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Hakak R, Poopak B, Majd A. Increased IDO expression and regulatory T cells in acute myeloid leukemia: implications for immune escape and therapeutic targeting. Blood Res 2024; 59:42. [PMID: 39695001 PMCID: PMC11655893 DOI: 10.1007/s44313-024-00048-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024] Open
Abstract
PURPOSE This study aimed to determine the frequency of regulatory T cells (Tregs) (CD4+/FOXP3+) and indoleamine 2,3-dioxygenase (IDO) expression in patients with acute myeloid leukemia (AML). METHODS This cross-sectional case-control study was conducted between Jan 2022 and Dec 2023. Bone marrow samples were collected from 20 healthy individuals and 15 patients with AML. Flow cytometry, real-time polymerase chain reaction (PCR), and western blotting were used to evaluate the frequency of Treg and IDO expression levels. RESULTS The Treg percentage among total lymphocytes was lower in the AML group than that in the normal group. However, Treg percentage among T-helper (Th) lymphocytes was significantly higher in the AML group than that in the normal group (p < 0.05). The mean IDO expression in the AML group was significantly higher than that in the normal group (p = 0.004). A significant relationship was observed between IDO expression and Treg percentage among Th lymphocytes in the AML group (correlation = 0.637; p = 0.003). Moreover, western blot analysis showed a significant increase in IDO protein intensity in the AML group compared with that in the control group (p < 0.001). A significant difference was observed between the IDO concentrations in the AML group and that in the control group (p < 0.001). In addition, a significant difference between TGF-β levels in the AML group and those in the control group (p < 0.01) was observed. CONCLUSION IDO inhibition using novel IDO inhibitors along with chemotherapy is a promising approach to overcome the immune escape mechanisms in patients with AML, who exhibit increased levels of IDO expression and Tregs.
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Affiliation(s)
- Raziyeh Hakak
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Behzad Poopak
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
- Payvand Clinical and Specialty Laboratory, Tehran, Iran.
| | - Ahmad Majd
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
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Zangiabadi I, Ilaghi M, Shamsara A, Eftekhar‐Vaghefi SH, Saheli M, Shabani M. Exploring the impact of acetylsalicylic acid and conditioned medium obtained from mesenchymal cells, individually and in combination, on cognitive function, histological changes, and oxidant-antioxidant balance in male rats with hippocampal injury. Brain Behav 2024; 14:e70010. [PMID: 39262160 PMCID: PMC11391022 DOI: 10.1002/brb3.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/16/2024] [Accepted: 08/03/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND The hippocampus is susceptible to damage, leading to negative impacts on cognition. Conditioned medium (CM) obtained from adipose tissue-derived mesenchymal stem cells (MSCs) and acetylsalicylic acid (ASA) have shown neuroprotective effects independently. This study explored the synergistic potential of ASA and CM from adipose-derived MSCs against hippocampal injury. METHODS Adult male Wistar rats received bilateral hippocampal ethidium bromide (EB) injections to induce hippocampal damage. Rats were treated with ASA and/or CM derived from adipose tissue MSCs every 48 h for 16 days. Behavioral tests (open field test, Morris water maze, novel object recognition, and passive avoidance), oxidative stress, Western blot analysis of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) expression, and hippocampal histological investigation were conducted. RESULTS Administration of EB caused impairments in spatial, recognition, and passive avoidance memory, as well as heightened oxidative stress, reduced BDNF/CDNF expression, and pyramidal cell loss in the hippocampal CA1 region. Administration of ASA, CM, or a combination of both mitigated these hippocampal damages and cognitive deficits, elevated BDNF and CDNF levels, and alleviated the CA1 necrosis caused by EB. Moreover, co-administering ASA and CM resulted in greater improvements in spatial memory compared to administering ASA alone, suggesting possible synergistic interactions. CONCLUSIONS The ability of ASA, CM obtained from adipose tissue-derived MSCs, and their combination therapy to alleviate hippocampal injuries highlights their promising therapeutic potential as a neuroprotection strategy against brain damage. Our findings provide preliminary evidence of the potential synergistic effects of ASA and CM, which warrants further investigations.
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Affiliation(s)
- Iman Zangiabadi
- Department of Anatomy, Afzalipour School of MedicineKerman University of Medical SciencesKermanIran
| | - Mehran Ilaghi
- Institute of Neuropharmacology, Kerman Neuroscience Research CenterKerman University of Medical SciencesKermanIran
| | - Ali Shamsara
- Department of Anatomy, Afzalipour School of MedicineKerman University of Medical SciencesKermanIran
- Institute of Neuropharmacology, Kerman Neuroscience Research CenterKerman University of Medical SciencesKermanIran
| | | | - Mona Saheli
- Department of Anatomy, Afzalipour School of MedicineKerman University of Medical SciencesKermanIran
| | - Mohammad Shabani
- Institute of Neuropharmacology, Kerman Neuroscience Research CenterKerman University of Medical SciencesKermanIran
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Mahmoud M, Abdel-Rasheed M, Galal ER, El-Awady RR. Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro. Stem Cell Rev Rep 2024; 20:175-205. [PMID: 37962697 PMCID: PMC10799834 DOI: 10.1007/s12015-023-10654-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 11/15/2023]
Abstract
Human adipose tissue-derived stem/stromal cells (hASCs) are adult multipotent mesenchymal stem/stromal cells with immunomodulatory capacities. Here, we present up-to-date knowledge on the impact of different experimental and donor-related factors on hASC immunoregulatory functions in vitro. The experimental determinants include the immunological status of hASCs relative to target immune cells, contact vs. contactless interaction, and oxygen tension. Factors such as the ratio of hASCs to immune cells, the cellular context, the immune cell activation status, and coculture duration are also discussed. Conditioning of hASCs with different approaches before interaction with immune cells, hASC culture in xenogenic or xenofree culture medium, hASC culture in two-dimension vs. three-dimension with biomaterials, and the hASC passage number are among the experimental parameters that greatly may impact the hASC immunosuppressive potential in vitro, thus, they are also considered. Moreover, the influence of donor-related characteristics such as age, sex, and health status on hASC immunomodulation in vitro is reviewed. By analysis of the literature studies, most of the indicated determinants have been investigated in broad non-standardized ranges, so the results are not univocal. Clear conclusions cannot be drawn for the fine-tuned scenarios of many important factors to set a standard hASC immunopotency assay. Such variability needs to be carefully considered in further standardized research. Importantly, field experts' opinions may help to make it clearer.
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Affiliation(s)
- Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt.
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Mazen Abdel-Rasheed
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt
- Department of Reproductive Health Research, National Research Centre, Cairo, Egypt
| | - Eman Reda Galal
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Rehab R El-Awady
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
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Zhang Y, Gu J, Wang X, Li L, Fu L, Wang D, Wang X, Han X. Opportunities and challenges: mesenchymal stem cells in the treatment of multiple sclerosis. Int J Neurosci 2023; 133:1031-1044. [PMID: 35579409 DOI: 10.1080/00207454.2022.2042690] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 01/08/2022] [Accepted: 02/09/2022] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) was once considered an untreatable disease. Through years of research, many drugs have been discovered and are widely used for the treatment of MS. However, the current treatment can only alleviate the clinical symptoms of MS and has serious side effects. Mesenchymal stem cells (MSCs) provide neuroprotection by migrating to injured tissues, suppressing inflammation, and fostering neuronal repair. Therefore, MSCs therapy holds great promise for MS treatment. This review aimed to assess the feasibility and safety of use of MSCs in MS treatment as well as its development prospect in clinical treatment by analysing the existing clinical studies.
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Affiliation(s)
- Yingyu Zhang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Jiebing Gu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiaoshuang Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Linfang Li
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Lingling Fu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Di Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiuting Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xuemei Han
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
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Mahmoud M, Abdel-Rasheed M. Influence of type 2 diabetes and obesity on adipose mesenchymal stem/stromal cell immunoregulation. Cell Tissue Res 2023; 394:33-53. [PMID: 37462786 PMCID: PMC10558386 DOI: 10.1007/s00441-023-03801-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 06/21/2023] [Indexed: 10/07/2023]
Abstract
Type 2 diabetes (T2D), associated with obesity, represents a state of metabolic inflammation and oxidative stress leading to insulin resistance and progressive insulin deficiency. Adipose-derived stem cells (ASCs) are adult mesenchymal stem/stromal cells identified within the stromal vascular fraction of adipose tissue. These cells can regulate the immune system and possess anti-inflammatory properties. ASCs are a potential therapeutic modality for inflammatory diseases including T2D. Patient-derived (autologous) rather than allogeneic ASCs may be a relatively safer approach in clinical perspectives, to avoid occasional anti-donor immune responses. However, patient characteristics such as body mass index (BMI), inflammatory status, and disease duration and severity may limit the therapeutic utility of ASCs. The current review presents human ASC (hASC) immunoregulatory mechanisms with special emphasis on those related to T lymphocytes, hASC implications in T2D treatment, and the impact of T2D and obesity on hASC immunoregulatory potential. hASCs can modulate the proliferation, activation, and functions of diverse innate and adaptive immune cells via direct cell-to-cell contact and secretion of paracrine mediators and extracellular vesicles. Preclinical studies recommend the therapeutic potential of hASCs to improve inflammation and metabolic indices in a high-fat diet (HFD)-induced T2D disease model. Discordant data have been reported to unravel intact or detrimentally affected immunomodulatory functions of ASCs, isolated from patients with obesity and/or T2D patients, in vitro and in vivo. Numerous preconditioning strategies have been introduced to potentiate hASC immunomodulation; they are also discussed here as possible options to potentiate the immunoregulatory functions of hASCs isolated from patients with obesity and T2D.
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Affiliation(s)
- Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt.
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Mazen Abdel-Rasheed
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt
- Department of Reproductive Health Research, National Research Centre, Cairo, Egypt
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Hoang DM, Nguyen QT, Phan TT, Ngo AT, Pham PT, Bach TQ, Le PT, Bui HT, Thanh LN. Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different? Heliyon 2023; 9:e15946. [PMID: 37229156 PMCID: PMC10205494 DOI: 10.1016/j.heliyon.2023.e15946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that can be isolated from bone marrow, adipose tissue, the umbilical cord, dental pulp, etc. These cells have unique properties that give them excellent therapeutic potential, including immunoregulation, immunomodulation, and tissue regeneration functions. MSC-based products are considered advanced therapy medicinal products (ATMPs) under European regulations (1394/2007); thus, they must be manufactured under good manufacturing practices and via effective manufacturing methods. The former can be achieved via a proper laboratory design and compliance with manufacturing protocols, whereas the latter requires an approach that ensures that the quality of the products is consistent regardless of the manufacturing procedure. To meet these daunting requirements, this study proposes an exchangeable approach that combines optimized and equivalent manufacturing processes under the Quality by Design (QbD) principle, allowing investigators to convert from small laboratory-scale to large-scale manufacturing of MSC-based products for clinical applications without altering the quality and quantity of the cell-based products.
