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   Table of Contents      
Year : 2016  |  Volume : 2  |  Issue : 1  |  Page : 1-7

Amnion-derived stem cell transplantation: A novel treatment for neurological disorders

Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Florida, USA

Date of Submission03-Aug-2015
Date of Decision03-Jan-2016
Date of Acceptance13-Jan-2016
Date of Web Publication11-Mar-2016

Correspondence Address:
Dr. Cesario V Borlongan
Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, Florida - 33612
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-8108.178537

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In this review, we evaluated the literature reporting the use of amniotic stem cells (ASCs) in regenerative medicine for the treatment of neurological disorders. There is an increasing amount of evidence that indicates the exacerbation of the primary injury by inflammation in neurological disorders characterized by rampant inflammation, thereby increasing damage to the central nervous system (CNS). To address this, we focus on the amnion cells' anti-inflammatory properties, which make their transplantation a promising treatment for these disorders. In addition, we offered insights into new applications of the ASC in the fields of regenerative medicine and tissue engineering.

Keywords: Amniotic stem cells (ASCs), human amniotic epithelial cells (hAECs), human amniotic mesenchymal stromal cells (hAMSCs), inflammation, neurological disorders, stroke

How to cite this article:
Carvajal HG, Suárez-Meade P, Borlongan CV. Amnion-derived stem cell transplantation: A novel treatment for neurological disorders. Brain Circ 2016;2:1-7

How to cite this URL:
Carvajal HG, Suárez-Meade P, Borlongan CV. Amnion-derived stem cell transplantation: A novel treatment for neurological disorders. Brain Circ [serial online] 2016 [cited 2023 Jun 3];2:1-7. Available from: http://www.braincirculation.org/text.asp?2016/2/1/1/178537

  Amniotic Stem Cells as Transplantable Cells Top

The discovery of placental- and fetal membrane-derived stem cells has added a new venue in the field of cell therapy. Among the placental origin cells, one of the most interesting has been the amnion, which is the two-layered membrane (made up of an epithelial monolayer and a stromal layer) that lines the fluid-filled sac surrounding the fetus. [1] After birth, the amnion is expelled, along with the placenta, preventing any ethical concern about the use of amniotic stem cells (ASCs). The amnion has been found to contain two types of cells: membrane-derived stem cells and fluid-derived stem cells. Amniotic membrane-derived stem cells also subdivide into human amniotic mesenchymal stromal cells (hAMSCs) and human amniotic epithelial cells (hAECs). [2] The hAECs originate from the embryonic ectoderm and express embryonic and pluripotent stem cell markers. [2] Meanwhile, hAMSCs present phenotypic characteristics similar to those of bone marrow-derived mesenchymal cells, and are harvested from the extraembryonic mesoderm. [2],[3],[4],[5] There are several published works about neuroglial differentiation of hAECs. In one article, the ability of hAECs to exert neural-like activity and their multipotentiality to become neurons, astrocytes, or oligodendrocytes was demonstrated. [6] A recent study in peripheral nerve injury differentiated hAECs into Schwann cells in order to help nerve regeneration and function. In this experiment, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) concentrations were upregulated, suggesting that they may play a key role in neuroregeneration. [7] Likewise, the ability of hAMSCs to proliferate as neural progenitor cells and their further potency on becoming glial cells has been demonstrated. [8]

In the studies of ASC transplants, neither allogeneic nor xenogeneic transplants have been shown to induce an immune response, making their therapeutic use a viable, low-risk treatment option. [9],[10] Human ASC shows low immunogenicity due to their expression of surface characteristics of antigen-presenting cells such as human leukocyte antigens (HLAs), specifically HLA-G, which has an important role in peripheral immune tolerance during pregnancy. [11] The expression of anti-inflammatory proteins interleukin (IL)-10, IL-1 receptor agonist, and tissue inhibitors of metalloproteinases 1-4 by hAEC and hAMSC further expands the potential therapeutic field of these cells to include autoimmune and degenerative disorders. [12] Furthermore, studies with human amnion cell transplantation into animal models have shown no induction of oncogenesis. [1] A study evaluating tumorigenicity by karyotype analysis has demonstrated that because of their chromosomal stability, ASCs represent a low-risk treatment option. [13] The lack of ethical dilemmas, the capacity to differentiate into a variety of tissues, the absence of an immune response, and the secretion of anti-inflammatory proteins by ASC makes them a perfect candidate for use in regenerative medicine.

  Therapeutic Applications of Amniotic Stem Cells Top

Recent studies have found a wide range of therapeutic applications for human amniotic membrane and amniotic fluid stem cells. Among these are the promotion of reepithelization, the modulation of cell differentiation and formation of new vessels, and a reduction in fibrosis, apoptosis, and inflammation. [14],[15],[16],[17] Currently, amnion-derived tissues have been obtained with the objective of using them in the clinical field. These are widely used for skin burns and wound healing in traumatology and general surgery. [18],[19],[20] These tissues have also been transplanted for the treatment of conditions such as diabetic foot ulcers and venous leg ulcers. [21],[22],[23] Altogether, these results suggest that ASCs could provide beneficial outcomes for several conditions. Nevertheless, further preclinical research in needed to standardize their isolation and differentiation, with the objective of expanding their use to other medical areas.

