The pros and cons of MSC-based therapies.
Abstract
Imbalance in immune responses plays an indispensable role in pathogenesis and development of multiple sclerosis (MS), as a neurodegenerative disorder. Current treatments are not always successful in preventing MS development and treating the disease. Stem cell-based cell therapy has provided a new window for treating neurodegenerative disorders. Stem cells can regulate the immune system and improve axonal remyelination. They can be isolated from different origins such as bone marrow, embryonic, neural, and adipose tissues. However, there is a challenge in choosing the best cell source for stem cell therapy. Mesenchymal stem cells (MSCs) derived from different origins have significant immunoregulatory impacts on different cells from the immune system. A growing body of evidence indicates that adipose tissue and umbilical cord can be a suitable source for obtaining MSCs. Moreover, human amniotic epithelial cell (hAEC), as a novel stem cell with immunoregulatory effects, regenerative effects, and low antigenicity, can be a candidate for MS treatment. This chapter discusses therapeutic impacts of MSCs and hAECs in MS disease.
Keywords
- multiple sclerosis
- mesenchymal stem cell
- human amniotic epithelial cell
- regenerative impacts
- immunomodulatory effects
1. Introduction
Neurodegenerative disorders are considered as a chronic and progressive inflammatory condition resulting in the deposition of abnormal forms of specific proteins in the nervous system and destruction of neurons in motor, sensory, or cognitive systems [1, 2]. These disorders mainly involve women and are observed in subjects with age ranging from 20 to 30 years [3]. It is reported that more than 2.5 million individuals suffer from multiple sclerosis (MS) around the world who require effective therapeutic approaches to control disability and recover the central nervous system (CNS) functions [3]. The major problem of the management of the disease is the lack of successful regeneration of neurons [4].
Until now, several therapeutic approaches for MS have been suggested to control abnormal immune responses including natalizumab, interferon-β (IFN-β), glatiramer acetate, and fingolimod (FTY720). These treatments mainly exert their inhibitory effects on immune reactions and thereby reduce the number of relapses and modulate the progression of neurologic disability. However, they have not been consistently successful and are suitable in arresting the disease in approximately 30% of relapsing-remitting (RR) MS patients as the most common form of MS [5, 6]. It is reported that these treatments fail to control the degeneration of nerve tissue in an aggressive form of MS [7]. Among these approaches, stem cell-based therapies show a hopeful outlook for decreasing neural damages in the neurological diseases through regenerative roles for remyelination, the secretions of neurotrophic mediators with immunomodulatory impacts, and differentiation into astrocytes and oligodendrocytes effectively
2. MS and its pathogenesis
Multiple sclerosis (MS) is the most common non-traumatic disabling disease, resulting in axonal loss and myelin disruption. The frequent features of MS are formations of lesions and sclerotic plaques in the central nervous system (CNS) and the cerebrospinal cord. The immune system plays a critical role in neural evolution through regulating oligodendrogenesis, neurogenesis, and synaptic organization. Therefore, immune cells can participate in the pathogenesis and development of MS [19, 20]. The pathogenesis of MS is largely related to hormone, environmental, and genetic factors. It is reported that alterations in expressions and functions of some immune agents such as major histocompatibility complex (MHC), immunoglobulin (Ig), T-cell receptor (TCR), and cytokines can contribute to the increased risk of MS [6, 21]. Today, studies on MS have indicated that autoreactive T-cell migration to the CNS occurs upon autoimmune cascade initiation and blood-brain barrier (BBB) disruption, which leads to destroy myelin sheath and creates sclerotic lesions and plaques [6, 22]. Destruction of the myelin sheath, which plays a significant role in survival and integration of axon, is a major reason for the development of MS [3]. T helper 1 (Th1) and T helper 17 (Th17) cells are the main effector cells that participate in the demyelination and destruction of the CNS [19, 20]. Th1 and Th17 produce some pro-inflammatory cytokines, including inerleukine-1 (IL-1), IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) [23]. Moreover, CD8+ T cells are found in MS lesions, especially around the blood vessels. Previous studies have revealed that the proliferation of CD8+ T cell in patients with MS is more than CD4+ T cell, which is largely associated with axon injury [1]. Besides the roles of T cells in the pathogenesis of MS, other immune cells play important roles in the formations of lesions and plaques. The activation of macrophage by Th1 cytokines leads to the destruction of the myelin and thereby exposes more CNS antigens. Although it is demonstrated that autoreactive T cells are the major effector cells for the pathogenesis of MS, some reports have indicated that autoreactive B cells have critical roles in disappearing the myelin sheaths and axonal loss, through cytokine secretions, antigen presentations, and autoantibody productions [24]. Autoantibodies can be major immune mediators that can be found in MS plaques. There are some reports pointing toward the association of immunoglobulin G (IgG) with MS signs. Furthermore, it is shown that IgG, especially IgG against proteolipid proteins (PLP) and myelin basic proteins (MBP), can be considered as the features of the disease, although their roles in MS pathogenesis are not well identified yet (Figure 1) [25].
![](http://cdnintech.com/media/chapter/86212/1687329894/media/F1.png)
Figure 1.
The impacts of immune responses in MS pathogenesis.
3. Mesenchymal stem cells
MSCs can be obtained from different tissues such as bone marrow, adipose tissue, umbilical cord, brain, dental tissue, and fetal lung [26, 27, 28]. MSCs can differentiate into monocytes and neurons
![](http://cdnintech.com/media/chapter/86212/1687329894/media/F2.png)
Figure 2.