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Affiliation(s)
- Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Quyen T. Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Trang T.K. Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Anh T.L. Ngo
- Vinmec High Tech Center, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Phuong T. Pham
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Trung Q. Bach
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Phuong T.T. Le
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Hoa T.P. Bui
- Vinmec High Tech Center, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
- College of Health Science, Vin University, Vinhomes Ocean Park, Gia Lam District, Hanoi 12400, Viet Nam
- Vinmec International Hospital – Times City, Vinmec Healthcare System, 458 Minh Khai, Hanoi 11622, Viet Nam
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Owen A, Patten D, Vigneswara V, Frampton J, Newsome PN. PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury. Stem Cells 2022; 40:1056-1070. [PMID: 35999023 PMCID: PMC9707286 DOI: 10.1093/stmcls/sxac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 07/06/2022] [Indexed: 11/12/2022]
Abstract
Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR+Thy-1+VCAM-1Hi). PaS MSC are a well-described population that demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T-lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (IL-10 and OPG) after stimulation (P = .004 and P = .003). The MDR2-/- model of biliary injury and hepatic ischemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplantation. Systemic MSC therapy in MDR2-/- mice led to reduced liver injury with an increase in restorative macrophages (5913 ± 333.9 vs 12 597 ± 665.8, P = .002, n = 7) and a change in lymphocyte ratios (3.55 ± 0.37 vs 2.59 ± 0.139, P = .023, n = 17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by Periodic acid-Schiff (PAS) staining (91.7% ± 2.8 vs 80.1% ± 4.6, P = .03). Systemically administered quantum dot-labeled MSC were tracked using single-cell resolution CryoViz imaging which demonstrated their sequestration in the lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.
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Affiliation(s)
| | | | | | | | - Philip N Newsome
- Corresponding author: Philip N. Newsome, Centre for Liver and Gastrointestinal Research, Institute of Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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Wise RM, Al-Ghadban S, Harrison MAA, Sullivan BN, Monaco ER, Aleman SJ, Donato UM, Bunnell BA. Short-Term Autophagy Preconditioning Upregulates the Expression of COX2 and PGE2 and Alters the Immune Phenotype of Human Adipose-Derived Stem Cells In Vitro. Cells 2022; 11:cells11091376. [PMID: 35563682 PMCID: PMC9101706 DOI: 10.3390/cells11091376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/28/2022] [Accepted: 04/07/2022] [Indexed: 12/28/2022] Open
Abstract
Human adipose-derived stem cells (hASCs) are potent modulators of inflammation and promising candidates for the treatment of inflammatory and autoimmune diseases. Strategies to improve hASC survival and immunoregulation are active areas of investigation. Autophagy, a homeostatic and stress-induced degradative pathway, plays a crucial role in hASC paracrine signaling—a primary mechanism of therapeutic action. Therefore, induction of autophagy with rapamycin (Rapa), or inhibition with 3-methyladenine (3-MA), was examined as a preconditioning strategy to enhance therapeutic efficacy. Following preconditioning, both Rapa and 3-MA-treated hASCs demonstrated preservation of stemness, as well as upregulated transcription of cyclooxygenase-2 (COX2) and interleukin-6 (IL-6). Rapa-ASCs further upregulated TNFα-stimulated gene-6 (TSG-6) and interleukin-1 beta (IL-1β), indicating additional enhancement of immunomodulatory potential. Preconditioned cells were then stimulated with the inflammatory cytokine interferon-gamma (IFNγ) and assessed for immunomodulatory factor production. Rapa-pretreated cells, but not 3-MA-pretreated cells, further amplified COX2 and IL-6 transcripts following IFNγ exposure, and both groups upregulated secretion of prostaglandin-E2 (PGE2), the enzymatic product of COX2. These findings suggest that a 4-h Rapa preconditioning strategy may bestow the greatest improvement to hASC expression of cytokines known to promote tissue repair and regeneration and may hold promise for augmenting the therapeutic potential of hASCs for inflammation-driven pathological conditions.
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Affiliation(s)
- Rachel M. Wise
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Mark A. A. Harrison
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Brianne N. Sullivan
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Emily R. Monaco
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Sarah J. Aleman
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Umberto M. Donato
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Bruce A. Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Correspondence:
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Guo X, Schaudinn C, Blume-Peytavi U, Vogt A, Rancan F. Effects of Adipose-Derived Stem Cells and Their Conditioned Medium in a Human Ex Vivo Wound Model. Cells 2022; 11:cells11071198. [PMID: 35406762 PMCID: PMC8998073 DOI: 10.3390/cells11071198] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 12/14/2022] Open
Abstract
Adult stem cells have been extensively investigated for tissue repair therapies. Adipose-derived stem cells (ASCs) were shown to improve wound healing by promoting re-epithelialization and vascularization as well as modulating the inflammatory immune response. In this study, we used ex vivo human skin cultured in a six-well plate with trans-well inserts as a model for superficial wounds. Standardized wounds were created and treated with allogeneic ASCs, ASCs conditioned medium (ASC-CM), or cell culture medium (DMEM) supplemented with fetal calf serum (FCS). Skin viability (XTT test), histology (hematoxylin and eosin, H and E), β-catenin expression as well as inflammatory mediators and growth factors were monitored over 12 days of skin culture. We observed only a moderate time-dependent decrease in skin metabolic activity while skin morphology was preserved, and re-epithelialization occurred at the wound edges. An increase in β-catenin expression was observed in the newly formed epithelia, especially in the samples treated with ASC-CM. In general, increased growth factors and inflammatory mediators, e.g., hepatocytes growth factor (HGF), platelet-derived growth factor subunit AA (PDGF-AA), IL-1α, IL-7, TNF-α, and IL-10, were observed over the incubation time. Interestingly, different expression profiles were observed for the different treatments. Samples treated with ASC-CM significantly increased the levels of inflammatory cytokines and PDGF-AA with respect to control, whereas the treatment with ASCs in DMEM with 10% FCS resulted in significantly increased levels of fibroblast growth factor-basic (FGF-basic) and moderate increases of immunomodulatory cytokines. These results confirm that the wound microenvironment can influence the type of mediators secreted by ASCs and the mode as to how they improve the wound healing process. Comparative investigations with pre-activated ASCs will elucidate further aspects of the wound healing mechanism and improve the protocols of ACS application.
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Affiliation(s)
- Xiao Guo
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Christoph Schaudinn
- Advanced Light and Electron Microscopy, Zentrum für Biologische Gefahren und Spezielle Pathogene 4 (ZBS4), Robert Koch Institute, 13353 Berlin, Germany;
| | - Ulrike Blume-Peytavi
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Annika Vogt
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Fiorenza Rancan
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
- Correspondence: ; Tel.: +49-30-450518347
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11
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Saitoh S, Van Wijk K, Nakajima O. Crosstalk between Metabolic Disorders and Immune Cells. Int J Mol Sci 2021; 22:ijms221810017. [PMID: 34576181 PMCID: PMC8469678 DOI: 10.3390/ijms221810017] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 12/22/2022] Open
Abstract
Metabolic syndrome results from multiple risk factors that arise from insulin resistance induced by abnormal fat deposition. Chronic inflammation owing to obesity primarily results from the recruitment of pro-inflammatory M1 macrophages into the adipose tissue stroma, as the adipocytes within become hypertrophied. During obesity-induced inflammation in adipose tissue, pro-inflammatory cytokines are produced by macrophages and recruit further pro-inflammatory immune cells into the adipose tissue to boost the immune response. Here, we provide an overview of the biology of macrophages in adipose tissue and the relationship between other immune cells, such as CD4+ T cells, natural killer cells, and innate lymphoid cells, and obesity and type 2 diabetes. Finally, we discuss the link between the human pathology and immune response and metabolism and further highlight potential therapeutic targets for the treatment of metabolic disorders.
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Affiliation(s)
- Shinichi Saitoh
- Department of Immunology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
| | - Koen Van Wijk
- Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
| | - Osamu Nakajima
- Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan;
- Correspondence:
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12
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Xiang XW, Wang R, Yao LW, Zhou YF, Sun PL, Zheng B, Chen YF. Anti-Inflammatory Effects of Mytilus coruscus Polysaccharide on RAW264.7 Cells and DSS-Induced Colitis in Mice. Mar Drugs 2021; 19:md19080468. [PMID: 34436307 PMCID: PMC8400803 DOI: 10.3390/md19080468] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Considerable literature has been published on polysaccharides, which play a critical role in regulating the pathogenesis of inflammation and immunity. In this essay, the anti-inflammatory effect of Mytilus coruscus polysaccharide (MP) on lipopolysaccharide-stimulated RAW264.7 cells and a dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice was investigated. The results showed that MP effectively promoted the proliferation of RAW264.7 cells, ameliorated the excessive production of inflammatory cytokines (TNF-α, IL-6, and IL-10), and inhibited the activation of the NF-κB signaling pathway. For DSS-induced colitis in mice, MP can improve the clinical symptoms of colitis, inhibit the weight loss of mice, reduce the disease activity index, and have a positive effect on the shortening of the colon caused by DSS, meliorating intestinal barrier integrity and lowering inflammatory cytokines in serum. Moreover, MP makes a notable contribution to the richness and diversity of the intestinal microbial community, and also regulates the structural composition of the intestinal flora. Specifically, mice treated with MP showed a repaired Firmicutes/Bacteroidetes ratio and an increased abundance of some probiotics like Anaerotruncus, Lactobacillus, Desulfovibrio, Alistipe, Odoribacter, and Enterorhabdus in colon. These data suggest that the MP could be a promising dietary candidate for enhancing immunity and protecting against ulcerative colitis.