Amnion cells in neurological disorders

Studies evaluating the effect of ASCs in new therapies have been geared toward their utility in several neurological disorders including Parkinson's disease (PD), stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). [1] Reports show that hAECs may be able to differentiate into different cells of the nervous system such as astrocytes, oligodendrocytes, and neurons. [6] In addition, these stem cells are capable of creating and secreting neurotrophic factors and neurotransmitters. [16],[17] These characteristics confer them neuroprotective and neuroregenerative properties, which have been observed in the early stages of injury in preclinical studies. [16],[17]

The capacity to differentiate into different neural cells greatly expands the viability of hAECs as a treatment for stroke. [1],[10],[24] In one study, rats underwent a middle cerebral artery occlusion in order to produce a stroke model and were treated with an hAEC injection into the dorsolateral striatum on the first day after stroke. Here, the hAECs were shown to be capable of differentiation into astrocyte- and neuron-like cells. [17] In another experiment, hAECs were transplanted into a hemorrhagic stroke model in rats, improving motor skills, and reducing cerebral edema, with survival of transplanted cells in the lateral ventricular wall at 4 weeks. [25] The efficacy of hAEC transplantation in PD has also been evaluated in several studies. One of these evaluated a rat model of PD with 6-hydroxydopamine lesions, observing a higher survival rate of cells in dopaminergic neurons, and showcasing the protective effects of hAEC transplantation. [26] An increase in the quantity of dopaminergic cells in the substantia nigra and no overgrowth of the stem cells were observed after grafting, leading to the conclusion that hAEC transplantation may be a viable treatment for PD, counteracting the depletion of dopaminergic neurons. [26]

Several studies have expanded on the use of ASC therapy in other diseases as well. In one study, a rat TBI model was treated with an hAMSC transplant, leading to improved brain function, brain tissue morphology, and increased quantities of nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), ciliary neurotrophic factor, and GDNF. [27] Further studies on TBI used amnion-derived multipotent progenitor stem cells to reduce the resulting decay of axons in the thalamus and the corpus callosum. [28] Another interesting field of research for the use of ASC transplantation has been SCI. In a contusion model of SCI in monkeys, ASCs were transplanted into the injury, resulting in an increase of new host axons and reduced degeneration of axotomized spinal cord neurons. [29]

Use of amniotic stem cells in noncentral nervous system-related diseases

Although the focus of this review is mainly the application of hAEC/hAMSC in primarily neurological disorders, a wide variety of disorders (including but not limited to cardiovascular, [30] pulmonary, [31] hepatic, [32] pancreatic, [33] muscular, [34] and cartilage [35] ) may affect the CNS as well.

Amniotic membrane stem cells have a variety of effects outside the nervous system. Among their effects on the cardiovascular system, the production of cardioprotective factors stands out. In a rat heart ischemia model, human amniotic membrane cells were transplanted in order to observe their ability to inhibit injury to the myocardium after ischemia and cardiac dysfunction. After the transplant, rats exhibited an improvement in cardiac contractile function and ejection fraction. [36] Another instance exhibited a reduction of myocardial scarring and inhibited thinning in myocardial infarction after a stem cell transplant. [37] Nevertheless, other studies have been unable to prove the differentiation of amniotic membrane stem cells toward cardiomyocytes, continuing the debate on the subject. [38]

The capacity of hAECs to differentiate into type II pneumocytes has also been explored in several studies. One of the studies that evaluate the effect of hAEC in lung injury induced lung inflammation and fibrosis in a mouse model with bleomycin, treating the mice with an hAEC transplant. [39] After the transplant, hAECs were able to differentiate into phenotypic alveolar epithelium and secrete surfactant protein. [39] The application of hAEC also helped fight lung fibrosis, with a reduction of lung collagen, and inflammatory and fibrotic cytokines. [39] A similar study examined the effect of fetal membrane-derived cells on bleomycin-induced lung fibrosis in a mouse model. [40] ASCs were administered by several routes, depending on their origin: Xenogeneic and allogeneic cells were transplanted through either intraperitoneal or intratracheal, and allogeneic cells through the intravenous route of administration. [40] The results showed a reduction in neutrophil infiltration and the severity of lung fibrosis significantly decreased in the stem cell-treated group. [40]

The potential of human amniotic membrane-derived stem cells for the treatment of hepatic disorders has also been examined. The capacity of these cells to differentiate into liver cells was evaluated, using periodic acid-Schiff staining on amniotic membrane cells in order to evaluate glycogen storage. [41] The positive staining demonstrated that the amniotic membrane cells were able to carry on important physiological function of hepatocytes such as glycogen storage. [41] In a similar study, rat amniotic membrane cells were found to be capable of low-density lipoprotein (LDL) uptake after being exposed to an environment suitable for hepatic differentiation. [42] Another disorder of the liver in which the use of amnion cells was found to be useful was biliary fibrosis, characterized by the loss of hepatic function due to fibrotic remodeling. The only treatment available at the moment is liver transplant but a study on a rat model of biliary fibrosis showed that treatment with human ASCs may be a viable option. In this study, a patch made of human amniotic membrane was placed on the liver surface after biliary duct ligation. [43] After treatment, the severity of fibrosis was reduced, and no signs of cirrhosis were present. These observations suggest that amniotic membrane patches applied directly onto the liver may protect against damage from fibrosis. [43]