Immunoregulatory and therapeutic effects of MSCs.
4. Human bone marrow-derived MSCs (hBM-MSCs)
MSCs obtained from bone marrow have multiple properties, which make them an attractive cell source for therapeutic applications (Table 1). These cells are the most frequent cell sources used in clinical settings [49]. Given therapeutic features of hBM-MSCs in neurological disorders, it is revealed that they can promote disease recovery in relapsing-remitting and chronic types of MS in EAE mice, due perhaps to reduce demyelination regions and inflammatory infiltrates, induce oligodendrogenesis, and enhance brain-derived neurotrophic factor (BDNF) production [65]. Several studies have reported that BM-MSCs have immunomodulatory effects in EAE through preventing the maturation of antigen-presenting cells (APCs) and proliferation of B and T cells [39]. These immunosuppressive impacts are mainly mediated by releasing various bioactive mediators [66]. Moreover, their neuroprotective effects can induce local progenitor cells and suppress scar creation, gliosis, and neuron apoptosis [67]. Besides having immunomodulatory impacts, they have the ability to differentiate into the neurons and improve the replacement of the cells [67]. Nonetheless, the isolation of BM-MSC is painful, invasive, and low efficiency [45], which may be considered a disadvantage in their clinical applications
Different sources of MSCs | Advantages | Disadvantages |
---|---|---|
hBM-MSCs |
| |
hUC-MSCs |
| |
AD-MSCs | ||
hAECs |
Table 1.
5. Human umbilical cord (hUC)-MSCs
HUC-MSCs have significant characteristics, which distinguish them from other sources of MSCs (Table 1). Several lines of evidence suggest the administration of hUC-MSCs in autoimmune disorders such as encephalomyelitis, type 1 diabetes, and rheumatoid arthritis due to its immunoregulatory impacts [68, 69, 70, 71]. Immunomodulatory effects of these cells have fundamental roles in tissue recovery [72]. They have the decreased expression of HLA-I, increased capacity of proliferation, and more rapid growth
![](http://cdnintech.com/media/chapter/86212/1687329894/media/F3.png)
Figure 3.
Immunomodulatory and therapeutic impacts of hUC-MSCs.
6. Human adipose-derived MSCs (AD-MSCs)
AD-MSC can be obtained from adipose tissue by collagenase digests. Adipose tissue contains high levels of MSCs (approximately 100–1000 MSCs per gram of fat) and is easily accessible for use. Thus, this tissue is an important source of the cell for cellular therapy. AD-MSCs show the adipogenic, cardiogenic, neurogenic, myogenic, chondrogenic, and osteogenic features
![](http://cdnintech.com/media/chapter/86212/1687329894/media/F4.png)
Figure 4.
Immunoregulatory and therapeutic impacts of AD-MSCs in degenerative disorders.
7. Human amniotic epithelial cells (hAECs)
hAECs are easily isolated from the amniotic membrane, the inner layer of the fetal membranes, and possess some stem cell-like properties [83, 84, 85, 86]. These cells express some markers of pluripotent stem cells, including FGF-T, Sox-2, Nanog, Rex-1, SSEA-4, and Oct4. Some of these markers have important roles in pluripotency and self-renewal properties in induced pluripotent stem (iPS) cells and embryonic stem cells (ESCs) [87]. hAEC can differentiate into different cells such as the pancreatic cells, neural cells, hepatocytes, cardiomyocytes, adipocytes, and myocytes, which originate from the endoderm, ectoderm, and mesoderm [18]. It is reported that hAECs have immunomodulatory impacts on adaptive and innate immune systems [17, 88, 89]. They exert suppressive effects on the activations of natural killer (NK) and CD4+ T cells, migrations of neutrophil and macrophage, secretions of pro-inflammatory cytokines of CD4+ T cells, and proliferation of B cells [23, 61, 90, 91]. These impacts are primarily mediated through the productions of immunoregulatory mediators, such as IL-4, PG-E2, and transforming growth factor-beta (TGF-β), which may participate in the increase of Tregs and Th2 cells, inhibition of pathogenic T-cell reactions, and protection of the peripheral naive CD4+ T-cell source [61, 63, 92, 93, 94, 95]. These effects suggest that hAECs may be considered as an effective cell source for MS treatment [62, 95]. To support this notion, they can contribute to a shift from Th1-type responses to Th2-type responses [95]. EAE mice treated with hAECs experienced significant reductions in demyelination and immune infiltration into the CNS [95]. It is indicated that hAECs have a negative effect on Th17 differentiation through reducing the productions of TGF-β and IL-6, which play indispensable roles in the differentiation of these cells [88]. Studies on animal models of MS have revealed that alpha-fetoprotein (AFP) produced from hAECs participates in the reduction of lymphocyte function and neuroinflammation [96, 97]. Others have indicated that these cells can reduce gray and white matter damages through residing in inflammation locations such as the brain [98]. Furthermore, they can release neurotrophic agents such as neurotrophin-3 (NT-3), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) (Figure 5) [59, 60]. These features along with low antigenicity provide additional confirmations to clarify therapeutic properties of hAECs in the treatment and management of inflammatory neurological disorders such as MS [99]. hAECs possess a limited proliferative potential due perhaps to the lack of telomerase [87, 92, 100, 101], which helps to reduce potential tumorigenicity of stem cell-based therapies. Nevertheless, it should be noted that further works and more information are needed to illustrate the possible capability of these cells in treating diseases with immune pathophysiology.