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Affiliation(s)
- Xing-Wei Xiang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Rui Wang
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Li-Wen Yao
- Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China; (L.-W.Y.); (B.Z.)
| | - Yu-Fang Zhou
- Zhejiang Marine Development Research Institute, Zhoushan 316000, China
- Correspondence: (Y.-F.Z.); (Y.-F.C.); Tel.: +86-151-0580-6692 (Y.-F.Z.); +86-133-7257-2058 (Y.-F.C.)
| | - Pei-Long Sun
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
| | - Bin Zheng
- Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China; (L.-W.Y.); (B.Z.)
| | - Yu-Feng Chen
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China; (X.-W.X.); (R.W.); (P.-L.S.)
- Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Hangzhou 310014, China
- Correspondence: (Y.-F.Z.); (Y.-F.C.); Tel.: +86-151-0580-6692 (Y.-F.Z.); +86-133-7257-2058 (Y.-F.C.)
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ŞEN HALICIOĞLU B, TUĞLU Mİ. Yağ doku kaynaklı mezenkimal kök hücrelerin ve koşullu besiyerinin deneysel prematür over yetmezliği modeli üzerine etkileri. CUKUROVA MEDICAL JOURNAL 2021. [DOI: 10.17826/cumj.852402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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14
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Ghasemi F, Khoshmirsafa M, Safari E, Asgari M, Alemrajabi M, Nojehdehi S, Khorrami S. Vitamin E and selenium improve mesenchymal stem cell conditioned media immunomodulatory effects. Stem Cell Investig 2021; 8:9. [PMID: 34124232 DOI: 10.21037/sci-2020-008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 03/24/2021] [Indexed: 01/01/2023]
Abstract
Background Mesenchymal stem cells (MSCs) with immunoregulatory properties affect immune systems. Many studies showed that antioxidants such as vitamin E (Vit E) and selenium (Se) could improve stem cells survival. This study aims to investigate the effects of MSC conditioned media (CM) treated with Vit E and Se on immune cells. Methods MSCs were isolated and cultured with Vit E and Se. Immature dendritic cells (DCs) and peripheral blood mononuclear cells (PBMCs) were cultured with MSC CM treated with Vit E and Se. The expression of HLA-DR, CD86, CD40, and CD83 on mature DC were evaluated. DC supernatant and PBMCs supernatant was collected for the study of TGF-β, IL-10, and IL-12. PBMCs evaluated for the expression of T-bet, GATA3, RORγt, and FOXP3. Results MSC CM increased CD40 on myeloid DC (mDC). CD40 has been decreased in DC treated with MSC (Vit E) and MSC (Se) CM. HLA-DR expression on DCs and IL-12 level were significantly reduced in MSC (Vit E) CM. IL-10 concentration increased in DCs treated with MSC (Vit E) and MSC (Se) CM. Treatment of PBMCs with MSC CM decreased IL-10 level, FOXP3, and RORγt expression. On the other hand, the MSC (Vit E) CM and MSC (Se) CM decreased the IL-10 level and increased IL-12, T-bet, and RORγt. Conclusions According to the results, the treatment of MSC with Vit E and Se enhanced the ability of MSCs to inhibit DCs and improved immunomodulatory effects. Concerning the effect of MSC on PBMC, it seems that it increased RORγt expression through monocytes.
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Affiliation(s)
- Fereshteh Ghasemi
- Department of Medical Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Majid Khoshmirsafa
- Department of Medical Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Elahe Safari
- Department of Medical Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Marzieh Asgari
- Department of Medical Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Mehdi Alemrajabi
- Department of General Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Firoozgar Clinical Research Development Center (FCRDC), Tehran, Iran
| | - Shahrzad Nojehdehi
- Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran.,Stem Cell Technology Research Center, Tehran, Iran
| | - Samane Khorrami
- Department of Medical Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
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15
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Semenova E, Grudniak MP, Machaj EK, Bocian K, Chroscinska-Krawczyk M, Trochonowicz M, Stepaniec IM, Murzyn M, Zagorska KE, Boruczkowski D, Kolanowski TJ, Oldak T, Rozwadowska N. Mesenchymal Stromal Cells from Different Parts of Umbilical Cord: Approach to Comparison & Characteristics. Stem Cell Rev Rep 2021; 17:1780-1795. [PMID: 33860454 PMCID: PMC8553697 DOI: 10.1007/s12015-021-10157-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) are a unique population of cells that play an important role in the regeneration potential of the body. MSCs exhibit a characteristic phenotype and are capable of modulating the immune response. MSCs can be isolated from various tissues such as: bone marrow, adipose tissue, placenta, umbilical cord and others. The umbilical cord as a source of MSCs, has strong advantages, such as no-risk procedure of tissue retrieval after birth and easiness of the MSCs isolation. As the umbilical cord (UC) is a complex organ and we decided to evaluate, whether the cells derived from different regions of umbilical cord show similar or distinct properties. In this study we characterized and compared MSCs from three regions of the umbilical cord: Wharton's Jelly (WJ), the perivascular space (PRV) and the umbilical membrane (UCM). The analysis was carried out in terms of morphology, phenotype, immunomodulation potential and secretome. Based on the obtained results, we were able to conclude, that MSCs derived from distinct UC regions differ in their properties. According to our result WJ-MSCs have high and stabile proliferation potential and phenotype, when compare with other MSCs and can be treated as a preferable source of cells for medical application.
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Affiliation(s)
- Ekaterina Semenova
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Mariusz P Grudniak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Eugeniusz K Machaj
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Katarzyna Bocian
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Faculty of Biology, Department of Immunology, University of Warsaw, Warsaw, Poland
| | | | - Marzena Trochonowicz
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Igor M Stepaniec
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Magdalena Murzyn
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Karolina E Zagorska
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Dariusz Boruczkowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Tomasz J Kolanowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Tomasz Oldak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.
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16
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Latest advances to enhance the therapeutic potential of mesenchymal stromal cells for the treatment of immune-mediated diseases. Drug Deliv Transl Res 2021; 11:498-514. [PMID: 33634433 DOI: 10.1007/s13346-021-00934-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal cells (MSCs) present the capacity to secrete multiple immunomodulatory factors in response to their microenvironment. This property grants them a golden status among the novel alternatives to treat multiple diseases in which there is an unneeded or exaggerated immune response. However, important challenges still make difficult the clinical implementation of MSC-based therapies, being one of the most remarkable the lack of efficacy due to their transient immunomodulatory effects. To overcome this issue and boost the regulatory potential of MSCs, multiple strategies are currently being explored. Some of them consist of ex vivo pre-conditioning MSCs prior to their administration, including exposure to pro-inflammatory cytokines or to low oxygen concentrations. However, currently, alternative strategies that do not require such ex vivo manipulation are gaining special attention. Among them, the recreation of a three dimensional (3D) environment is remarkable. This approach has been reported to not only boost the immunomodulatory potential of MSCs but also increase their in vivo persistence and viability. The present work revises the therapeutic potential of MSCs, highlighting their immunomodulatory activity as a potential treatment for diseases caused by an exacerbated or unnecessary immune response. Moreover, it offers an updated vision of the most widely employed pre-conditioning strategies and 3D systems intended to enhance MSC-mediated immunomodulation, to conclude discussing the major challenges still to overcome in the field.
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17
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Xie F, Teng L, Xu J, Lu J, Zhang C, Yang L, Ma X, Zhao M. Adipose-derived mesenchymal stem cells inhibit cell proliferation and migration and suppress extracellular matrix synthesis in hypertrophic-scar and keloid fibroblasts. Exp Ther Med 2021; 21:139. [PMID: 33456506 PMCID: PMC7791925 DOI: 10.3892/etm.2020.9571] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 03/26/2020] [Indexed: 12/13/2022] Open
Abstract
Pathological scars occur during skin wound healing, and the use of adipose-derived stem cells (ADSCs) is one of the various treatments. The present study aimed to investigate the in vitro effects of ADSCs on the biological properties of hypertrophic scar fibroblasts (HSFs) and keloid fibroblasts (KFs), such as proliferation, migration, and the synthesis of extracellular matrix proteins. Transwell chambers were used to establish a co-culture system of ADSCs with normal skin fibroblasts (NFs), HSFs or KFs. The effect of ADSCs on the proliferation of fibroblasts was evaluated by CCK8 measurement, while the migration ability of fibroblasts was assessed using cell scratch assay. The expression of extracellular matrix proteins was measured by immunoblotting. Co-culture of NFs with ADSCs did not affect cell proliferation and migration, nor the expression of extracellular matrix proteins [collagen-I, collagen-III, fibronectin (FN) and α-smooth muscle actin (α-SMA)] in NFs. However, as with the inhibitor SB431542, ADSCs significantly inhibited cell proliferation and migration and the expression of extracellular matrix proteins (collagen-I, collagen-III, FN and α-SMA), but also suppressed the protein expression of transforming growth factor β1 (TGF-β1), phosphorylated (p-) mothers against decapentaplegic homolog (Smad) 2, p-Smad3 and Smad7 in HSFs and KFs. The results show that ADSCs inhibited cell proliferation and migration and the expression of extracellular matrix proteins in HSCs and KFs in vitro, possibly through inhibition of the TGF-β1/Smad pathway.
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Affiliation(s)
- Fang Xie
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Li Teng
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Jiajie Xu
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Jianjian Lu
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Chao Zhang
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Liya Yang
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Xiaoyang Ma
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
| | - Minghao Zhao
- Cranio-Maxillo-Facial Surgery Department 2, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P.R. China
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Kuca-Warnawin E, Janicka I, Bonek K, Kontny E. Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation. Cells 2021; 10:cells10020280. [PMID: 33573252 PMCID: PMC7912699 DOI: 10.3390/cells10020280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 12/17/2022] Open
Abstract
The domination of pro-inflammatory Th subsets (Th1, Th17) is characteristic of ankylosing spondylitis (AS). Mesenchymal stem cells (MSC) were reported to normalize Th imbalance, but whether MSCs from AS adipose tissue (AS/ASCs) possess such properties is unknown. We examined AS/ASCs' impact on Th-cell differentiation, using healthy donors ASCs (HD/ASCs) as a control. The assessment of the expression of transcription factors defining Th1 (T-bet), Th2 (GATA3), Th17 (RORc), and Treg (FoxP3) subsets by quantitative RT-PCR, the concentrations of subset-specific cytokines by ELISA, and Treg (CD4+CD25highFoxP3+) formation by flow cytometry, were performed in the co-cultures of ASCs with activated CD4+ T cells or peripheral blood mononuclear cells (PBMCs). AS/ASCs and HD/ASCs exerted similar immunomodulatory effects. Acting directly on CD4+ T cells, ASCs decreased the T-bet/GATA3 and RORc/FoxP3 ratios, diminished Treg formation, but increase IFNγ and IL-17AF production, while ASCs co-cultured with PBMCs enhanced Treg generation and reduced IFNγ release. ASCs failed to up-regulate the anti-inflammatory IL-10 and TGFβ. AS/ASCs' impact on allogeneic and autologous PBMCs was similar. In conclusion, to shift Th differentiation to a functional anti-inflammatory direction, ASCs require accessory cell support, whereas their direct effect may be pro-inflammatory. Because ASCs neither inhibit IL-17AF nor up-regulate anti-inflammatory cytokines, their usefulness for AS patients' treatment remains uncertain.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
- Correspondence: ; Tel.: +48-22-6-709-260
| | - Iwona Janicka
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
| | - Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland;
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, 02-637 Warsaw, Poland; (I.J.); (E.K.)