  Role Of Amniotic Stem Cells in Modulating Inflammation Top

In the early stages of neurological disorders, both the short- and long-term responses mounted by brain cells can have a detrimental effect. The primary injury results from the initial trauma, and consists of the loss of neurons and necrosis. [44] At this stage, a biochemical cascade begins, eventually leading to degeneration and secondary cell death. [45] The progressive nature of the injury has been shown to produce a chronic inflammatory state, worsening cell death, and therefore, neurological damage. [44]

During the acute phase of primary injury, such as stroke or TBI, inflammation provides a protective environment for damaged cells, acting as a defense mechanism against infectious microorganisms. However, inflammation can be detrimental to cell recovery in the chronic phase, worsening the preexistent damage from the primary injury. [46] The initial release of necrotic cell products, such as ATP, UTP, and high-mobility group protein B1 serve as chemotactic factors, stimulating the migration of immune cells into the CNS. [24] These cells include monocytes, macrophages, dendritic cells, T cells, neutrophils, and B cells, which permeate through the blood-brain barrier (BBB) in order to clear dead tissue and promote neuroregeneration. [24] The production of proinflammatory cytokines and molecules, such as interferon-γ, reactive oxygen species (ROS), IL-6 and IL-17, nitric oxide (NO), matrix metalloproteinase, and tumor necrosis factor (TNF) by these cells, lead to an increase of immune cell and glia migration toward the intrathecal compartment. [24],[47] This, in turn, creates an adverse environment for regeneration, with an increased immune response leading to an aggravation of neural damage during the chronic stage.

One of the most interesting characteristics of amnion cells is their ability to modulate the immune response by inhibiting excessive inflammation. [47] Amnion cells have been shown to possess the ability both to suppress the proinflammatory cytokines produced by the immune cells at the injury site, and produce anti-inflammatory cytokines such as IL-10 and IL-6. [48] Among the various immunomodulating effects of ASCS are the inhibition of metalloproteinases, reduction of antigen-presenting cells, upregulation of heat shock protein 27 (hsp27), suppression of T cell multiplication, and modification of M1 microglia, which favor inflammation, into the anti-inflammatory M2 type. [49],[50],[51] This reversal from an environment favorable for inflammation into an anti-inflammatory one promotes the regeneration of damaged brain cells. [24]

Although inflammation initially has a beneficial effect on stroke and TBI, its prolonged presence can be detrimental. In order to provide the best treatment, the application of ASC has to be administered at a specific time window, exploiting the benefits of both inflammation and the cell's anti-inflammatory properties. If given too early, ASCs may worsen the inflammatory process in its benefic stage, suppressing chemokines such as stromal cell-derived factor-1 (SDF-1). This chemokine helps transplanted cells migrate toward the site of injury so that its suppression would hinder the transplanted cells' ability to reach the injured area.­ [24] Therefore, ASC therapy must be regulated in order to favor inflammation in the early stages of brain injury and to suppress it in the later stages.

  Amnion Cell Therapy in Inflammation-Plagued Stroke Top

Among the most common causes of death in the United States, stroke ranks fourth, with ischemic stroke being the most common variety. [51] Currently, ischemic stroke is treated with tissue plasminogen activator (tPA) and therapies derived from it. [52] However, this treatment carries a risk of severe complications and a small therapeutic window, along with a series of contraindications (such as blood glucose level, blood pressure, and age). [53],[54],[55] Evidence shows that inflammation in stroke is not only caused by the primary injury but can also occur later as a result of the events occurring after stroke. [54],[55] The area around the lesion, known as the ischemic penumbra, suffers from low oxygen levels due to the cutoff in blood supply. This lack of oxygen causes astrocytes and microglia to produce proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-4, and chemokines such as NO. [54],[56] As previously mentioned, inflammation plays an important protective role in the early phase of stroke but increases the damage done to the brain when prolonged. Therefore, astrocytes and microglia not only have the capacity to secrete proinflammatory substances but can also produce anti-inflammatory factors (such as BDNF, erythropoietin, vascular endothelial growth factor, and others). Nevertheless, these regulatory mechanisms often fall short of preventing further damage and recovering neurological function, creating the need for an appropriate therapy.

Since inflammation is a process that takes place over an extended period of time, there are a variety of possible treatment options. Evidence from animal models of stroke has found treatment with stem cells to be a safe and effective alternative. Among the available stem cell therapies, hAMSCs have shown promising results. [57] Human placenta stem cells, as described above, have a great potential for differentiation. [58] Due to their inflammation-modulating capacity, treatment with these cells allows us to fully take advantage of the beneficial effects of inflammation in the early stages while regulating it later on. [59],[60],[61] Therefore, the best time to inject ASCs is during the early stages of stoke. As stated previously, these stem cells have the ability to reduce proinflammatory signals and secrete anti-inflammatory and neurotrophic factors, promoting healing and inhibiting inflammation. In animal models, placenta-derived stem cell transplants have been observed to lead to a better outcome though their exact mechanism in stroke treatment is not yet completely understood. Nevertheless, most studies have shown evidence pointing toward the stem cells' ability to regulate inflammation as the cornerstone of this therapy.