![](http://cdnintech.com/media/chapter/86212/1687329894/media/F5.png)
Figure 5.
Immunomodulatory and stem cell characteristics of hAECs.
8. Comparison of hAECs with MSCs derived from different sources
There are some differences and similarities between hAECs and MSCs derived from different sources, for example, morphologic and tumorigenic properties, immunoregulatory characteristics, angiogenesis capacities, and ethical issues associated with their isolations and applications [45, 102]. In line with morphology, hAECs show a cobblestone-like morphology, while the cultured hAMSCs have a spindle fibroblast-like morphology [103]. The morphologic feature of the cultured MSCs derived from BM can range from fibroblast-like spindle-shaped cells to large flat cells [104]. MSCs from other sources, such as AD-MSCs and hUC-MSCs, indicate spindle shapes in the culture [105, 106]. The amniotic membrane can be collected by standard isolation methods following cesarean section, which is not invasive and does not have unfavorable effects on human embryos and ethical issues [102]. The isolation of amniotic cells can simply be performed upon prenatal testing. However, there are some ethical problems in regard to clinical applications of MSCs and the isolation of some sources of MSCs [104, 107]. As mentioned above, the isolation of hBM-MSCs is done by invasive techniques with low efficiency, which is painful [45]. Today, there is no document pointing to the tumorigenicity of amnion membrane or membrane-originated cells after clinical applications [17]. However, some reports have shown that MSCs may raise tumor growth in some cancer mouse models [108]. Several lines of evidence propose that hAECs, BM-MSCs, and AD-MSCs participate in enhancing angiogenesis through the productions of some cytokines and angiogenic factors, such as VEGF, HGF, and EGF, and mechanisms associated with protease [103, 109]. According to evidence, hAECs possess better immunomodulatory impacts but lesser osteogenic effects than BM-MSCs and MSCs derived from the human amniotic fluid (hAF) [110]. hAECs express some MSC markers such as CD90, CD44, and CD105. However, the levels of SSEA4 and SSEA3 expressions are higher on hAECs than those on hBM-MSCs and hAFMSC, revealing more multipotent potential of these cells [17, 111]. Furthermore, hAECs and hAFMSC possess higher levels of PD-L1 and PD-L2 than hBM-MSCs, which may make them more successful in providing peripheral tolerance in immune cells [110, 112].
9. Mesenchymal stem cell-based cell therapy and clinical trials
Until now, several clinical trials were carried out using MSCs as a therapeutic approach for MS. In a phase II clinical trial, intravascular MSCs were employed in the treatment of nine relapsing-remitting multiple sclerosis (RRMS) patients. After 6 months, the results revealed a significant reduction in MS lesions in magnetic resonance imaging (MRI) [67]. In a phase IIa clinical trial, autologous BM-MSCs were injected to one RRMS and nine secondary progressive multiple sclerosis (SPMS) patients. After 3 months to 1 year, authors observed that BM-MSCs improved clinical features in the treated patients. In this clinical trial, 10 SPMS patients were treated with intravascular MSCs for 6 months, and the results revealed neuroprotection effect of MSCs and remyelination [67]. Furthermore, in a study conducted by Bonab et al., in 2007, therapeutic impacts of intrathecal injection of MSC were studied on 10 MS patients. This study indicated that the disease progression was gradually reduced in half of the participants [113]. Another study on 22 patients with primary progressive multiple sclerosis (PPMS) demonstrated that intravascular and intrathecal injections of BM-MSCs were effective in MS treatment [35]. In a triple-blind and placebo-controlled study on 30 patients with SPMS, the researchers indicated that AD-MSC injection is a possible and safe method in the treatment of SPMS patients [114]. Staff et al
10. Conclusion
There are many documents pointing to stem cell-based cell therapy as a treatment for MS and other neurological disorders. However, an inconsistency in the results of these studies is observed. Among different types of stem cells, MSCs are more possible to consider as a therapeutic approach for MS treatment because they utilize different mechanisms involved in regulating immune responses and repairing CNS damages. Furthermore, MSCs have anti-oxidant and anti-apoptotic properties and trophic factor secretion, which exert positive effects on the axon and neural stability. Numerous studies have recommended that MSCs derived from umbilical cord and adipose tissue can be more effective for stem cell therapy. Moreover, hAECs are mentioned as a novel source of the cells, which have immunoregulatory effects and show a potential for differentiation into the cells originating from three germinal layers. Consequently, hAECs may be considered a therapeutic method to manage and control MS. However, more experimental studies should be done to illustrate their efficiency and mechanisms involved in the treatment of MS.
Conflicts of interest
The authors declare that there is no conflict of interest.
Finding
This study was not financially supported and was performed in personal capacity.
References
- 1.
Martin JB. Molecular basis of the neurodegenerative disorders. The New England Journal of Medicine. 1999; 340 (25):1970-1980 - 2.
ArefNezhad R, Motedayyen H, Mohammadi A. Therapeutic aspects of mesenchymal stem cell-based cell therapy with a focus on human amniotic epithelial cells in multiple sclerosis: A mechanistic review. International Journal of Stem Cells. 2021; 14 (3):241-251 - 3.
