphocyte maturation, as well as the reduction in macrophage activation and secretion of immunomodulatory factors [54]. Important immunomodulatory factors produced by MSCs include indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), macrophage colony-stimulating factor (M-CSF), human leukocyte antigen-G (HLA-G), transforming growth factor-β (TGF-β), IL-10, and tumour necrosis factor-inducible gene 6 protein (TSG6), all of which have been shown to have a role in reducing inflammation [55,56]. ...
Regenerative medicine, using cells as therapeutic agents for the repair or regeneration of tissues and organs, offers great hope for the future of medicine. Cell therapy for treating defects in articular cartilage has been an exemplar of translating this technology to the clinic, but it is not without its challenges. These include applying regulations, which were designed for pharmaceutical agents, to living cells. In addition, using autologous cells as the therapeutic agent brings additional costs and logistical challenges compared with using allogeneic cells. The main cell types used in treating chondral or osteochondral defects in joints to date are chondrocytes and mesenchymal stromal cells derived from various sources such as bone marrow, adipose tissue or umbilical cord. This review discusses some of their biology and pre-clinical studies before describing the most pertinent clinical trials in this area.
... 21,32 In fact, these cells are marked by the classical MSC proteins CD90, CD44, CD73, and CD105, while they lack hematopoietic markers CD45, CD34, CD14, 33 and human leukocyte antigen-antigen D-related (HLA-DR) and present the in vitro differentiation potential toward one or more lineages including osteogenic, adipogenic, chondrogenic, and vascular/endothelial. 21,34 hAMSC also have immunomodulatory activity and are proposed as treatments of inflammatory-related disorders. 35,36 Indeed, several papers reported that hAMSC transplantation triggers regeneration in animal models of liver 37 and lung fibrosis, 38 collagen-induced arthritis, inflammatory bowel disease, dextran-induced severe colitis, experimental autoimmune encephalomyelitis (EAE, an animal model for multiple sclerosis), 39 traumatic brain injury, 40 and cardiac ischemia. 41 The therapeutic effects were observed in the absence of cell engraftment in the injured tissue suggesting that hAMSC act in a paracrine manner. ...
... 41 The therapeutic effects were observed in the absence of cell engraftment in the injured tissue suggesting that hAMSC act in a paracrine manner. 35,36 This hypothesis was confirmed by studies using conditioned medium (CM) derived from hAMSC that also demonstrated beneficial effects in preclinical models of lung fibrosis, 42,43 cardiac ischemia, 44 Huntington's disease, 45 and skin wound in diabetic mice. 46 Herein, we investigated if hAMSC could represent a valid alternative to BM-MSC as a feeder layer to support HSC and HPC ex vivo expansion. ...
Currently over 30 000 allogeneic hematopoietic stem cell (HSC) transplantations have been performed for the treatment of hematological and nonhematological diseases using HSC from umbilical cord blood (CB). However, the wide utilization of CB as a source of HSC is limited by the low number of cells recovered. One strategy to expand ex vivo CB-HSC is represented by the use of bone marrow mesenchymal stromal cells (BM-MSCs) as a feeder to enhance HSC proliferation while maintaining HSC stemness. Indeed, BM-MSCs have been recognized as one of the most relevant players in the HSC niche. Thus, it has been hypothesized that they can support the ex vivo expansion of HSC by mimicking the physiological microenvironment present in the hematopoietic niche. Due to the role of placenta in supporting fetal hematopoiesis, MSC derived from the amniotic membrane (hAMSC) of human term placenta could represent an interesting alternative to BM-MSC as a feeder layer to enhance the proliferation and maintain HSC stemness. Therefore, in this study we investigated if hAMSC could support the ex vivo expansion of HSC and progenitor cells. The capacity of hAMSCs to support the ex vivo expansion of CB-HSC was evaluated in comparison to the control condition represented by the CB-CD34+ cells without a feeder layer. The coculture was performed at two different CD34+ :MSC ratios (1:2 and 1:8) in both cell-to-cell contact and transwell setting. After 7 days, the cells were collected and analyzed for phenotype and functionality. Our results suggest that hAMSCs represent a valuable alternative to BM-MSC to support: (a) the ex vivo expansion of CB-HSC in both contact and transwell systems, (b) the colony forming unit ability, and (c) long-term culture initiating cells ability. Overall, these findings may contribute to address the unmet need of high HSC content in CB units available for transplantation.
... Studies revealed that AM-derived cells secrete several soluble factors and the AM stromal matrix maintains a wide range of growth factors acting as a local reservoir for these proteins [Koizumi et al., 2000;Silini et al., 2013;Kopaczka et al., 2016]. Differences in preservation methods can significantly affect the composition and properties of the hAM. ...