In order to regulate inflammation, the recognition of the role of stem cells in various key points of inflammation signaling cascades is warranted. In an in vitro stroke model, hAECs were shown to confer neuroprotection by acting on melatonin receptor type 1A (MT1) and the cells' ability to survive increased when administered with a simultaneous melatonin treatment. [62] Another study of in vivo and in vitro stroke models found that dog placenta cells (DPC) had neuroprotective properties by way of Hsp27. [49] In this study, DPCs were shown to increase the expression of Hsp27 near the area surrounding the ischemic lesion. [45] Since Hsp27 has been shown to have neuroprotective effects, its increased expression is indicative of the mechanism through which DPCs confer neuroprotection. [63],[64],[65] These studies evaluated the different stages of inflammatory mechanisms, demonstrating that ASCs could have neuroprotective capacities through immunomodulation.

  Amniotic Stem Cell Applications in Regenerative Medicine: Possible Delivery Mechanisms Top

One of the possible applications of ASCs in the treatment of stroke and TBI is through a subdural patch. This method consists of placing a patch of amniotic membrane directly on the brain, harnessing its therapeutic properties, and providing a noninmunogenic graft due to its ability to differentiate and integrate into brain tissue. [66] The stem cells from the patch would facilitate the movement of pluripotent cells, both transplanted and generated in the brain, toward the injury site. [67] These connections, or biobridges, have been observed in previous studies utilizing human bone marrow-derived mesenchymal stromal cells as treatment for TBI in a rat model. [67] The ability to form biobridges and differentiate into neural progenitor cells makes amniotic subdural patches an ideal therapy not just for regulating inflammation but for promoting neuroregeneration as well. Although there have not been any experimental models of biobridge formation in stroke, it has been hypothesized that stem cells have the capacity to act in a similar manner, allowing neurogenic stem cells to migrate toward the stroke core and ischemic penumbra. [68]

The ability to regulate inflammation makes hAECs useful in the treatment of inflammatory neural disorders. [24] The immunomodulatory factors secreted by hAEC, such as prostaglandin E-2 (PGE2), regulate the immune response, suppressing inflammation and thus reducing its adverse effects. [69] Another interesting characteristic of these cells is their expression of human leukocyte antigen G (HLA-G), which allows them to evade the immune system and induce apoptosis in immune cells. [24] This effect has also been observed in multiple sclerosis (MS) mouse models where alpha-fetoprotein inhibits inflammation, and outside the CNS in lung injury models in which hAEC cells inhibited the secretion of proinflammatory cytokines and increased secretion of anti-inflammatory cytokines. [24] Modifying hAECs in order to produce anti-inflammatory cytokines and chemokines in vivo would permit the quantification and evaluation of their clinical use in diseases associated with inflammation. In addition, the use of these factors alongside ASC therapy would potentiate their anti-inflammatory effects, providing a more effective treatment.

Both hAECs and amniotic membrane grafts have similar immunomodulatory properties, which have been described above. Amniotic membrane patches have been shown to promote the formation of a microenvironment conducive to injury-healing by host cells, allowing for better wound-healing. [30],[34],[37] Another advantage of human amniotic membrane patches is their relative ease of preparation, requiring only the separation of the amnion from the chorion without the need for culture or isolation. [30] However, their therapeutic action stems from the modulation of the injury microenvironment, rather than differentiation of ASCs. On the other hand, hAECs have exhibited the ability to differentiate into neural stem cells as well as modulate the inflammatory response, increasing their potential field of action. [1],[6],[10],[24] Despite the beneficial effects shown by undifferentiated hAEC transplantation, trials conducted with neural stem-like cells acquired from differentiated hAEC have shown an increased secretion of neurotrophic factors. [28] Therefore, hAEC should be cultured in a medium conducive to differentiation in order to fully harness their therapeutic potential.

The transplantation of tissues from one species to another, known as xenografting, has shown a lot of promise in the treatment of a variety of diseases. However, a variety of immunologic complications arise due to rejection of the grafts by the host's immune system. This rejection leads to the production of xenoreactive antibodies, which cause systemic inflammation and activate the complement system. [70],[71] Though a variety of tolerance techniques have been tried, such as neonatal desensitization, these have not improved the rate of rejection. [72] An option that has worked in previous studies has been the application of circulating anti-inflammatory alpha-1-antitrypsin (ATT), along with anti-CD4/CD8 therapy, protecting xenografts from inflammation and therefore, from rejection. [73] This mechanism opens up the possibility of using hASCs to prevent xenograft rejection by modulating the immune response. [73] By transplanting hASC at the same time as xenografts, their rate of rejection would decrease.