Bejargafshe MJ, Hedayati M, Zahabiasli S, Tahmasbpour E, Rahmanzadeh S, Nejad-Moghaddam A. Safety and efficacy of stem cell therapy for treatment of neural damage in patients with multiple sclerosis. Stem cell Investigation. 2019; 6 :44 - 4.
Minzenberg MJ. Dousing the flames to repair brains. Science Translational Medicine. 2010; 2 :27ec60-27ec60 - 5.
Yousefi F, Arab FL, Saeidi K, Amiri H, Mahmoudi MJ. Various Strategies to Improve Efficacy of Stem Cell Transplantation in Multiple Sclerosis: Focus on Mesenchymal Stem Cells and Neuroprotection. Journal of neuroimmunology. 2019; 328 :20-34 - 6.
Bejargafshe MJ, Hedayati M, Zahabiasli S, Tahmasbpour E, Rahmanzadeh S, Nejad-Moghaddam A. Safety and Efficacy of Stem Cell Therapy for Treatment of Neural Damage in Patients with Multiple Sclerosis. Stem Cell Investigation. 2019; 6 :44 - 7.
Ghasemi N. Therapeutic effects of adipose derived mesenchymal stem cells on remyelination process in inflammatory demyelinating diseases. Channels. 2015; 4 :6 - 8.
Abdallah AN, Shamaa AA, El-Tookhy OS. Evaluation of treatment of experimentally induced canine model of multiple sclerosis using laser activated non-expanded adipose derived stem cells. Research in Veterinary Science. 2019; 125 :71-81 - 9.
Nguyen H, Zarriello S, Coats A, Nelson C, Kingsbury C, Gorsky A, et al. Stem cell therapy for neurological disorders: A focus on aging. Neurobiology of Disease. 2019; 126 :85-104 - 10.
Pouryousefi-Koodehi T, Shayegan S, Hashemi S, Arefnezhad R, Roghani-Shahraki H, Motedayyen H, et al. Can mesenchymal stem cells derived from adipose tissue and their conditioned medium improve ovarian functions? A mini-review. Zygote. 2022; 2022 :1-4 - 11.
Nguyen H, Zarriello S, Coats A, Nelson C, Kingsbury C, Gorsky A, et al. Stem Cell Therapy for Neurological Disorders: A Focus on Aging. Neurobiology of disease. 2019; 126 :85-104 - 12.
Namchaiw P, Wen H, Mayrhofer F, Chechneva O, Biswas S, Deng W. Temporal and partial inhibition of GLI1 in neural stem cells (NSCs) results in the early maturation of NSC derived oligodendrocytes in vitro. Stem Cell Research & Therapy. 2019; 10 (1):272 - 13.
Mansoor SR, Zabihi E, Ghasemi-Kasman M. The potential use of mesenchymal stem cells for the treatment of multiple sclerosis. Life sciences. 2019; 235 :1-8 - 14.
Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, et al. Inflammatory CNS demyelination: Histopathologic correlation with in vivo quantitative proton MR spectroscopy. American Journal of Neuroradiology. 1999; 20 (9):1619-1627 - 15.
Akle C, Welsh K, Adinolfi M, Leibowitz S, McColl I. Immunogenicity of human amniotic epithelial cells after transplantation into volunteers. The Lancet. 1981; 318 (8254):1003-1005 - 16.
Darlington PJ, Boivin M-N, Bar-Or A. Harnessing the therapeutic potential of mesenchymal stem cells in multiple sclerosis. Expert Review of Neurotherapeutics. 2011; 11 (9):1295-1303 - 17.
Miki T, Lehmann T, Cai H, Stolz DB, Strom SC. Stem cell characteristics of amniotic epithelial cells. Stem Cells. 2005; 23 (10):1549-1559 - 18.
Motedayyen H, Zarnani A-H, Tajik N, Ghotloo S, Rezaei A. Immunomodulatory effects of human amniotic epithelial cells on naive CD4+ T cells from women with unexplained recurrent spontaneous abortion. Placenta. 2018; 71 :31-40 - 19.
Rahmati M, Ghannadian SM, Kasiri N, Ahmadi L, Motedayyen H, Shaygannejad V, et al. Modulation of Th17 proliferation and IL-17A gene expression by acetylated form of apigenin in patients with multiple sclerosis. Immunological Investigations. 2020; 2020 :1-14 - 20.
Sedaghat N, Motedayyen H, Alsahebfosoul F, Etemadifar M, Ostadi V, Kianpour F, et al. Increased expression of lymphocyte activation gene-3 by regulatory t cells in multiple sclerosis patients with fingolimod treatment multiple sikleroz hastalar ฤ ฑ nda fingolimod tedavisi sonucu d ร ผ zenleyici t h ร ผ crelerinde lenfosit aktivasyon gen-3 ekspresyonunda art ฤ ฑ ล. Turkish Journal of Immunology. 2019; 7 (1):31-39 - 21.
Imitola J. Regenerative neuroimmunology: The impact of immune and neural stem cell interactions for translation in neurodegeneration and repair. Journal of Neuroimmunology. 2019; 331 :1-3 - 22.
Yousefi F, Arab FL, Saeidi K, Amiri H, Mahmoudi M. Various strategies to improve efficacy of stem cell transplantation in multiple sclerosis: Focus on mesenchymal stem cells and neuroprotection. Journal of Neuroimmunology. 2019; 328 :20-34 - 23.
