Edited by: Jorge Matias-Guiu, Complutense University of Madrid, Spain
Reviewed by: Marwa M. Mahfouz, Menofia University, Egypt; Laura Leyva Fernández, University of Málaga, Spain
This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology
†These authors share first authorship
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Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system with unknown etiology. It is accompanied by demyelination of the nerves during immunological processes in the presence of oxidative stress, hypoxia, cerebral hypo-perfusion, and dysregulation in matrix metalloproteinases (MMPs). Human amniotic mesenchymal stem cells (hAMSCs) as pluripotent stem cells possess some conspicuous features which could be of therapeutic value in MS therapy. hAMSCs could mimic the cascade of signals and secrete factors needed for promoting formation of stable neovasculature and angiogenesis. hAMSCs also have immunomodulatory and immunosuppressive effects on inflammatory processes and reduce the activity of inflammatory cells, migration of microglia and inhibit recruitment of certain immune cells to injury sites. hAMSCs attenuate the oxidative stress supported by the increased level of antioxidant enzymes and the decreased level of lipid peroxidation products. Furthermore, hAMSCs enhance neuroprotection and neurogenesis in brain injuries by inhibition of inflammation and promotion of neurogenesis. hAMSCs could significantly increase the expression of neurotrophic factors, which prevents neurons from initiating programmed cell death and improves survival, development, and function of neurons. In addition, they induce differentiation of neural progenitor cells to neurons. hAMSCs could also inhibit MMPs dysregulation and consequently promote the survival of endothelial cells, angiogenesis and the stabilization of vascular networks. Considering the mentioned evidences, we hypothesized here that hAMSCs and their conditioned medium could be of therapeutic value in MS therapy due to their unique properties, including immunomodulation and inflammation suppression; angiogenesis promotion; oxidative stress inhibition; neurogenesis induction and neuroprotection; matrix metalloproteinases regulation; and remyelination stimulation.
Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system which is accompanied by neural demyelination, axonal loss, and disability. Although the main etiology of MS is unknown, genetic, environmental and infectious agents may be among the factors that play a role in the development of MS (
Although various pharmacological and non-pharmacological therapeutic approaches have been used in the treatment of MS, no definite cure of MS has been discovered to date. Moreover, all the approved therapeutic approaches are expected to be life-long, while their potential adverse effects may compromise their safety or patients' adherence to treatment. Therefore, it is imperative yet challenging to find new safe therapies with fewer delivery concerns and less adverse effects that are more effective in slowing or preventing MS progression, have the potential to reverse patients' disability, and consequently improve patients' adherence.
Cell-based therapy by mesenchymal stem cells (MSCs) is one of the therapeutic approaches that has drawn attention as a potential approach to address these challenges, considering initial promising research results (
Human amniotic membrane is considered a potential source for MSCs which possesses unique biological properties, including anti-inflammatory, anti-fibrosis, anti-scarring and low immunogenicity characteristics (
Altogether, it seems that hAMSCs have potential therapeutic features that could be promising in MS therapy. There is some evidence for some hAMSCs properties including immunomodulation and inflammation suppression (
Inflammation in the central nervous system is one of the major pathogenic processes in MS. Although the trigger of the inflammatory response in MS is still not clear, it is suggested that MS is developed when auto-reactive T cells target proteins which exist predominantly in myelin and on axons (
Efficient treatment of MS depends on developing a therapeutic method that can specifically target and regulate immune responses. A number of immunomodulatory or immunosuppressive drugs including Interferon-β, Glatiramer acetate, Natalizumab, and Fingolimod have been designed to target the immune component of MS. Although these drugs have displayed beneficial effects for halting MS, they have shown little impact on its progression (
hAMSCs could lead to a decrease of peripheral blood mononuclear cells, interferon-gamma and interleukin-17 production (
Cerebral hypoperfusion as well as vascular factors are involved in neurovascular dysfunction, vascular oxidative stress, and relative tissue hypoxia, which could increase the risk of developing demyelinating lesions as observed in MS. Therefore, cerebral hypoperfusion may represent pathologic factors or neuroprotective processes involved in recovery or progression of MS (
Although various therapeutic approaches have been utilized to promote angiogenesis, most approaches still cannot fully mimic the process of natural vessel development. The use of hAMSCs has been explored to mimic the cascade of signals needed for enhancing viability and promoting formation of stable neovasculature (
The inflammatory processes play a significant role in neural tissue injury (
Treatment of mice model of MS with antioxidant enzymes markedly suppressed the severity of MS (