Allografts, or the transplantation of tissue from one individual to another of the same species, are not immune to rejection, with the possibility of being targeted by the host's defenses being very high. The first obstacle encountered by allografts is the host's innate immune response, which is nonspecific. The allograft then faces the specific immune response, mediated by T cells specifically designed to recognize alloantigens. [74] A number of studies have utilized ASCs in conjunction with allografts in order to modulate the immune response to the graft, reduce the necessity for immunosuppressive treatment, and favor acceptance by the host. [75]

The inflammation that characterizes CNS disorders is not only present in the CNS but also reaches the peripheral nervous system (PNS). [76],[77],[78],[79] This involvement of the PNS in inflammatory response after injury creates an interesting array of diagnostic and therapeutical opportunities such as the possibility of treating PNS inflammation with ASCs. Among the peripheral organs that present inflammation after stroke is the spleen, which could easily be targeted by stem cells. [80],[81] This would be accomplished either by a systemic transplantation of stem cells directed specifically to the spleen or by transplanting the cells into the organ. Once ASCs reach the spleen, their anti-inflammatory properties alleviate peripheral inflammation.

Although there are many pluripotent cells derived from gestational tissues (such as umbilical cord blood, Wharton's jelly, and amniotic fluid), ASCs are the only ones that can be used without previous cultivation. [82] Since hAECs have shown a very diverse potential for differentiation in vitro, they could be useful in a variety of diseases. Studies have demonstrated their ability to differentiate into a number of tissues including adipose, cardiomyocytic, pancreatic, hepatic, neural, osteogenic, and chondrogenic. [83],[84],[85] Therefore, ASCs could be harvested at birth and directed toward specific treatments for those at risk of developing diseases. Through genetic testing, individuals at risk of developing diseases in their adulthood could start with prophylactic ASC therapy, slowing down or even stopping the development of these disorders.

  Future Applications of Amniotic Stem Cell Therapy in Central Nervous System Diseases and Inflammation Top

Throughout the text, substantial evidence of the therapeutic potential of ASCs has been presented. Among these experimental applications, their use in regenerative medicine for neurological diseases stands out, as well as in other pathologies that affect the nervous system such as cardiovascular, respiratory, hepatic, pancreatic, and muscular disorders. Despite the amount of evidence of amnion cell therapy's efficacy in the treatment of CNS and non-CNS disorders in animal models, their application still needs to be refined and adapted for clinical application. Among the many translational issues, an effective and less invasive application route for stem cells needs to be determined as well as the need for optimization of doses and timing of their delivery in clinically relevant animal models. The regulatory effects of ASCs on inflammation must be taken into account in order to determine the safe and effective therapy for different diseases. Consequently, more research is still needed in order to determine and standardize the optimal stem cell transplantation treatment in diseases characterized by inflammation.

Financial support and sponsorship

CVB is funded by the National Institutes of Health 1R01NS071956, the National Institutes of Health R21 1R21NS089851, the Department of Defense W81XWH-11-1-0634, and VA Merit Review.

Conflicts of interest

There are no conflicts of interest.