Motedayyen H, Rezaei A, Zarnani A-H, Tajik N. Human amniotic epithelial cells inhibit activation and pro-inflammatory cytokines production of naive CD4+ T cells from women with unexplained recurrent spontaneous abortion. Reproductive Biology. 2018; 18 (2):182-188 - 24.
Sedaghat NMH, Etemadifar M, Zarkesh H, Kianpour F, Vestri E, et al. Effect of Fingolimod on the frequency of regulatory T cells in patients with relapsing-remitting multiple sclerosis. Journal of Immune Research. 2018; 1 (5):1032 - 25.
Pirttilä T, Nurmikko T. CSF oligoclonal bands, MRI, and the diagnosis of multiple sclerosis. Acta Neurologica Scandinavica. 1995; 92 (6):468-471 - 26.
Markarian CF, Frey GZ, Silveira MD, Milani AR, Ely PB, Horn AP, et al. Isolation of adipose-derived stem cells: A comparison among different methods. Biotechnology Letters. 2014; 36 (4):693-702 - 27.
Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, Tsuji K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells. 2004; 22 (5):649-658 - 28.
Schwab KE, Hutchinson P, Gargett CE. Identification of surface markers for prospective isolation of human endometrial stromal colony-forming cells. Human Reproduction. 2008; 23 (4):934-943 - 29.
Xu C, Diao Y-F, Wang J, Liang J, Xu H-H, Zhao M-L, et al. Intravenously infusing the secretome of adipose-derived mesenchymal stem cells ameliorates neuroinflammation and neurological functioning after traumatic brain injury. Stem Cells and Development. 2020; 29 (4):222-234 - 30.
Song C-G, Zhang Y-Z, Wu H-N, Cao X-L, Guo C-J, Li Y-Q , et al. Stem cells: A promising candidate to treat neurological disorders. Neural Regeneration Research. 2018; 13 (7):1294 - 31.
Samper Agrelo I, Schira-Heinen J, Beyer F, Groh J, Bütermann C, Estrada V, et al. Secretome analysis of mesenchymal stem cell factors fostering Oligodendroglial differentiation of neural stem cells In vivo. International Journal of Molecular Sciences. 2020; 21 (12):4350 - 32.
Jaramillo-Merchan J, Jones J, Ivorra J, Pastor D, Viso-León M, Armengol JA, et al. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model. Cell Death & Disease. 2013; 4 (8):e779 - 33.
Forte A, Finicelli M, Mattia M, Berrino L, Rossi F, De Feo M, et al. Mesenchymal stem cells effectively reduce surgically induced stenosis in rat carotids. Journal of Cellular Physiology. 2008; 217 (3):789-799 - 34.
Peng Z, Gao W, Yue B, Jiang J, Gu Y, Dai J, et al. Promotion of neurological recovery in rat spinal cord injury by mesenchymal stem cells loaded on nerve-guided collagen scaffold through increasing alternatively activated macrophage polarization. Journal of Tissue Engineering and Regenerative Medicine. 2018; 12 (3):e1725-e1e36 - 35.
Brück W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmarch HA, et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1995; 38 (5):788-796 - 36.
Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, Lazarus H, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: Consensus report of the International MSCT Study Group. Multiple Sclerosis Journal. 2010; 16 (4):503-510 - 37.
Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: An update. Cell Transplantation. 2016; 25 (5):829-848 - 38.
Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L. Mesenchymal stromal cells of the bone marrow and natural killer cells: Cell interactions and cross modulation. Journal of Cell Communication and Signaling. 2018; 12 (4):673-688 - 39.
Liu X, Ren S, Qu X, Ge C, Cheng K, Zhao RCH. Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-γ-mediated SOCS3 activation. Immunologic Research. 2015; 61 (3):219-229 - 40.
Wang D, Huang S, Yuan X, Liang J, Xu R, Yao G, et al. The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cellular & Molecular Immunology. 2017; 14 (5):423-431 - 41.
Selmani Z, Naji A, Gaiffe E, Obert L, Tiberghien P, Rouas-Freiss N, et al. HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells. Transplantation. 2009; 87 (9S):S62-SS6 - 42.
Lu Z, Chang W, Meng S, Xu X, Xie J, Guo F, et al. Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury. Stem Cell Research & Therapy. 2019; 10 (1):1-16 - 43.
Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Research & Therapy. 2011; 2 (4):34 - 44.
Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. The Lancet Neurology. 2011; 10 (7):649-656 - 45.
Quirici N, Soligo D, Bossolasco P, Servida F, Lumini C, Deliliers GL. Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies. Experimental Hematology. 2002; 30 (7):783-791 - 46.
Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, et al. Long-term cultures of bone marrow–derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Research. 2009; 69 (13):5331-5339 - 47.
Huang X-P, Sun Z, Miyagi Y, McDonald Kinkaid H, Zhang L, Weisel RD, et al. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation. 2010; 122 (23):2419-2429 - 48.
Ding Y, Yang H, Feng JB, Qiu Y, Li DS, Zeng Y. Human umbilical cord-derived MSC culture: The replacement of animal sera with human cord blood plasma. In Vitro Cellular & Developmental Biology. Animal. 2013; 49 (10):771-777 - 49.
Musiał-Wysocka A, Kot M, Majka M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transplantation. 2019; 28 (7):801-812 - 50.
Dong H, Li G, Shang C, Yin H, Luo Y, Meng H, et al. Umbilical cord mesenchymal stem cell (UC-MSC) transplantations for cerebral palsy. American Journal of Translational Research. 2018; 10 (3):901 - 51.
Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. Journal of Translational Medicine. 2011; 9 (1):1-14 - 52.
Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochemical and Biophysical Research Communications. 2013; 431 (2):203-209 - 53.
Mazini L, Rochette L, Amine M, Malka G. Regenerative capacity of adipose derived stem cells (ADSCs), comparison with mesenchymal stem cells (MSCs). International Journal of Molecular Sciences. 2019; 20 (10):2523 - 54.
Chen G, Yue A, Ruan Z, Yin Y, Wang R, Ren Y, et al. Monitoring the biology stability of human umbilical cord-derived mesenchymal stem cells during long-term culture in serum-free medium. Cell and Tissue Banking. 2014; 15 (4):513-521 - 55.
Kashani IR, Hedayatpour A, Pasbakhsh P, Kafami L, Atlasi N, Mahabadi VP, et al. 17β-Estradiol enhances the efficacy of adipose-derived mesenchymal stem cells on remyelination in mouse model of multiple sclerosis. Acta Medica Iranica. 2012; 2012 :789-797 - 56.
Dai R, Wang Z, Samanipour R, Koo K-i, Kim K. Adipose-derived stem cells for tissue engineering and regenerative medicine applications. Stem Cells International. 2016; 2016 :1-19 - 57.
Kim J-H, Jo CH, Kim H-R, Hwang Y-i. Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue. Stem Cells International. 2018; 2018 :1-13 - 58.
Motedayyen H, Esmaeil N, Tajik N, Khadem F, Ghotloo S, Khani B, et al. Method and key points for isolation of human amniotic epithelial cells with high yield, viability and purity. BMC Research Notes. 2017; 10 (1):1-8 - 59.
Uchida S, Suzuki Y, Araie M, Kashiwagi K, Otori Y, Sakuragawa N. Factors secreted by human amniotic epithelial cells promote the survival of rat retinal ganglion cells. Neuroscience Letters. 2003; 341 (1):1-4 - 60.
Xt M, Chen D, Dong, y Z, Liu J. Enhanced neural differentiation of neural stem cells and neurite growth by amniotic epithelial cell co-culture. Cell Biology International. 2007; 31 (7):691-698 - 61.
Taheri RA, Motedayyen H, Ghotloo S, Masjedi M, Mosaffa N, Mirshafiey A, et al. The effect of lipopolysaccharide on the expression level of immunomodulatory and immunostimulatory factors of human amniotic epithelial cells. BMC Research Notes. 2018; 11 (1):1-5 - 62.
McDonald CA, Payne NL, Sun G, Moussa L, Siatskas C, Lim R, et al. Immunosuppressive potential of human amnion epithelial cells in the treatment of experimental autoimmune encephalomyelitis. Journal of Neuroinflammation. 2015; 12 (1):1-14 - 63.
Xu H, Zhang J, Tsang KS, Yang H, Gao W-Q. Therapeutic potential of human amniotic epithelial cells on injuries and disorders in the central nervous system. Stem Cells International. 2019; 2019 :1-12 - 64.
Li J-Y, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends in Neurosciences. 2008; 31 (3):146-153 - 65.
Ryu CH, Park KY, Hou Y, Jeong CH, Kim SM, Jeun S-S. Gene therapy of multiple sclerosis using interferon β-secreting human bone marrow mesenchymal stem cells. BioMed Research International. 2013; 2013 :1-10 - 66.
Patel SA, Sherman L, Munoz J, Rameshwar P. Immunological properties of mesenchymal stem cells and clinical implications. Archivum Immunologiae et Therapiae Experimentalis. 2008; 56 (1):1-8 - 67.
Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study. Journal of Neuroimmunology. 2010; 227 (1-2):185-189 - 68.
Hu J, Yu X, Wang Z, Wang F, Wang L, Gao H, et al. Long term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Endocrine Journal. 2012; 2021 :EJ12 - 69.
Li J-F, Yin H-L, Shuboy A, Duan H-F, Lou J-Y, Li J, et al. Differentiation of hUC-MSC into dopaminergic-like cells after transduction with hepatocyte growth factor. Molecular and Cellular Biochemistry. 2013; 381 (1):183-190 - 70.
Liu R, Zhang Z, Lu Z, Borlongan C, Pan J, Chen J, et al. Human umbilical cord stem cells ameliorate experimental autoimmune encephalomyelitis by regulating immunoinflammation and remyelination. Stem Cells and Development. 2013; 22 (7):1053-1062 - 71.
Tavakoli A, Kahrizi MS, Safa K, ArefNezhad R, Rezaei-Tazangi F. Umbilical cord mesenchymal stem cells and breast cancer: A good therapeutic candidate or not? A minireview. Molecular Biology Reports. 2022; 2022 :1-6 - 72.
Rong L, Chi Y, Yang S, Chen D, Chen F, Xu S, et al. Effects of interferon-γ on biological characteristics and immunomodulatory property of human umbilical cord-derived mesenchymal stem cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012; 20 (2):421-426 - 73.
Lu Z, Zhao H, Xu J, Zhang Z, Zhang X. Human umbilical cord mesenchymal stem cells in the treatment of secondary progressive multiple sclerosis. Journal of Stem Cell Research Theraphy. 2013; 6 :2 - 74.
Yang H, Yang H, Xie Z, Wei L, Bi J. Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AβPPswe/PS1dE9 transgenic mice. PLoS One. 2013; 8 (7):1-10 - 75.