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Chin YT, Liu CM, Chen TY, Chung YY, Lin CY, Hsiung CN, Jan YS, Chiu HC, Fu E, Lee SY. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside-stimulated dental pulp stem cells-derived conditioned medium enhances cell activity and anti-inflammation. J Dent Sci 2020; 16:586-598. [PMID: 33854707 PMCID: PMC8025232 DOI: 10.1016/j.jds.2020.10.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
Background/purpose Dental pulp stem cells (DPSCs) contribute to the regeneration of various tissues and have superior proliferation, immune privilege, and anti-inflammation properties to other mesenchymal stem cells. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) not only enhances the aforementioned properties of DPSCs but also promotes self-renewal and reprogramming-like ability. However, whether THSG enhances the aforementioned properties and abilities through direct or indirect interaction mechanisms remains unclear. To address this knowledge gap, we examined the effects of THSG-stimulated DPSC-derived conditioned medium (THSG-CM) on the activity and anti-inflammation properties of cells. Materials and methods DPSCs were treated with various concentrations of THSG to produce THSG-CM, which was then collected, analyzed, and lyophilized. A cytokine profiling antibody assay was used to compare protein components between THSG-treated and nontreated CM. Human skin fibroblasts (HSFs) and human gingival fibroblasts (HGFs) were used to investigate the effect of THSG-CM on cell proliferation, anti-inflammation, and wound healing abilities; for this investigation, MTS assay, quantitative real-time PCR analysis, and 2-well silicone inserts wound model were conducted. Results We observed that THSG enhanced the secretion of growth- and immune-associated proteins in THSG-CM and increased the proliferation of HSFs and HGFs. Furthermore, THSG-CM significantly attenuated lipopolysaccharide-stimulated mRNA levels of cytokines in both cells and improved wound healing abilities. Conclusion We conclude that THSG-CM had more beneficial effects on cell activity and anti-inflammation in the HSFs and HGFs than DPSC-derived CM. DPSC-derived CM can be developed into a cell-free regenerative strategy in the future, and its therapeutic efficacy may be improved by THSG-CM.
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Affiliation(s)
- Yu-Tang Chin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Che-Ming Liu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
| | - Ting-Yi Chen
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
| | - Yao-Yu Chung
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chi-Yu Lin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Chao-Nan Hsiung
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yun-Shen Jan
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Hsien-Chung Chiu
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Earl Fu
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Xindian, New Taipei City, Taiwan
| | - Sheng-Yang Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan.,Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
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Azevedo RI, Minskaia E, Fernandes-Platzgummer A, Vieira AIS, da Silva CL, Cabral JMS, Lacerda JF. Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro. Stem Cells 2020; 38:1007-1019. [PMID: 32352186 PMCID: PMC7497276 DOI: 10.1002/stem.3185] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Treg) play a critical role in immune tolerance. The scarcity of Treg therapy clinical trials in humans has been largely due to the difficulty in obtaining sufficient Treg numbers. We performed a preclinical investigation on the potential of mesenchymal stromal cells (MSCs) to expand Treg in vitro to support future clinical trials. Human peripheral blood mononuclear cells from healthy donors were cocultured with allogeneic bone marrow‐derived MSCs expanded under xenogeneic‐free conditions. Our data show an increase in the counts and frequency of CD4+ CD25high Foxp3+ CD127low Treg cells (4‐ and 6‐fold, respectively) after a 14‐day coculture. However, natural Treg do not proliferate in coculture with MSCs. When purified conventional CD4 T cells (Tcon) are cocultured with MSCs, only cells that acquire a Treg‐like phenotype proliferate. These MSC‐induced Treg‐like cells also resemble Treg functionally, since they suppress autologous Tcon proliferation. Importantly, the DNA methylation profile of MSC‐induced Treg‐like cells more closely resembles that of natural Treg than of Tcon, indicating that this population is stable. The expression of PD‐1 is higher in Treg‐like cells than in Tcon, whereas the frequency of PDL‐1 increases in MSCs after coculture. TGF‐β levels are also significantly increased MSC cocultures. Overall, our data suggest that Treg enrichment by MSCs results from Tcon conversion into Treg‐like cells, rather than to expansion of natural Treg, possibly through mechanisms involving TGF‐β and/or PD‐1/PDL‐1 expression. This MSC‐induced Treg population closely resembles natural Treg in terms of phenotype, suppressive ability, and methylation profile.
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Affiliation(s)
- Rita I Azevedo
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ekaterina Minskaia
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Ana I S Vieira
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - João F Lacerda
- Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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21
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Jeske SS, Theodoraki MN, Boelke E, Laban S, Brunner C, Rotter N, Jackson EK, Hoffmann TK, Schuler PJ. Adenosine production in mesenchymal stromal cells in relation to their developmental status. HNO 2020; 68:87-93. [PMID: 31915882 DOI: 10.1007/s00106-019-00805-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status. METHODS We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry. RESULTS Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC. CONCLUSION Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.
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Affiliation(s)
- S S Jeske
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany
| | - M N Theodoraki
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany
| | - E Boelke
- Department of Radiotherapy and Radiooncology, Heinrich Heine University, Düsseldorf, Germany
| | - S Laban
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany
| | - C Brunner
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany
| | - N Rotter
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Mannheim University Medical Center, Mannheim, Germany
| | - E K Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - T K Hoffmann
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany
| | - P J Schuler
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, Frauensteige 12, 89075, Ulm, Germany.
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22
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Bulati M, Miceli V, Gallo A, Amico G, Carcione C, Pampalone M, Conaldi PG. The Immunomodulatory Properties of the Human Amnion-Derived Mesenchymal Stromal/Stem Cells Are Induced by INF-γ Produced by Activated Lymphomonocytes and Are Mediated by Cell-To-Cell Contact and Soluble Factors. Front Immunol 2020; 11:54. [PMID: 32117234 PMCID: PMC7028706 DOI: 10.3389/fimmu.2020.00054] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 01/09/2020] [Indexed: 02/05/2023] Open
Abstract
Human mesenchymal stromal/stem cells (MSCs), being immunoprivileged and having immunomodulatory ability, represent a promising tool to be applied in the field of regenerative medicine. Based on numerous in vitro evidences, the immunological effects of MSCs on immune cells could depend on different mechanisms as cell-to-cell contact and paracrine signals. Furthermore, recent studies have shown that the immunomodulatory activity of MSCs is initiated by activated immune cells; thus, their interaction represents a potential homeostatic mechanism by which MSCs regulate the immune response. MSCs also release exosomes able to give different effects, in a paracrine manner, by influencing inflammatory processes. In this study, we aimed to establish the potential role of human amnion-derived MSCs (hAMSCs), in immunomodulation. We found that the immunosuppressive properties of hAMSCs are not constitutive, but require "supportive signals" capable of promoting these properties. Indeed, we observed that hAMSCs alone are not able to produce an adequate amount of soluble immunomodulatory factors. Here, we studied, in depth, the strong immunomodulatory licensing signal deriving from the direct interaction between hAMSCs and stimulated peripheral blood mononuclear cells. We found that the immunomodulatory effect of hAMSCs also depends on cell-to-cell contact through the contribution of the PDL-1/PD-1 axis. We then investigated the IFN-γ priming of hAMSCs (γ-hAMSCs), which induce the increase of PDL-1 expression, high production of IDO, and upregulation of different immunomodulatory exosome-derived miRNAs. Our miRNA-target network analysis revealed that nine of the deregulated miRNAs are involved in the regulation of key proteins that control both T cell activation/anergy and monocyte differentiation pathways. Finally, we observed that γ-hAMSCs induce in monocytes both M2-like phenotype and the increase of IL-10 production. The extensive implications of MSCs in modulating different aspects of the immune system make these cells attractive candidates to be employed in therapeutic application in immune-based diseases. For these reasons, we aimed, with this study, to shed light on the potential of hAMSCs, and how they could become a useful tool for treating different inflammatory diseases, including end-stage pathologies or adverse effects in transplanted patients.
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Affiliation(s)
- Matteo Bulati
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Vitale Miceli
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Alessia Gallo
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Giandomenico Amico
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
- Ri.MED Foundation, Palermo, Italy
| | | | - Mariangela Pampalone
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
- Ri.MED Foundation, Palermo, Italy
| | - Pier Giulio Conaldi
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
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23
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Moghadam M, Tokhanbigli S, Baghaei K, Farivar S, Asadzadeh Aghdaei H, Zali MR. Gene expression profile of immunoregulatory cytokines secreted from bone marrow and adipose derived human mesenchymal stem cells in early and late passages. Mol Biol Rep 2020; 47:1723-1732. [PMID: 32040706 DOI: 10.1007/s11033-020-05264-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/18/2020] [Indexed: 01/01/2023]
Abstract
Mesenchymal Stem Cells (MSCs) have therapeutic potential in a variety of diseases; however, the safety and efficacy of their use remain ambiguous. Clinical applications of MSCs are under intensive investigation due to their immunomodulatory features and lack of immune reactivity. Therefore, having a clear perspective on the exact mechanisms underlying the regulation of cytokine secretion in different microenvironments seems crucially important.In the current study, samples from human bone marrow and adipose were collected, and peripheral blood mononuclear cells (PBMCs) were isolated and cultured in conventional medium. After MSC expansion, the cells from passage 3 (P3) and passage 9 (P9) were utilized to identify MSC cell surface markers and their differentiation capacity. The P3, P5, P7, and P9 cells were used for RNA extraction to qualify the expression of the main immunomodulatory cytokines IDO, VCAM-1, TGF-β, IL-6, IL-10, and PGE2 at mRNA levels. The results indicate that VCAM-1 expression in the subcultures was reduced in bone marrow-derived MSCs. After an increase in P5, P7, and P9, IL-6 expression was reduced. In adipose-derived MSCs, the mRNA levels of IL-10 in higher passages were decreased compared with P3; other studied cytokines had no significant changes in their expression levels in either bone marrow or adipose-derived MSCs. Based on these results, it can be concluded that a suitable source for MSCs in cell therapy with stable expression of main cytokines, even in higher subcultures, appears to be adipose-derived MSCs with the exception of IL-10 secretion.