  References Top

Yu SJ, Soncini M, Kaneko Y, Hess DC, Parolini O, Borlongan CV. Amnion: A potent graft source for cell therapy in stroke. Cell Transplant 2009;18:111-8.  Back to cited text no. 1
Parolini O, Alviano F, Bagnara GP, Bilic G, Bühring HJ, Evangelista M, et al. Concise review: Isolation and characterization of cells from human term placenta: Outcome of the first international workshop on placenta derived stem cells. Stem Cells 2008;26:300-11.  Back to cited text no. 2
Kobayashi M, Yakuwa T, Sasaki K, Sato K, Kikuchi A, Kamo I, et al. Multilineage potential of side population cells from human amnion mesenchymal layer. Cell Transplant 2008;17:291-301.  Back to cited text no. 3
Portmann-Lanz CB, Schoeberlein A, Huber A, Sager R, Malek A, Holzgreve W, et al. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am J Obstet Gynecol 2006;194:664-73.  Back to cited text no. 4
Soncini M, Vertua E, Gibelli L, Zorzi F, Denegri M, Albertini A, et al. Isolation and characterization of mesenchymal cells from human fetal membranes. J Tissue Eng Regen Med 2007;1:296-305.  Back to cited text no. 5
Sakuragawa N, Thangavel R, Mizuguchi M, Hirasawa M, Kamo I. Expression of markers for both neuronal and glial cells in human amniotic epithelial cells. Neurosci Lett 1996;209:9-12.  Back to cited text no. 6
Banerjee A, Nürnberger S, Hennerbichler S, Riedl S, Schuh CM, Hacobian A, et al. In toto differentiation of human amniotic membrane towards the Schwann cell lineage. Cell Tissue Bank 2014;15:227-39.  Back to cited text no. 7
Sakuragawa N, Kakinuma K, Kikuchi A, Okano H, Uchida S, Kamo I, et al. Human amnion mesenchyme cells express phenotypes of neuroglial progenitor cells. J Neurosci Res 2004;78:208-14.  Back to cited text no. 8
Wolbank S, Peterbauer A, Fahrner M, Hennerbichler S, van Griensven M, Stadler G, et al. Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: A comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 2007;13:1173-83.  Back to cited text no. 9
Bailo M, Soncini M, Vertua E, Signoroni PB, Sanzone S, Lombardi G, et al. Engraftment potential of human amnion and chorion cells derived from term placenta. Transplantation 2004;78:1439-48.  Back to cited text no. 10
Hammer A, Hutter H, Blaschitz A, Mahnert W, Hartmann M, Uchanska-Ziegler B, et al. Amnion epithelial cells, in contrast to trophoblast cells, express all classical HLA class I molecules together with HLA-G. Am J Reprod Immunol 1997;37:161-71.  Back to cited text no. 11
Hao Y, Ma DH, Hwang DG, Kim WS, Zhang F. Identification of antiangiogenic and antiinflammatory proteins in human amniotic membrane. Cornea 2000;19:348-52.  Back to cited text no. 12
Sessarego N, Parodi A, Podestà M, Benvenuto F, Mogni M, Raviolo V, et al. Multipotent mesenchymal stromal cells from amniotic fluid: Solid perspectives for clinical application. Heamatologica 2008;93:339-46.  Back to cited text no. 13
Parolini O, Soncini M, Evangelista M, Schmidt D. Amniotic membrane and amniotic fluid-derived cells: Potential tools for regenerative medicine? Regen Med 2009;4:275-91.  Back to cited text no. 14
Parolini O, Alviano F, Betz AG, Bianchi DW, Götherström C, Manuelpillai U, et al. Meeting report of the first conference of the International Placenta Stem Cell Society (IPLASS). Placenta 2011;32(Suppl 4):S285-90.  Back to cited text no. 15
Uchida S, Inanaga Y, Kobayashi M, Hurukawa S, Araie M, Sakuragawa N. Neurotrophic function of conditioned medium from human amniotic epithelial cells. J Neurosci Res 2000;62:585-90.  Back to cited text no. 16
Liu T, Wu J, Huang Q, Hou Y, Jiang Z, Zang S, et al. Human amniotic epithelial cells ameliorate behavioral dysfunction and reduce infarct size in the rat middle cerebral artery occlusion model. Shock 2008;29:603-11.  Back to cited text no. 17
Mohammadi AA, Seyed Jafari SM, Kiasat M, Tavakkoliann AR, Imani MT, Ayaz M, et al. Effect of fresh human amniotic membrane dressing on graft take in patients with chronic burn wounds compared with conventional methods. Burns 2013;39:349-53.  Back to cited text no. 18
Maan ZN, Rennert RC, Koob TJ, Januszyk M, Li WW, Gurtner GC. Cell recruitment by amnion chorion grafts promotes neovascularization. J Surg Res 2015;193:953-62.   Back to cited text no. 19
Mohammadi AA, Johari HG, Eskandari S. Effect of amniotic membrane on graft take in extremity burns. Burns 2013;39:1137-41.   Back to cited text no. 20
Serena TE, Carter MJ, Le TL, Sabo MJ, Dimarco DT; EpiFix VLU Study Group. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen 2014;22:688-93.  Back to cited text no. 21
Zelen CM, Serena TE, Snyder RJ. A prospective, randomized comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J 2014;11:122-8.   Back to cited text no. 22
Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomized comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J 2013;10:502-7.   Back to cited text no. 23
Broughton BR, Lim R, Arumugam TV, Drummond GR, Wallace EM, Sobey CG. Post-stroke inflammation and the potential efficacy of novel stem cell therapies: Focus on amnion epithelial cells. Front Cell Neurosci 2013;6:66.  Back to cited text no. 24
Dong W, Chen H, Yang X, Guo L, Hui G. Treatment of intracerebral haemorrhage in rats with intraventricular transplantation of human amniotic epithelial cells. Cell Biol Int 2010;34:573-7.  Back to cited text no. 25
Kakishita K, Nakao N, Sakuragawa N, Itakura T. Implantation of human amniotic epithelial cells prevents the degeneration of nigral dopamine neurons in rats with 6-hydroxydopamine lesions. Brain Res 2003;980:48-56.  Back to cited text no. 26