Yang H, Sun J, Wang F, Li Y, Bi J, Qu T. Umbilical cord-derived mesenchymal stem cells reversed the suppressive deficiency of T regulatory cells from peripheral blood of patients with multiple sclerosis in a co-culture–a preliminary study. Oncotarget. 2016; 7 (45):72537 - 76.
Mazini L, Rochette L, Amine M, Malka GJIjoms. Regenerative capacity of adipose derived stem cells (ADSCs). Comparison with Mesenchymal Stem Cells (MSCs). 2019; 20 (10):2523 - 77.
Stepien A, Dabrowska NL, Maciagowska M, Macoch RP, Zolocinska A, Mazur S, et al. Clinical application of autologous adipose stem cells in patients with multiple sclerosis: Preliminary results. Mediators of Inflammation. 2016; 2016 :1-6 - 78.
Gadelkarim M, Abushouk AI, Ghanem E, Hamaad AM, Saad AM, Abdel-Daim MM. Adipose-derived stem cells: Effectiveness and advances in delivery in diabetic wound healing. Biomedicine & Pharmacotherapy. 2018; 107 :625-633 - 79.
Chi K, Fu R-H, Huang Y-C, Chen S-Y, Hsu C-J, Lin S-Z, et al. Adipose-derived stem cells stimulated with n-butylidenephthalide exhibit therapeutic effects in a mouse model of Parkinson’s disease. Cell Transplantation. 2018; 27 (3):456-470 - 80.
Li J, Chen Y, Chen Z, Huang Y, Yang D, Su Z, et al. Therapeutic effects of human adipose tissue-derived stem cell (hADSC) transplantation on experimental autoimmune encephalomyelitis (EAE) mice. Scientific Reports. 2017; 7 (1):1-10 - 81.
Ghasemi N, Razavi S, Mardani M, Esfandiari E, Salehi H, Esfahani SHZ. Transplantation of human adipose-derived stem cells enhances remyelination in lysolecithin-induced focal demyelination of rat spinal cord. Molecular Biotechnology. 2014; 56 (5):470-478 - 82.
Tomita K, Madura T, Mantovani C, Terenghi G. Differentiated adipose-derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation. Journal of Neuroscience Research. 2012; 90 (7):1392-1402 - 83.
Motedayyen H, Rezaei A, Zarnani A-H, Tajik NJRb. Human amniotic epithelial cells inhibit activation and pro-inflammatory cytokines production of naive CD4+ T cells from women with unexplained recurrent spontaneous abortion. 2018; 18 (2):182-188 - 84.
Li H, Niederkorn JY, Neelam S, Mayhew E, Word RA, McCulley JP, et al. Immunosuppressive factors secreted by human amniotic epithelial cells. 2005; 46 (3):900-907 - 85.
Insausti CL, Blanquer M, García-Hernández AM, Castellanos G, Moraleda JM, et al. Amniotic membrane-derived stem cells: immunomodulatory properties and potential clinical application. 2014; 7 :53 - 86.
Fathi F, Atapour A, Eskandari N, Keyhanmehr N, Hafezi H, Mohammadi S, et al. Regulatory T-cells and their impacts on cytokine profile of end-stage renal disease patients suffering from systemic lupus erythematosus. International Journal of Immunopathology and Pharmacology. 2019; 33 :2058 - 87.
Yang P-j, Yuan W-x, Liu J, Li J-y, Tan B, Qiu C, et al. Biological characterization of human amniotic epithelial cells in a serum-free system and their safety evaluation. Acta Pharmacologica Sinica. 2018; 39 (8):1305-1316 - 88.
McDonald CA, Short M, Jenkin G, Bernard CCA. The Potential of Human Amnion Epithelial Cells as an Immunomodulatory and Neuroregenerative Treatment for Multiple Sclerosis. Perinatal stem cells. Springer; 2014:231-242 - 89.
Li H, Niederkorn JY, Neelam S, Mayhew E, Word RA, McCulley JP, et al. Immunosuppressive factors secreted by human amniotic epithelial cells. Investigative Ophthalmology & Visual Science. 2005; 46 (3):900-907 - 90.
Alipour R, Motedayyen H, Sereshki N, Rafiee M, Alsahebfosul F, Pourazar A. Human amniotic epithelial cells affect the functions of neutrophils. International Journal of Stem Cells. 2020; 13 (2):212-220 - 91.
İnsan TGKOK, Öldürücü AEHD. Immunoregulatory effects of human amnion epithelial cells on natural killer and T cells in women with recurrent spontaneous abortion (RSA). Turkish Journal of Immunology. 2019; 7 (1):21-30 - 92.
McDonald CA, Payne NL, Sun G, Moussa L, Siatskas C, Lim R, et al. Immunosuppressive potential of human amnion epithelial cells in the treatment of experimental autoimmune encephalomyelitis. Journal of neuroinflammation. 2015; 12 (1):112 - 93.
Motedayyen H, Esmaeil N, Tajik N, Khadem F, Ghotloo S, Khani B, et al. Method and key points for isolation of human amniotic epithelial cells with high yield, viability and purity. BMC Research Notes. 2017; 10 (1):552 - 94.
Motedayyen H, Fathi F, Fasihi-Ramandi M, Taheri RA. The effect of lipopolysaccharide on anti-inflammatory and pro-inflammatory cytokines production of human amniotic epithelial cells. Reproductive Biology. 2018; 18 (4):404-409 - 95.