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Affiliation(s)
- Maryam Moghadam
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Shirin Farivar
- Department of Molecular and Cell Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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24
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Gonzalez-Pujana A, Igartua M, Santos-Vizcaino E, Hernandez RM. Mesenchymal stromal cell based therapies for the treatment of immune disorders: recent milestones and future challenges. Expert Opin Drug Deliv 2020; 17:189-200. [PMID: 31918562 DOI: 10.1080/17425247.2020.1714587] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Mesenchymal stromal cells (MSCs) present unique immunomodulatory properties that make them promising candidates for the treatment of inflammatory and immune disorders. MSC-mediated immunomodulation is a complex combination of mechanisms, in which the secretome plays a fundamental role. The plethora of bioactive molecules MSCs produce, such as indoleamine 2,3-dioxygenase (IDO) or prostaglandin E2 (PGE2), efficiently regulates innate and adaptive immunity. As a result, MSCs have been extensively employed in preclinical studies, leading to the conduction of multiple clinical trials.Areas covered: This review summarizes the effects of some of the key biomolecules in the MSC secretome and the advances in preclinical studies exploring the treatment of disorders including graft-versus-host disease (GvHD) or inflammatory bowel disease (IBD). Further, late-stage clinical trials and the first MSC-based therapies that recently obtained regulatory approval are discussed.Expert opinion: Extensive research supports the potential of MSC-based immunomodulatory therapies. However, to establish the bases for clinical translation, the future of study lies in the standardization of protocols and in the development of strategies that boost the therapeutic properties of MSCs.
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Affiliation(s)
- Ainhoa Gonzalez-Pujana
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Manoli Igartua
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Rosa Maria Hernandez
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
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25
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Zanoni M, Cortesi M, Zamagni A, Tesei A. The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis. Int J Mol Sci 2019; 20:E3876. [PMID: 31398940 PMCID: PMC6719901 DOI: 10.3390/ijms20163876] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field.
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Affiliation(s)
- Michele Zanoni
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Michela Cortesi
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
| | - Alice Zamagni
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
| | - Anna Tesei
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
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26
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Tumangelova-Yuzeir K, Naydenov E, Ivanova-Todorova E, Krasimirova E, Vasilev G, Nachev S, Kyurkchiev D. Mesenchymal Stem Cells Derived and Cultured from Glioblastoma Multiforme Increase Tregs, Downregulate Th17, and Induce the Tolerogenic Phenotype of Monocyte-Derived Cells. Stem Cells Int 2019; 2019:6904638. [PMID: 31191680 PMCID: PMC6525812 DOI: 10.1155/2019/6904638] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/08/2019] [Accepted: 02/24/2019] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess immunosuppressive properties and have been described in the tumor microenvironment of glioblastoma multiforme (GBM). This manuscript has two major topics-first, to describe isolated and cultured MSCs derived from GBM (GB-MSCs) and second, to examine their in vitro immunosuppressive capacity. Our results display cells with morphology and phenotype, clonogenic ability, and osteogenic potential, typical for MSCs. Furthermore, the cultured cells show intracellular expression of the neural markers Nestin and GFAP. They express PD-L1 and secrete TGFβ, CCL-2, PGE2, IL-6, and sVEGF. Coculturing of GB-MSCs with PBMCs isolated from healthy donors results in a decreased percentage of Th17 lymphocytes and an increased percentage of Tregs. Regarding the impact of GB-MSCs on monocytes, we establish an augmented expression of CD14 and CD86 along with diminished expression of HLA-DR and CD80, which is associated with tolerogenic phenotype monocyte-derived cells. In conclusion, our results describe in detail GBM-derived and cultured cells that meet the criteria for MSCs but at the same time express Nestin and GFAP. GB-MSCs express and secrete suppressive molecules, influencing in vitro T cells and monocytes, and are probably another factor involved in the immune suppression exerted by GBM.
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Affiliation(s)
- Kalina Tumangelova-Yuzeir
- Laboratory of Clinical Immunology, University Hospital “St. Ivan Rilski,” Department of Clinical Laboratory and Clinical Immunology, Medical University of Sofia, Sofia 1431, Bulgaria
| | - Emanuil Naydenov
- Clinic of Neurosurgery, University Hospital “St. Ivan Rilski,” Medical University Sofia, 15 “Acad. Ivan Geshov” Str., 1431 Sofia, Bulgaria
| | - Ekaterina Ivanova-Todorova
- Laboratory of Clinical Immunology, University Hospital “St. Ivan Rilski,” Department of Clinical Laboratory and Clinical Immunology, Medical University of Sofia, Sofia 1431, Bulgaria
| | - Ekaterina Krasimirova
- Laboratory of Clinical Immunology, University Hospital “St. Ivan Rilski,” Department of Clinical Laboratory and Clinical Immunology, Medical University of Sofia, Sofia 1431, Bulgaria
| | - Georgi Vasilev
- Laboratory of Clinical Immunology, University Hospital “St. Ivan Rilski,” Department of Clinical Laboratory and Clinical Immunology, Medical University of Sofia, Sofia 1431, Bulgaria
| | - Sevdalin Nachev
- Laboratory of Clinical Pathology, University Hospital “St. Ivan Rilski,” Medical University Sofia, 15 “Acad. Ivan Geshov” Str., 1431 Sofia, Bulgaria
| | - Dobroslav Kyurkchiev
- Laboratory of Clinical Immunology, University Hospital “St. Ivan Rilski,” Department of Clinical Laboratory and Clinical Immunology, Medical University of Sofia, Sofia 1431, Bulgaria
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27
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Luque-Campos N, Contreras-López RA, Jose Paredes-Martínez M, Torres MJ, Bahraoui S, Wei M, Espinoza F, Djouad F, Elizondo-Vega RJ, Luz-Crawford P. Mesenchymal Stem Cells Improve Rheumatoid Arthritis Progression by Controlling Memory T Cell Response. Front Immunol 2019; 10:798. [PMID: 31040848 PMCID: PMC6477064 DOI: 10.3389/fimmu.2019.00798] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/26/2019] [Indexed: 12/14/2022] Open
Abstract
In the last years, mesenchymal stem cell (MSC)-based therapies have become an interesting therapeutic opportunity for the treatment of rheumatoid arthritis (RA) due to their capacity to potently modulate the immune response. RA is a chronic autoimmune inflammatory disorder with an incompletely understood etiology. However, it has been well described that peripheral tolerance defects and the subsequent abnormal infiltration and activation of diverse immune cells into the synovial membrane, are critical for RA development and progression. Moreover, the imbalance between the immune response of pro-inflammatory and anti-inflammatory cells, in particular between memory Th17 and memory regulatory T cells (Treg), respectively, is well admitted to be associated to RA immunopathogenesis. In this context, MSCs, which are able to alter the frequency and function of memory lymphocytes including Th17, follicular helper T (Tfh) cells and gamma delta (γδ) T cells while promoting Treg cell generation, have been proposed as a candidate of choice for RA cell therapy. Indeed, given the plasticity of memory CD4+ T cells, it is reasonable to think that MSCs will restore the balance between pro-inflammatory and anti-inflammatory memory T cells populations deregulated in RA leading to prompt their therapeutic function. In the present review, we will discuss the role of memory T cells implicated in RA pathogenesis and the beneficial effects exerted by MSCs on the phenotype and functions of these immune cells abnormally regulated in RA and how this regulation could impact RA progression.
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Affiliation(s)
- Noymar Luque-Campos
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Rafael A Contreras-López
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - María Jose Paredes-Martínez
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Maria Jose Torres
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | | | - Mingxing Wei
- Cellvax, SAS, Parc BIOCITECH, Romainville, France
| | | | | | - Roberto Javier Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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28
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Vasilev G, Ivanova M, Ivanova-Todorova E, Tumangelova-Yuzeir K, Krasimirova E, Stoilov R, Kyurkchiev D. Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients. Rheumatol Int 2019; 39:819-826. [PMID: 30944956 DOI: 10.1007/s00296-019-04296-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 03/25/2019] [Indexed: 01/01/2023]
Abstract
We aimed to assess the immunoregulatory effects of secretory factors produced by adipose tissue-derived MSC (AT-MSC) on Th17 and Treg subsets from patients with rheumatoid arthritis (RA). 17 patients with active disease matching the ACR/EULAR 2010 criteria for RA were included. Patients' peripheral blood mononuclear cells (PBMC) were cultured in AT-MSC-conditioned medium (AT-MSCcm) and in control medium. The cytokine production of AT-MSC and PBMC was quantified by ELISA. Th17 and Treg were determined by flow cytometry. AT-MSCcm contained: IL-6, IL-17, IL-21, CCL2, CCL5, IL-8, sVEGF-A and PGE2. Cultivation of patients' PBMC with AT-MSCcm increased TGF-β1 (8318 pg/ml; IQR 6327-11,686) vs control medium [6227 pg/ml (IQR 1681-10,148, p = 0.013)]. PBMC cultivated with AT-MSCcm downregulated TNF-α, IL-17A, and IL-21 compared to control PBMC: 5 pg/ml IQR (1.75-11.65) vs 1 pg/ml (IQR 0.7-1.9), p = 0.001; 4.2 pg/ml (IQR 3.1-6.1) vs 2.3 pg/ml (IQR.75-5.42), p = 0.017; 66.9 pg/ml (IQR 40.6-107.2) vs 53 pg/ml (IQR 22-73), p = 0.022. Th17 decreased under the influence of AT-MSCcm: 10.13 ± 3.88% vs 8.98 ± 3.58%, p = 0.02. CD4+FoxP3+, CD4+CD25-FoxP3+, and CD4+CD25+FoxP3+ was 11.35 ± 4.1%; 7.13 ± 3.12% and 4.22 ± 2% in control PBMC. Accordingly, CD4+FoxP3+, CD4+CD25-FoxP3+, and CD4+CD25+FoxP3+ significantly increased in PBMC cultured with AT-MSCcm: 15.6 ± 6.1%, p = 0.001; 9.56 ± 5.4%, p = 0.004 and 6.04 ± 3.6%, p = 0.001. All these effects could define MSC-based approaches as adequate avenues for further treatment development in RA.