... Given that the AM stromal matrix acts as a reservoir of growth factors and hAM is mostly stored in a nonviable state, our result on the quantification of soluble proteins is a very important finding and corroborates the most accepted mechanism for the beneficial effects observed after AM transplantation. This is associated with the release of soluble factors by cells and molecules bound to the collagenous stromal matrix of the AM patch that operate paracrine mechanisms to support tissue regeneration [Manuelpillai et al., 2011;Silini et al., 2013]. More recently, Fénelon et al. [2018] demonstrated that the cryopreserved AM, with the stromal side in contact with the defect, was more efficient in increasing bone regeneration of calvarial defects in mice, when compared to the fresh membrane, even though the cellular viability of the cryopreserved AM was low. ...
The human amniotic membrane (AM) is emerging as an interesting biomaterial for regenerative medicine due to its biological and mechanical proprieties. The beneficial effects of the AM are probably related to its bioactive factors produced by local cells and stored in the stromal matrix. However, the search for a preservation method capable of preserving AM properties remains a challenge. The aim of this study was to evaluate important features of 2 anatomical regions of the human AM (reflected and placental amnion) after different preservation methods. For this purpose, human placentas were harvested and processed for AM isolation and storage at 2 different conditions: room temperature for 18 h in DMEM (fresh AM) and −80°C in DMEM/glycerol solution for 30 days (cryopreserved AM). After the storage period, the structural integrity of the membrane was assessed by histological and Picrosirius polarization analysis, cellular viability analysis was performed using the MTT assay, and the soluble proteins were quantified with the Qubit Protein Assay Kit. Both preservation protocols reduced the cell viability, mainly in the placental amnion region of the AM, but preserved the morphology of epithelial and stromal layers, as well as the organization and distribution of collagen fibers. There was a reduction in soluble proteins only in fresh AM. Importantly, the cryopreserved AM group presented the same concentration as the control group. In conclusion, the cryopreservation using DMEM/glycerol was ideal for preserving the structural integrity and soluble protein content, indicating the feasibility of this method in preserving AM for its use in regenerative medicine.
... Soluble factors of amnion-derived cells are shown to be effective in lung, liver, ocular pathologies, as well as chronic ulcer treatment and adhesion prevention through soluble cytokines that modulate inflammatory and fibrotic processes. 27 The significance of all these findings has to be interpreted carefully because these findings are the results from surgical wound model. In real clinical scenario, on the other hand, the tracheal stenosis develops from more prolonged mechanical impacts such as prolonged intubation or from more complex biological cascades, such as radiation injury. ...
Introduction:
Prolonged inflammation after tracheal injury invariably results in a degree of stenosis. The topical application of platelet-rich plasma (PRP) and human amniotic fluid-derived cell culture medium (ACCM) have been shown to promote wound healing. The effects of PRP and amniotic cell culture medium (Gibco AmnioMAX - II ) were investigated in a rat model through morphometric, histological, and biochemical parameters.
Material methods:
Thirty-two male Sprague Dawley rats were included in the study: 4 rats provided for the preparation of PRP. Three groups of 7 rats were divided into PRP and ACCM groups, a control and a sham group respectively. A transverse incision on the ventral aspect of the third trachea spanning half of the tracheal circumference was performed. The incision was repaired with 7/0 polypropylene in the sham group. In the control group, 0.5 ml saline solution was applied on to the repaired injury site. In the other two groups, 0.5 mL PRP or ACCM were applied topically on the tracheal repair. Tissue samples were harvested 30 days after surgery for morphometric measurements and biochemical analyses for oxidative stress markers, IL-1beta, IL-6, and VEGF. Connective tissue thickness was evaluated histologically. Statistical analysis included the Mann-Whitney U and Kruskal Wallis tests.
Results:
A notable difference was detected (P = 0,025) in cartilage segment length measurements of the trachea between the ACCM group and the sham and control groups (P < 0.03). A significant difference was found in the analysis of TAS, TOS, and OSI values between the study groups and the control and sham groups (P < 0.005). There were also differences in IL1-beta and IL-6 levels between ACCM and PRP groups (P < 0.05). For the same parameters, the differences were significant between the PRP and, sham and control groups (P = 0,004 and P = 0,002 respectively), and between the ACCM and, sham and control groups (P = 0,003 and P = 0,002 respectively).VEGF values demonstrated a significant difference between the PRP and sham group (P = 0,002), and between ACCM and sham/control groups (p=0,002 for both), the highest VEGF value was in ACCM group while the lowest value was in the sham group. In the histological assessment of connective tissue, a significant difference was observed between ACCM and the other groups.
Conclusion:
Amniotic fluid-derived cell culture medium shows less oxidative stress status than the other applications. ACCM is more effective on inflammatory and angiogenetic processes. Connective tissue thickness results were consistent with those biochemical and morphologic results. Additionally, a significant difference was observed in histological data between ACCM and PRP. Overall, ACCM proved to be efficient on tracheal healing. These effects can be attributed to the abundance of growth factors in both PRP and amniotic fluid-derived cell culture medium (ACCM).