The utilization of MSCs in mice models of MS can inhibit the production of inflammatory factors, including nitric oxide (NO), tumor necrosis factor, IL1-β and reactive oxygen species by activated microglia and preventing neuronal damage. The intravenous injection of MSCs showed a string antioxidant effect in a mice model of MS through the high expression of antioxidant enzymes including catalase, superoxide desmutase and poly (ADP-ribose) polymerase-1 during MSC treatment (
In addition, hAMSCs transplantation into transgenic mice increased the level of antioxidant enzymes and decreased the level of lipid peroxidation and oxidative stress (
Neurodegeneration is considered as a major contributor to neurological disability in MS and might be the dominant underlying process of progressive MS. Whether the neurodegeneration is an independent process or due to inflammatory processes remains unknown (
Another process involved in pathogenesis of MS is demyelination. Demyelination causes myelin-producing oligodendrocytes to undergo apoptosis and thus results in myelin loss (
Treatment of MS with hAMSCs could significantly increase the expression of neurotrophic factors including NGF, CNTF, and BDNF (
MMPs are a family of a large number of proteolytic enzymes that have received much attention in neuro-inflammatory diseases. Leukocyte infiltration through the blood-brain-barrier is dependent on several factors including secretion of tumor necrotizing factor-α, gelatinase B/MMP-9 and gelatinase A/MMP-2 (
Mesenchymal stem cells application in inflammatory diseases resulted in decreased levels of MMPs or reduced MMPs activity. In another study, a conditioned medium of MSCs decreased disease severity by inhibition of the MMPs activity rate in inflammatory arthritis (
Considering the supporting evidences, we hypothesize that hAMSCs have potential therapeutic features in multiple sclerosis via angiogenesis promotion, inflammation suppression, oxidative stress inhibition, neurogenesis induction, neuroprotection, MMPs regulation, and remyelination stimulation (
Human Amniotic Mesenchymal Stem Cells (hAMSCs) have potential therapeutic features in multiple sclerosis via supporting evidences illustrated above. ROS, Reactive Oxidative Species; ECM, Extracellular Matrix; MMPs, Matrix Metalloproteinases.
The hypothesis will be evaluated by conducting
To evaluate the
To evaluate the
To evaluate direct injection of hAMSCs, the cells would be locally injected in the affected regions of the brain tissue. In addition, as MSCs express a variety of chemokine receptors including CXCR4 and CCR2, and cell adhesion molecules including CD44, integrins α4 and β1, and CD99 (
To evaluate oxidative stress inhibition by hAMSCs, the reactive oxygen species and glutathione reduction is measured before and after treatment with hAMSCs conditioned medium by glutathione assay kit.
To evaluate the effects of hAMSCs conditioned media on OPC differentiation for neurogenesis and remyelination, oligodendrocyte precursor marker, Olig2, and adult myelin markers, PLP, MBP, MOG, will be measured by real-time PCR and Western blot analyses. To further investigate the effects of hAMSCs, cellular and molecular tests using immunohistochemistry, Western blot and real time-PCR analyses on the myelin genes and proteins as well as microscopic examinations will be carried out. Finally, to determine the effect of hAMSCs conditioned medium on MMPs regulation, MMPs activity will be determined by MMPs activity assay.
hAMSCs have unique properties including inflammation suppression, angiogenesis promotion, oxidative stress inhibition, neurogenesis induction, neuroprotection, MMPs regulation, and remyelination stimulation, which are of potential therapeutic value for MS therapy. The anti-inflammatory feature of hAMSCs, along with their ability to promote neurogenesis and differentiation of progenitor cells to neurons, could make them valuable sources for prevention and therapy in both early and advanced stages of MS. hAMSCs possess other conspicuous characteristics to make them practical sources for cell-based therapies against MS, which are discussed further here in brief. The amniotic membrane, which will be obtained from elective Cesarean sections to eliminate contaminations, is an attractive source of MSCs since large quantities of hAMSCs could be cost-effectively collected without invasive procedures and ethical concerns (
To the best of our knowledge, no studies have focused on the unique properties of hAMSCs for MS therapy. Therefore, it is essential to investigate the potential therapeutic values of hAMSCs for MS.
hAMSCs and their conditioned medium could be of therapeutic value in MS therapy due to their unique properties including immunomodulation and inflammation suppression; angiogenesis promotion; oxidative stress inhibition; neurogenesis induction and neuroprotection; MMPs regulation; and remyelination stimulation. Therefore, it is required to evaluate the hypothesis in future
MA-K, S-HG, FS, and HN hypothesized the idea, wrote the manuscript and revised it. SB revised the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Research reported in this publication was supported by Department of Pharmacology of School of Medicine, Shahid Beheshti University of Medical Sciences and Researcher Grant Committee under award number [963951] from the National Institutes for Medical Research Development (NIMAD), Tehran, Iran. Authors would also like to express their most sincere words of appreciation to Professor Heinz Redl, Dr. Susanne Wolbank, and Ms. Tahereh Tayebi for their valuable contribution.