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Affiliation(s)
- Georgi Vasilev
- Laboratory of Clinical Immunology, Department of Clinical Immunology, University Hospital "St. Ivan Rilski"-Sofia, Medical University of Sofia, Sofia, Bulgaria.
| | - Mariana Ivanova
- Clinic of Rheumatology, University Hospital "St. Ivan Rilski"-Sofia, Department of Internal Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Ekaterina Ivanova-Todorova
- Laboratory of Clinical Immunology, Department of Clinical Immunology, University Hospital "St. Ivan Rilski"-Sofia, Medical University of Sofia, Sofia, Bulgaria
| | - Kalina Tumangelova-Yuzeir
- Laboratory of Clinical Immunology, Department of Clinical Immunology, University Hospital "St. Ivan Rilski"-Sofia, Medical University of Sofia, Sofia, Bulgaria
| | - Ekaterina Krasimirova
- Laboratory of Clinical Immunology, Department of Clinical Immunology, University Hospital "St. Ivan Rilski"-Sofia, Medical University of Sofia, Sofia, Bulgaria
| | - Rumen Stoilov
- Clinic of Rheumatology, University Hospital "St. Ivan Rilski"-Sofia, Department of Internal Medicine, Medical University of Sofia, Sofia, Bulgaria
| | - Dobroslav Kyurkchiev
- Laboratory of Clinical Immunology, Department of Clinical Immunology, University Hospital "St. Ivan Rilski"-Sofia, Medical University of Sofia, Sofia, Bulgaria
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29
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Immunomodulatory effect of mesenchymal stem cells: Cell origin and cell quality variations. Mol Biol Rep 2019; 46:1157-1165. [PMID: 30628022 DOI: 10.1007/s11033-018-04582-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 12/18/2018] [Indexed: 12/11/2022]
Abstract
The immunomodulatory property of mesenchymal stem cells (MSCs) has been previously reported. Still it is unclear if this property can be affected by the cell origin and cell quality. Using primary MSCs expanded from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) of mice, we investigated whether the immunomodulatory property of MSCs varied with cell origin and cell quality (early- vs. late-passaged BM-MSCs). BM-MSCs (p1) and AD-MSCs (p1) had a typical spindle shape, but morphological changes were observed in late-passaged BM-MSCs (p6). A pathway-focused array showed that the expression of chemokine/cytokine genes varied with different cell origins and qualities. By co-culturing with spleen mononuclear cells (MNC) for 3 days, the expression of CD4 was suppressed by all types of MSCs. By contrast, the expression of CD8 was suppressed by BM-MSCs and increased by AD-MSCs. The expression ratio of CD206 to CD86 was at a comparable level after co-culture with AD-MSCs and BM-MSCs, but was lower with late-passaged BM-MSCs. AD-MSCs highly induced the release of IL6, IL-10 and TGF-β in culture medium. Compared with early-passaged BM-MSCs (p1), late-passaged BM-MSCs (p6) released less TGF-β. Our data suggests that the immunomodulatory properties of MSCs vary with cell origin and cell quality and that BM-MSCs of good quality are likely the optimal source of immunomodulation.
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Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Front Immunol 2018; 9:2837. [PMID: 30564236 PMCID: PMC6288292 DOI: 10.3389/fimmu.2018.02837] [Citation(s) in RCA: 368] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. For this reason, MSCs' secretome is currently being explored in several clinical contexts, either using MSC-conditioned media (CM) or purified MSC-derived extracellular vesicles (EVs) to modulate tissue response to a wide array of injuries. Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome.
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Affiliation(s)
- Joana R Ferreira
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Graciosa Q Teixeira
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Susana G Santos
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Mário A Barbosa
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States
| | - Raquel M Gonçalves
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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31
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Nakhaeifard M, Haji Ghasem Kashani M, Goudarzi I, Rezaei A. Conditioned Medium Protects Dopaminergic Neurons in Parkinsonian Rats. CELL JOURNAL 2018; 20:348-354. [PMID: 29845788 PMCID: PMC6004993 DOI: 10.22074/cellj.2018.5343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/04/2017] [Indexed: 12/19/2022]
Abstract
Objective Adipose derived stem cells (ASCs) secrete numerous neurotrophic factors and cytokines in conditioned medium
(CM), which protect neurons by its antioxidative and trophic effects. This research assesses the neuroprotective effect of ASC-
CM on neurotrophins genes expressions and tyrosine hydroxylase positive (TH+) cell density in male Wistar rats lesioned by
6-hydroxydopamine (6-OHDA).
Materials and Methods In this experimental study, the groups consisted of lesioned and sham rats with unilateral
injections of 20 µg of 6-OHDA neurotoxin and phosphate buffered saline (PBS) into the striatum, respectively. Another
groups received intravenous injections of 3×106 cells (ASCs group), 500 µl of CM (ASC-CM group) or medium [α-minimal
essential medium (α-MEM) group)]. All rats underwent evaluations with the rotarod and apomorphine-induced rotation
tests at 2, 4, 6, and 8 weeks post-injection. At 8 weeks we sacrificed some of the animals for real-time polymerase chain
reaction (PCR) analysis, and evaluation of TH+cell counts.
Results We observed a significant decrease in contralateral turns to the lesions in the ASCs and ASC-CM groups
compared to the neurotoxin lesioned or α-MEM groups at 8 weeks post transplantation. Cell and CM- injected rats
showed a significant increase of staying on the rotarod compared to the lesion or α-MEM groups. Cell and CM-treated
rats showed significant increases in the NGF and NT3 genes, respectively, compared with the lesion group. Both
treated groups showed significant increases in BDNF gene expression and TH+ cell density.
Conclusion The results suggested that ASCs and ASC-CM protected dopaminergic neurons through the expressions
of neurotrophin genes.
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Affiliation(s)
| | - Maryam Haji Ghasem Kashani
- School of Biology, Damghan University, Damghan, Iran.,Institute of Biological Sciences, Damghan University, Damghan, Iran.Electronic Address:
| | - Iran Goudarzi
- School of Biology, Damghan University, Damghan, Iran
| | - Arezou Rezaei
- Institute of Biological Sciences, Damghan University, Damghan, Iran
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Studies on Conditioned Media in Human Cells: Evaluation Using Various Cell and Culture Conditions, Animal Disease Models. JOURNAL OF ANIMAL REPRODUCTION AND BIOTECHNOLOGY 2018. [DOI: 10.12750/jet.2018.33.1.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Cheung TS, Dazzi F. Mesenchymal-myeloid interaction in the regulation of immunity. Semin Immunol 2018; 35:59-68. [PMID: 29395680 DOI: 10.1016/j.smim.2018.01.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 01/24/2018] [Indexed: 12/13/2022]
Abstract
Several studies have demonstrated how different cell types of mesenchymal and myeloid origin can independently exhibit immunoregulatory activities. In response to inflammatory cues, they transcribe a molecular repertoire that restores the tissue microenvironment to what it was before the injury. There is accumulating evidence that stromal and myeloid-derived cells do not act independently but that the establishment of a cross-talk between them is a fundamental requirement. Stromal cells, prompted by inflammatory molecules, orchestrate and initiate myeloid cell recruitment and their functional reprogramming. Once instructed, myeloid cells effect the anti-inflammatory activity or, if alternatively required, enhance immune responses. The cross-talk plays a fundamental role in tissue homeostasis, not only to regulate inflammation, but also to promote tissue regeneration and cancer progression.
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Affiliation(s)
- Tik Shing Cheung
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | - Francesco Dazzi
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom.
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Dahbour S, Jamali F, Alhattab D, Al-Radaideh A, Ababneh O, Al-Ryalat N, Al-Bdour M, Hourani B, Msallam M, Rasheed M, Huneiti A, Bahou Y, Tarawneh E, Awidi A. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther 2017; 23:866-874. [PMID: 28961381 PMCID: PMC5698713 DOI: 10.1111/cns.12759] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 08/16/2017] [Accepted: 09/01/2017] [Indexed: 12/30/2022] Open
Abstract
AIMS This open-label prospective phase I/IIa clinical study used autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) followed by mesenchymal stromal cells conditioned media (MSC-CM) for the first time to treat multiple sclerosis (MS) patients. The primary goal was to assess the safety and feasibility and the secondary was efficacy. The correlation between the MSC-CM content and treatment outcome was investigated. METHODS Ten MS patients who failed conventional therapy were enrolled. Adverse events were recorded to assess safety. The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9-PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests. The MSCs-CM concentration of 27 inflammatory biomarkers was investigated. RESULTS The treatment protocol was well tolerated by patients. There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly. A decrease of 4 and 3.5 points on the EDSS was achieved in two patients. We report a correlation between a decreased lesion number at baseline and higher IL-6, IL-8, and VEGF MSC-CM content. CONCLUSION The used protocol was safe and feasible with possible efficacy. The addition of MSC-CM could be related to the magnitude of EDSS improvement observed.
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Affiliation(s)
- Said Dahbour
- Department of Neurology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Fatima Jamali
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Dana Alhattab
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Ali Al-Radaideh
- Department of Medical Imaging, Faculty of Allied Health Sciences, Hashemite University, Zarqa, Jordan
| | - Osama Ababneh
- Department of Ophthalmology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Nosaiba Al-Ryalat
- Department of Diagnostic Radiology and Nuclear Medicine, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Muawyeh Al-Bdour
- Department of Ophthalmology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Bayan Hourani
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Mohammed Msallam
- Department of Ophthalmology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Murad Rasheed
- Department of Neurology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Ammar Huneiti
- Department of Computer Information Systems, King Abdullah II School for Information Technology, The University of Jordan, Jordan
| | - Yacoub Bahou
- Department of Neurology, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Emad Tarawneh
- Department of Diagnostic Radiology and Nuclear Medicine, Jordan University Hospital, The University of Jordan, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Medicine and Hematology, Jordan University Hospital, University of Jordan, Amman, Jordan
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Intrinsic Variability Present in Wharton's Jelly Mesenchymal Stem Cells and T Cell Responses May Impact Cell Therapy. Stem Cells Int 2017; 2017:8492797. [PMID: 28757881 PMCID: PMC5516721 DOI: 10.1155/2017/8492797] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/26/2017] [Indexed: 12/18/2022] Open
Abstract
Wharton's jelly mesenchymal stem cells (WJ-MSC) exhibit immunomodulatory effects on T cell response. WJ-MSC are easy to collect, process, and proliferate rapidly in culture, but information on the variability of individual cell samples impacting upon in vitro expansion, immunomodulatory potential, and aging processes is still lacking. We propose to evaluate the immunomodulatory cytokine profile and capacity to inhibit T cell proliferation of WJ-MSC progressing to replicative senescence in order to analyze if expected responses are affected. Our results show that the gene expression of immunomodulatory molecules varied among samples with no specific pattern present. In coculture, all WJ-MSC were capable of inhibiting mitogen-activated CD3+ T cell proliferation, although to different degrees, and each PBMC responded with a different level of inhibition. Thus, we suggest that each WJ-MSC displays unique behavior, differing in patterns of cytokine mRNA expression and immunomodulatory capacity. We believe that variability between samples may play a role in the effectiveness of WJ-MSC employed therapeutically.