Liu YH, Vaghjiani V, Tee JY, To K, Cui P, Oh DY, et al. Amniotic epithelial cells from the human placenta potently suppress a mouse model of multiple sclerosis. PLoS One. 2012; 7 (4):e35758 - 96.
Han K, Lee J, Kwon S, Park S, Shim S, Kim H, et al. Human amnion-derived mesenchymal stem cells are a potential source for uterine stem cell therapy. Cell Proliferation. 2008; 41 (5):709-725 - 97.
Irony-Tur-Sinai M, Grigoriadis N, Tsiantoulas D, Touloumi O, Abramsky O, Brenner T. Immunomodulation of EAE by alpha-fetoprotein involves elevation of immune cell apoptosis markers and the transcription factor FoxP3. Journal of the Neurological Sciences. 2009; 279 (1-2):80-87 - 98.
Yawno T, Schuilwerve J, Moss TJ, Vosdoganes P, Westover AJ, Afandi E, et al. Human amnion epithelial cells reduce fetal brain injury in response to intrauterine inflammation. Developmental Neuroscience. 2013; 35 (2-3):272-282 - 99.
McDonald CA, Payne NL, Sun G, Moussa L, Siatskas C, Lim R, et al. Immunosuppressive potential of human amnion epithelial cells in the treatment of experimental autoimmune encephalomyelitis. Journal of Neuroinflammation. 2015; 12 (1):112 - 100.
Liu YH, Vaghjiani V, Tee JY, To K, Cui P, Oh DY, et al. Amniotic epithelial cells from the human placenta potently suppress a mouse model of multiple sclerosis. 2012; 7 (4):e35758 - 101.
Uchida S, Inanaga Y, Kobayashi M, Hurukawa S, Araie M, Sakuragawa NJ. Neurotrophic function of conditioned medium from human amniotic epithelial cells. Journal of neuroscience research. 2000; 62 (4):585-590 - 102.
Kim EY, Lee K-B, Kim MK. The potential of mesenchymal stem cells derived from amniotic membrane and amniotic fluid for neuronal regenerative therapy. BMB Reports. 2014; 47 (3):135 - 103.
Wu Q , Fang T, Lang H, Chen M, Shi P, Pang X, et al. Comparison of the proliferation, migration and angiogenic properties of human amniotic epithelial and mesenchymal stem cells and their effects on endothelial cells. International Journal of Molecular Medicine. 2017; 39 (4):918-926 - 104.
Motamedi B, Ibrahim T, Abdul A, Allaudin Z, Moshrefi M, Hajghani M, et al. Characteristics of human amniotic epithelial cells and bone marrow mesenchymal stem cells in a parallel study: Hanging drop colony formation and doubling time. Journal of Regenerated Medicine. 2015; 4 :2-10 - 105.
Wu K-C, Chang Y-H, Liu H-W, Ding D-C. Transplanting human umbilical cord mesenchymal stem cells and hyaluronate hydrogel repairs cartilage of osteoarthritis in the minipig model. Tzu-Chi Medical Journal. 2019; 31 (1):11 - 106.
Debnath T, Chelluri LK. Standardization and quality assessment for clinical grade mesenchymal stem cells from human adipose tissue. Hematology, Transfusion and Cell Therapy. 2019; 41 (1):7-16 - 107.
Serras ASM, Cipriano MZdRF, da Graça Silva PM, Miranda JPG. Challenges for Deriving Hepatocyte-like Cells from Umbilical Cord Mesenchymal Stem Cells for In Vitro Toxicology Applications. Novel Perspectives of Stem Cell Manufacturing and Therapies. 2020 - 108.
Xu Z, Wei W, Gagneur J, Perocchi F, Clauder-Münster S, Camblong J, et al. Bidirectional promoters generate pervasive transcription in yeast. Nature. 2009; 457 (7232):1033-1037 - 109.
Kachgal S, Putnam AJ. Mesenchymal stem cells from adipose and bone marrow promote angiogenesis via distinct cytokine and protease expression mechanisms. Angiogenesis. 2011; 14 (1):47-59 - 110.
Si J, Dai J, Zhang J, Liu S, Gu J, Shi J, et al. Comparative investigation of human amniotic epithelial cells and mesenchymal stem cells for application in bone tissue engineering. Stem Cells International. 2015; 2015 :1-15 - 111.
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 (2):300-311 - 112.
Banas RA, Trumpower C, Bentlejewski C, Marshall V, Sing G, Zeevi A. Immunogenicity and immunomodulatory effects of amnion-derived multipotent progenitor cells. Human Immunology. 2008; 69 (6):321-328 - 113.
Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F, et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iranian Journal of Immunology. 2007; 4 (1):50-57 - 114.
Fernández O, Izquierdo G, Fernández V, Leyva L, Reyes V, Guerrero M, et al. Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PLoS One. 2018; 13 (5):e0195891 - 115.
Staff NP, Madigan NN, Morris J, Jentoft M, Sorenson EJ, Butler G, et al. Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology. 2016; 87 (21):2230-2234 - 116.
Li J-F, Zhang D-J, Geng T, Chen L, Huang H, Yin H-L, et al. The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis. Cell Transplantation. 2014; 23 (1_suppl):113-122 - 117.
Riordan NH, Morales I, Fernández G, Allen N, Fearnot NE, Leckrone ME, et al. Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. Journal of Translational Medicine. 2018; 16 (1):1-12