Yan ZJ, Zhang P, Hu YQ, Zhang HT, Hong SQ, Zhou HL, et al. Neural stem-like cells derived from human amnion tissue are effective in treating traumatic brain injury in rat. Neurochem Res 2013;38:1022-33.  Back to cited text no. 27
Chen Z, Tortella FC, Dave JR, Marshall VS, Clarke DL, Sing G, et al. Human amnion-derived multipotent progenitor cell treatment alleviates traumatic brain injury-induced axonal degeneration. J Neurotrauma 2009;26:1987-97.  Back to cited text no. 28
Sankar V, Muthusamy R. Role of human amniotic epithelial cell transplantation in spinal cord injury repair research. Neuroscience 2003;118:11-7.  Back to cited text no. 29
Moran, JF. Neurologic complications of cardiomyopathies and other myocardial disorders. Chapter 9. In: José B, José MF, editors. Handbook of Clinical Neurology. Amsterdam, The Netherlands: Elsevier; 2014. p. 111-28.  Back to cited text no. 30
Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj 2006;20:263-71.  Back to cited text no. 31
Ryan JM, Shawcross DL. Hepatic encephalopathy. Medicine 2011;39:617-20.  Back to cited text no. 32
Pandey MK, Mittra P, Doneria J, Maheshwari PK. Neurological complications in diabetic ketoacidosis - before and after insulin therapy. Int J Med Sci Public Health 2013;2:88-93.  Back to cited text no. 33
Blake DJ, Kröger S. The neurobiology of duchenne muscular dystrophy: Learning lessons from muscle? Trends Neurosci 2000;23:92-9.  Back to cited text no. 34
Morawski M, Brückner G, Arendt T, Matthews RT. Aggrecan: Beyond cartilage and into the brain. Int J Biochem Cell Biol 2012;44:690-3.  Back to cited text no. 35
Cargnoni A, Di Marcello M, Campagnol M, Nassuato C, Albertini A, Parolini O. Amniotic membrane patching promotes ischemic rat heart repair. Cell Transplant 2009;18:1147-59.  Back to cited text no. 36
Fujimoto KL, Miki T, Liu LJ, Hashizume R, Strom SC, Wagner WR, et al. Naive rat amnion-derived cell transplantation improved left ventricular function and reduced myocardial scar of postinfarcted heart. Cell Transplant 2009;18:477-86.  Back to cited text no. 37
Parolini O, Caruso M. Review: Preclinical studies on placenta-derived cells and amniotic membrane: An update. Placenta 2011;32(Suppl 2):S186-95.  Back to cited text no. 38
Moodley Y, Ilancheran S, Samuel C, Vaghjiani V, Atienza D, Williams ED, et al. Human amnion epithelial cell transplantation abrogates lung fibrosis and augments repair. Am J Respir Crit Care Med 2010;182:643-51.  Back to cited text no. 39
Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, et al. Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 2009;18:405-22.  Back to cited text no. 40
Tamagawa T, Oi S, Ishiwata I, Ishikawa H, Nakamura Y. Differentiation of mesenchymal cells derived from human amniotic membranes into hepatocyte-like cells in vitro. Hum Cell 2007;20:77-84.  Back to cited text no. 41
Marcus AJ, Coyne TM, Rauch J, Woodbury D, Black IB. Isolation, characterization, and differentiation of stem cells derived from the rat amniotic membrane. Differentiation 2008;76:130-44.  Back to cited text no. 42
Sant′Anna LB, Cargnoni A, Ressel L, Vanosi G, Parolini O. Amniotic membrane application reduces liver fibrosis in a bile duct ligation rat model. Cell Transplant 2011;20:441-53.  Back to cited text no. 43
Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Front Neurol 2013;4:30.  Back to cited text no. 44
Tajiri N, Acosta SA, Shahaduzzaman M, Ishikawa H, Shinozuka K, Pabon M, et al. Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: Cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 2014;34:313-26.  Back to cited text no. 45
Schmidt OI, Heyde CE, Ertel W, Stahel PF. Closed head injury - An inflammatory disease? Brain Res Brain Res Rev 2005;48:388-99.  Back to cited text no. 46
Lozano D, Gonzales-Portillo GS, Acosta S, de la Pena I, Tajiri N, Kaneko Y, et al. Neuroinflammatory responses to traumatic brain injury: Etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 2015;11:97-106.  Back to cited text no. 47
Manuelpillai U, Moodley Y, Borlongan CV, Parolini O. Amniotic membrane and amniotic cells: potential therapeutic tools to combat tissue inflammation and fibrosis? Placenta 2011;32(Suppl 4):S320-5.  Back to cited text no. 48
Yu S, Tajiri N, Franzese N, Franzblau M, Bae E, Platt S, et al. Stem cell-like dog placenta cells afford neuroprotection against ischemic stroke model via heat shock protein upregulation. PLoS One 2013;8:e76329.  Back to cited text no. 49
Castillo-Melendez M, Yawno T, Jenkin G, Miller SL. Stem cell therapy to protect and repair the developing brain: A review of mechanisms of action of cord blood and amnion epithelial derived cells. Front Neurosci 2013;7:194.  Back to cited text no. 50
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2014 update: A report from the American Heart Association. Circulation 2014;129:e28-292.  Back to cited text no. 51
Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003;CD000213.  Back to cited text no. 52
Demchuk AM, Bal S. Thrombolytic therapy for acute ischaemic stroke: What can we do to improve outcomes? Drugs 2012;72:1833-45.  Back to cited text no. 53
Konsman JP, Drukarch B, Van Dam AM. (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond) 2007;112:1-25.  Back to cited text no. 54
Amantea D, Tassorelli C, Petrelli F, Certo M, Bezzi P, Micieli G, et al. Understanding the multifaceted role of inflammatory mediators in ischemic stroke. Curr Med Chem 2014;21:2098-117.  Back to cited text no. 55