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Immunomodulatory effect of low molecular-weight seleno-aminopolysaccharides in intestinal epithelial cells. Int J Biol Macromol 2017; 99:570-577. [DOI: 10.1016/j.ijbiomac.2017.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/18/2017] [Accepted: 03/02/2017] [Indexed: 12/16/2022]
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Li X, Lu X, Sun D, Wang X, Yang L, Zhao S, Nian H, Wei R. Adipose-Derived Mesenchymal Stem Cells Reduce Lymphocytic Infiltration in a Rabbit Model of Induced Autoimmune Dacryoadenitis. Invest Ophthalmol Vis Sci 2017; 57:5161-5170. [PMID: 27699412 PMCID: PMC6016434 DOI: 10.1167/iovs.15-17824] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose To investigate the immunoregulatory roles of adipose-derived mesenchymal stem cells (ADSCs) in autoimmune dacryoadenitis. Methods Rabbits were treated with ADSCs or phosphate-buffered solution on days 1, 3, 5, 7, and 9 after injection of activated peripheral blood lymphocytes, and clinical scores were determined by assessing tear production, break-up time, and fluorescein and hematoxylin and eosin staining. Inflammatory response was determined by measuring the expression of different mediators of inflammation in the lacrimal glands. The Th1/Th17-mediated autoreactive responses were evaluated by determining the proliferative response and the expression of cytokine genes and the lineage-determining transcription factors. The frequency of regulatory T cells (Tregs) was also examined. Results The ADSC-treated rabbits showed decreased autoimmune responses, and the secretory function of their lacrimal gland was restored significantly. Treatment with ADSCs downregulated the Th1 and Th17 responses but enhanced Tregs function. In addition, ADSC treatment noticeably suppressed the expression of matrix metalloproteinase (MMP)-9, MPP-2, IL-1β, and IL-6, whereas it enhanced the expression of the anti-inflammatory cytokine IL-10. Conclusions Our results demonstrated that ADSC administration efficiently ameliorates autoimmune dacryoadenitis mainly via modulating Th1/Th17 responses.
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Affiliation(s)
- Xue Li
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - Xiaoxiao Lu
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - Deming Sun
- Doheny Eye Institute, and Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, United States
| | | | - Liyuan Yang
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - Shaozhen Zhao
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - Hong Nian
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - Ruihua Wei
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
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Impact of bone marrow-derived mesenchymal stem cells on remodeling the lung injury induced by lipopolysaccharides in mice. Future Sci OA 2017; 3:FSO162. [PMID: 28344826 PMCID: PMC5351512 DOI: 10.4155/fsoa-2016-0036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 11/08/2016] [Indexed: 12/17/2022] Open
Abstract
AIM This study evaluated the potential of bone marrow derived mesenchymal stem cells (MSCs) to regulate cytokines and remodel the lung induced by lipopolysaccharide (LPS; O-antigen). MATERIALS & METHODS A group of mice (n = 21) was inoculated intraperitoneally with one dose 0.1 ml containing 0.025 mg LPS/mouse, and another treated intravenously with one dose of labeling bone marrow derived MSCs at 7.5 × 105 cell/mouse 4 h after LPS injection. All animals were sacrificed on the 1st, 7th and 14th days post-injection. RESULTS MSCs increased the level of IL-10 with suppression of TNF-α, decrease of collagen fibers and renewal of alveolar type I cells, together with lung tissue remodeling. CONCLUSION MSCs were shown to modulate inflammatory cytokines (TNF-α and IL-10) and to differentiate into alveolar type I cells, which prevented fibrosis in lung tissue from LPS-treated mice.
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Enhancement of Anti-Inflammatory and Osteogenic Abilities of Mesenchymal Stem Cells via Cell-to-Cell Adhesion to Periodontal Ligament-Derived Fibroblasts. Stem Cells Int 2017; 2017:3296498. [PMID: 28167967 PMCID: PMC5266859 DOI: 10.1155/2017/3296498] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 12/14/2016] [Accepted: 12/22/2016] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are involved in anti-inflammatory events and tissue repair; these functions are activated by their migration or homing to inflammatory tissues in response to various chemokines. However, the mechanism by which MSCs interact with other cell types in inflammatory tissue remains unclear. We investigated the role of periodontal ligament fibroblasts (PDL-Fs) in regulating the anti-inflammatory and osteogenic abilities of bone marrow-derived- (BM-) MSCs. The expression of monocyte chemotactic protein- (MCP-)1 was significantly enhanced by stimulation of PDL-Fs with inflammatory cytokines. MCP-1 induced the migratory ability of BM-MSCs but not PDL-Fs. Expression levels of anti-inflammatory and inflammatory cytokines were increased and decreased, respectively, by direct-contact coculture between MSCs and PDL-Fs. In addition, the direct-contact coculture enhanced the expression of MSC markers that play important roles in the self-renewal and maintenance of multipotency of MSCs, which in turn induced the osteogenic ability of the cells. These results suggest that MCP-1 induces the migration and homing of BM-MSCs into the PDL inflammatory tissue. The subsequent adherence of MSCs to PDL-Fs plays an immunomodulatory role to terminate inflammation during wound healing and upregulates the expression stem cell markers to enhance the stemness of MSCs, thereby facilitating bone formation in damaged PDL tissue.
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Bowles AC, Wise RM, Bunnell BA. Anti-inflammatory Effects of Adipose-Derived Stem Cells (ASCs). ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-46733-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Rajan TS, Giacoppo S, Diomede F, Ballerini P, Paolantonio M, Marchisio M, Piattelli A, Bramanti P, Mazzon E, Trubiani O. The secretome of periodontal ligament stem cells from MS patients protects against EAE. Sci Rep 2016; 6:38743. [PMID: 27924938 PMCID: PMC5141419 DOI: 10.1038/srep38743] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022] Open
Abstract
Manipulation of stem cells or stem cells-derived secretome has emerged as a novel alternative therapeutic option for multiple sclerosis (MS). Here we show that human periodontal ligament stem cells (hPDLSCs)-derived conditioned medium (hPDLSCs-CM) and purified exosomes/microvesicles (hPDLSCs-EMVs) obtained from Relapsing Remitting (RR)-MS patients and healthy donors block experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing anti-inflammatory and immunosuppressive effects in spinal cord and spleen, and reverse disease progression by restoring tissue integrity via remyelination in the spinal cord. We show that hPDLSCs-CM and hPDLSCs-EMVs reduce pro-inflammatory cytokines IL-17, IFN-γ, IL-1β, IL-6, TNF-α, and induce anti-inflammatory IL-10. In addition, apoptosis related STAT1, p53, Caspase 3, and Bax expressions were attenuated. Our findings unravel the immunosuppressive effects of hPDLSCs-CM and hPDLSCs-EMVs in EAE mice, and suggest simple alternative autologous source for patient-customized cell-free targeting treatment in MS patients.
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Affiliation(s)
- Thangavelu Soundara Rajan
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Sabrina Giacoppo
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Francesca Diomede
- Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
| | - Patrizia Ballerini
- Department of Psychological, Health and Territorial Sciences, University “G. d’Annunzio” Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
| | - Michele Paolantonio
- Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
| | - Marco Marchisio
- Department of Medicine and Aging Science, University “G. d’Annunzio” Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
| | - Adriano Piattelli
- Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Oriana Trubiani
- Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti-Pescara, via dei Vestini, 31, 66100, Chieti, Italy
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Mesenchymal Stromal Cells from Osteoarthritic Synovium Are a Distinct Population Compared to Their Bone-Marrow Counterparts regarding Surface Marker Distribution and Immunomodulation of Allogeneic CD4+ T-Cell Cultures. Stem Cells Int 2016; 2016:6579463. [PMID: 27516777 PMCID: PMC4969547 DOI: 10.1155/2016/6579463] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 06/13/2016] [Indexed: 01/15/2023] Open
Abstract
Introduction. The participation of an inflammatory joint milieu has been described in osteoarthritis (OA) pathogenesis. Mesenchymal stromal cells (MSCs) play an important role in modulating inflammatory processes. Based on previous studies in an allogeneic T-cell coculture model, we aimed at further determining the role of synovial MSCs in OA pathogenesis. Methods. Bone-marrow (BM) and synovial membrane (SM) MSCs from hip joints of late stage OA patients and CD4+ T-cells from healthy donors were analysed regarding surface marker expression before and after coculture. Proliferation upon CD3/CD28 stimulation and cytokine analyses were compared between MSCs. Results. SM-MSCs differed from BM-MSCs in several surface markers and their osteogenic differentiation potential. Cocultures of both MSCs with CD4+ T-cells resulted in recruitment of CD45RA+ FoxP3+ regulatory T-cells. Upon stimulation, only SM-MSCs suppressed CD4+ T-cell proliferation, while both SM-MSCs and BM-MSCs modified cytokine profiles through suppressing IL-2 and TNF-α as well as increasing IL-6 secretion. Conclusions. Synovial MSCs from OA joints are a unique fraction that can be distinguished from their bone-marrow derived counterparts. Their unique ability to suppress CD3/CD28 induced CD4+ T-cell proliferation makes them a potential target for future therapeutic approaches.