Sairanen TR, Lindsberg PJ, Brenner M, Sirén AL. Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J Cereb Blood Flow Metab 1997;17:1107-20.  Back to cited text no. 56
Barlow S, Brooke G, Chatterjee K, Price G, Pelekanos R, Rossetti T, et al. Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev 2008;17:1095-107.  Back to cited text no. 57
Ilancheran S, Moodley Y, Manuelpillai U. Human fetal membranes: A source of stem cells for tissue regeneration and repair? Placenta 2009;30:2-10.  Back to cited text no. 58
Wan H, Li F, Zhu L, Wang J, Yang Z, Pan Y. Update on therapeutic mechanism for bone marrow stromal cells in ischemic stroke. J Mol Neurosci 2014;52:177-85.  Back to cited text no. 59
van Velthoven CT, Gonzalez F, Vexler ZS, Ferriero DM. Stem cells for neonatal stroke - The future is here. Front Cell Neurosci 2014;8:207.  Back to cited text no. 60
Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int 2014;2014:468748.  Back to cited text no. 61
Kaneko Y, Hayashi T, Yu S, Tajiri N, Bae EC, Solomita MA, et al. Human amniotic epithelial cells express melatonin receptor MT1, but not melatonin receptor MT2: A new perspective to neuroprotection. J Pineal Res 2011;50:272-80.  Back to cited text no. 62
Teramoto S, Shimura H, Tanaka R, Shimada Y, Miyamoto N, Arai H, et al. Human-derived physiological heat shock protein 27 complex protects brain after focal cerebral ischemia in mice. PLoS One 2013;8:e66001.  Back to cited text no. 63
An JJ, Lee YP, Kim SY, Lee SH, Lee MJ, Jeon MS, et al. Transduced human PEP-1-heat shock protein 27 efficiently protects against brain ischemic insult. FEBS J 2008;275:1296-308.  Back to cited text no. 64
Stetler RA, Cao G, Gao Y, Zhang F, Wang S, Weng Z, et al. Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci 2008;28:13038-55.  Back to cited text no. 65
Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian AM. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater 2008;15:88-99.  Back to cited text no. 66
Tajiri N, Duncan K, Antoine A, Pabon M, Acosta SA, de la Pena I, et al. Stem cell-paved biobridge facilitates neural repair in traumatic brain injury. Front Syst Neurosci 2014;8:116.  Back to cited text no. 67
Duncan K, Gonzales-Portillo GS, Acosta SA, Kaneko Y, Borlongan CV, Tajiri N. Stem cell-paved biobridges facilitate stem cell transplant and host brain cell interactions for stroke therapy. Brain Res 2015;1623:160-5.  Back to cited text no. 68
Insausti CL, Blanquer M, García-Hernández AM, Castellanos G, Moraleda JM. Amniotic membrane-derived stem cells: Immunomodulatory properties and potential clinical application. Stem Cells Cloning 2014;7:53-63.  Back to cited text no. 69
Zeyland J, Gawrońska B, Juzwa W, Jura J, Nowak A, S³omski R, et al. Transgenic pigs designed to express human a-galactosidase to avoid humoral xenograft rejection. J Appl Genet 2013;54:293-303.  Back to cited text no. 70
Ezzelarab MB, Ekser B, Azimzadeh A, Lin CC, Zhao Y, Rodriguez R, et al. Systemic inflammation in xenograft recipients precedes activation of coagulation. Xenotransplantation 2015;22:32-47.  Back to cited text no. 71
Mattis VB, Wakeman DR, Tom C, Dodiya HB, Yeung SY, Tran AH, et al. Neonatal immune-tolerance in mice does not prevent xenograft rejection. Exp Neurol 2014;254:90-8.  Back to cited text no. 72
Ashkenazi E, Baranovski BM, Shahaf G, Lewis EC. Pancreatic islet xenograft survival in mice is extended by a combination of alpha-1-antitrypsin and single-dose anti-CD4/CD8 therapy. PLoS One 2013;8:e63625.  Back to cited text no. 73
Sordi V, Piemonti L. Therapeutic plasticity of stem cells and allograft tolerance. Cytotherapy 2011;13:647-60.  Back to cited text no. 74
Anam K, Lazdun Y, Davis PM, Banas RA, Elster EA, Davis TA. Amnion-derived multipotent progenitor cells support allograft tolerance induction. Am J Transplant 2013;13:1416-28.  Back to cited text no. 75
Ahmad M, Graham SH. Inflammation after stroke: Mechanisms and therapeutic approaches. Transl Stroke Res 2010;1:74-84.  Back to cited text no. 76
McGeer PL, McGeer EG. The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995; 21:195-218.  Back to cited text no. 77
Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009;65:304-12.  Back to cited text no. 78
Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, Diamond DM, et al. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One 2013;8:e53376.  Back to cited text no. 79
Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006;26:654-65.  Back to cited text no. 80
Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 2006;203:1623-8.  Back to cited text no. 81
Zhu D, Wallace EM, Lim R. Cell-based therapies for the preterm infant. Cytotherapy 2014;16:1614-28.  Back to cited text no. 82
Diaz-Prado S, Muiños-López E, Hermida-Gómez T, Cicione C, Rendal-Vázquez ME, Fuentes-Boquete I, et al. Human amniotic membrane as an alternative source of stem cells for regenerative medicine. Differentiation 2011;81:162-71.  Back to cited text no. 83
Diaz-Prado S, Muiños-López E, Hermida-Gómez T, Rendal-Vázquez ME, Fuentes-Boquete I, de Toro FJ, et al. Multilineage differentiation potential of cells isolated from the human amniotic membrane. J Cell Biochem 2010;111:846-57.  Back to cited text no. 84
Casey ML, MacDonald PC. Interstitial collagen synthesis and processing in human amnion: A property of the mesenchymal cells. Biol Reprod 1996;55:1253-60.  Back to cited text no. 85

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