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Al-Sharabi N, Mustafa M, Ueda M, Xue Y, Mustafa K, Fristad I. Conditioned medium from human bone marrow stromal cells attenuates initial inflammatory reactions in dental pulp tissue. Dent Traumatol 2016; 33:19-26. [PMID: 27145147 DOI: 10.1111/edt.12277] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2016] [Indexed: 12/19/2022]
Abstract
AIM To evaluate the effect of MSC-conditioned medium (CM) on the secretion of pro- and anti-inflammatory cytokines from dental pulp cells (hDPC) in vitro, and on the gene expression in vivo after replantation of rat molars. MATERIALS AND METHODS hDPC were cultured in CM for 24 h, and the concentration of interleukin IL-10, IL-4, IL-6, and IL-8, regulated on activation, normal T Cell expressed and secreted (RANTES), and prostaglandin E2 (PGE2 ) in the media were measured by multiplex assay and ELISA, respectively. Expression of cyclooxygenase-2 (COX-2) was also examined by Western blot analysis after 24 h. Left and right maxillary first rat molars (n = 20) were elevated for 2 min and then replanted with or without application of CM into the tooth sockets. Levels of IL-1β, IL-10, IL-4, IL-6, and IL-8, and tumor necrosis factor-alpha (TNF-α) mRNA were evaluated by real-time qRT-PCR 3 and 14 days following tooth replantation. RESULTS The production of IL-8, IL-10, and IL-6, RANTES and PGE2 by cells cultured in CM was significantly higher than production by cells cultured in standard medium (DMEM). At day 3 following replantation in vivo, the levels of IL-1β and IL-6, and TNF-α mRNA were significantly lower in the CM-treated replanted teeth compared with control teeth. Further, at day 3, the IL-6/IL-10 ratio was significantly lower in the CM-treated replanted teeth compared with control. At day 14 following replantation, no differences in the mRNA ratios were detected between the pulp tissues of replanted and control teeth. CONCLUSIONS These findings indicated that CM promotes secretion of pro- and anti-inflammatory cytokines from hDPCin vitro and attenuates the initial inflammatory response in the rat dental pulp in vivo following tooth replantation.
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Affiliation(s)
- Niyaz Al-Sharabi
- Department of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Manal Mustafa
- Oral Health Centre of Expertise in Western Norway, Bergen, Norway
| | - Minoru Ueda
- Department of Oral and Maxillofacial Surgery, University of Nagoya, Nagoya, Japan
| | - Ying Xue
- Department of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Kamal Mustafa
- Department of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Inge Fristad
- Department of Clinical Dentistry, University of Bergen, Bergen, Norway
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Mansour I, Zayed RA, Said F, Latif LA. Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia. ACTA ACUST UNITED AC 2016; 21:447-53. [PMID: 27077762 DOI: 10.1080/10245332.2015.1106814] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES The microenvironment of acute myeloid leukemia (AML) is suppressive for immune cells. Regulatory T cells (Tregs) have been recognized to play a role in helping leukemic cells to evade immunesurveillance. The mesenchymal stem cells (MSCs) are essential contributors in immunomodulation of the microenvironment as they can promote differentiation of Tregs via the indoleamine 2,3-dioxygenase (IDO) pathway. The aim of the present work was to evaluate the expression of IDO in bone marrow derived MSCs and to study its correlation to percentage of Tregs. METHODS Thirty-seven adult bone marrow samples were cultured in appropriate culture medium to isolate MSCs. Successful harvest of MSCs was determined by plastic adherence, morphology, and positive expression of CD271 and CD105; negative expression of CD34 and CD45 using flowcytometry. MSCs were examined for IDO expression by immunocytochemistry using anti-IDO monoclonal antibody. CD4+ CD25+ cells (Tregs) were measured in bone marrow samples by flowcytometry. RESULTS MSCs were successfully isolated from 20 of the 37 bone marrow samples cultured. MSCs showed higher expression of IDO and Tregs percentage was higher in AML patients compared to control subjects (P = 0.002 and P < 0.001, respectively). A positive correlation was found between IDO expression and Tregs percentage (P value = 0.012, r = 0.5). CONCLUSION In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which could have an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.
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Affiliation(s)
- Iman Mansour
- a Clinical and Chemical Pathology Department, Faculty of Medicine , Cairo University , El Saraya Street, Infront of El Manial Palace, Cairo 11451 , Egypt
| | - Rania A Zayed
- a Clinical and Chemical Pathology Department, Faculty of Medicine , Cairo University , El Saraya Street, Infront of El Manial Palace, Cairo 11451 , Egypt
| | - Fadwa Said
- a Clinical and Chemical Pathology Department, Faculty of Medicine , Cairo University , El Saraya Street, Infront of El Manial Palace, Cairo 11451 , Egypt
| | - Lamyaa Abdel Latif
- a Clinical and Chemical Pathology Department, Faculty of Medicine , Cairo University , El Saraya Street, Infront of El Manial Palace, Cairo 11451 , Egypt
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Pianta S, Bonassi Signoroni P, Muradore I, Rodrigues MF, Rossi D, Silini A, Parolini O. Amniotic membrane mesenchymal cells-derived factors skew T cell polarization toward Treg and downregulate Th1 and Th17 cells subsets. Stem Cell Rev Rep 2016; 11:394-407. [PMID: 25348066 PMCID: PMC4451472 DOI: 10.1007/s12015-014-9558-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We previously demonstrated that cells derived from the mesenchymal layer of the human amniotic membrane (hAMSC) and their conditioned medium (CM-hAMSC) modulate lymphocyte proliferation in a dose-dependent manner. In order to understand the mechanisms involved in immune regulation exerted by hAMSC, we analyzed the effects of CM-hAMSC on T-cell polarization towards Th1, Th2, Th17, and T-regulatory (Treg) subsets. We show that CM-hAMSC equally suppresses the proliferation of both CD4+ T-helper (Th) and CD8+ cytotoxic T-lymphocytes. Moreover, we prove that the CM-hAMSC inhibitory ability affects both central (CD45RO+CD62L+) and effector memory (CD45RO+CD62L−) subsets. We evaluated the phenotype of CD4+ cells in the MLR setting and showed that CM-hAMSC significantly reduced the expression of markers associated to the Th1 (T-bet+CD119+) and Th17 (RORγt+CD161+) populations, while having no effect on the Th2 population (GATA3+CD193+/GATA3+CD294+cells). T-cell subset modulation was substantiated through the analysis of cytokine release for 6 days during co-culture with alloreactive T-cells, whereby we observed a decrease in specific subset-related cytokines, such as a decrease in pro-inflammatory, Th1-related (TNFα, IFNγ, IL-1β), Th2 (IL-5, IL-6), Th9 (IL-9), and Th17 (IL-17A, IL-22). Furthermore, CM-hAMSC significantly induced the Treg compartment, as shown by an induction of proliferating CD4+FoxP3+ cells, and an increase of CD25+FoxP3+ and CD39+FoxP3+ Treg in the CD4+ population. Induction of Treg cells was corroborated by the increased secretion of TGF-β. Taken together, these data strengthen the findings regarding the immunomodulatory properties of CM-hAMSC derived from human amniotic membrane MSC, and in particular provide insights into their effect on regulation of T cell polarization.
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Affiliation(s)
- Stefano Pianta
- Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Via Bissolati, 57, I-25124, Brescia, Italy
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46
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Strong AL, Bowles AC, Wise RM, Morand JP, Dutreil MF, Gimble JM, Bunnell BA. Human Adipose Stromal/Stem Cells from Obese Donors Show Reduced Efficacy in Halting Disease Progression in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis. Stem Cells 2016; 34:614-26. [PMID: 26700612 DOI: 10.1002/stem.2272] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 10/11/2015] [Accepted: 10/30/2015] [Indexed: 12/18/2022]
Abstract
Multiple sclerosis is an autoimmune disease that affects the white matter of the central nervous system and involves inflammation and demyelination. The recent advances in our understanding of adipose-derived stromal/stem cells (ASCs) and the utilization of these cells in clinical settings to treat diseases have made it essential to identify the most effective ASCs for therapy. Studies have not yet investigated the impact of obesity on the therapeutic efficacy of ASCs. Obesity is characterized by adipocyte hyperplasia and hypertrophy and can extend to metabolic and endocrine dysfunction. Investigating the impact obesity has on ASC biology will determine whether these cells are suitable for use in regenerative medicine. The therapeutic efficacy of ASCs isolated from lean subjects (body mass index [BMI] < 25; lnASCs) and obese subjects (BMI > 30; obASCs) were determined in murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Compared with the EAE disease-modifying effects of lnASCs, obASCs consistently failed to alleviate clinical symptoms or inhibit inflammation in the central nervous system. When activated, obASCs expressed higher mRNA levels of several pro-inflammatory cytokines compared with lnASCs. Additionally, conditioned media (CM) collected from the obASCs markedly enhanced the proliferation and differentiation of T cells; whereas, CM from lnASC did not. These results indicate that obesity reduces, or eliminates, the anti-inflammatory effects of human ASCs such that they may not be a suitable cell source for the treatment of autoimmune diseases. The data suggest that donor demographics may be particularly important when identifying suitable stem cells for treatment.
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Affiliation(s)
- Amy L Strong
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Annie C Bowles
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Rachel M Wise
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Joseph P Morand
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Maria F Dutreil
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Jeffrey M Gimble
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.,LaCell LLC, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Bruce A Bunnell
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.,Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, USA
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47
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Zwezdaryk KJ, Ferris MB, Strong AL, Morris CA, Bunnell BA, Dhurandhar NV, Gimble JM, Sullivan DE. Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage. Adipocyte 2016; 5:53-64. [PMID: 27144097 DOI: 10.1080/21623945.2015.1119957] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/03/2015] [Accepted: 11/05/2015] [Indexed: 12/27/2022] Open
Abstract
Human adipose-derived stromal/stem cells (ASCs) display potential to be used in regenerative stem cell therapies and as treatments for inflammatory and autoimmune disorders. Despite promising use of ASCs as therapeutics, little is known about their susceptibility to infectious agents. In this study, we demonstrate that ASCs are highly susceptible to human cytomegalovirus (HCMV) infection and permissive for replication leading to release of infectious virions. Additionally, many basic ASC functions are inhibited during HCMV infection, such as differentiation and immunomodulatory potential. To our knowledge this is the first study examining potential adverse effects of HCMV infection on ASC biology. Our results suggest, that an active HCMV infection during ASC therapy may result in a poor clinical outcome due to interference by the virus.
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48
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Laroni A, Rosbo NKD, Uccelli A. Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection. Immunol Lett 2015; 168:183-90. [DOI: 10.1016/j.imlet.2015.08.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 08/13/2015] [Indexed: 02/08/2023]
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Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, Lagneaux L. Bone Marrow Mesenchymal Stromal Cells Induce Proliferative, Cytokinic and Molecular Changes During the T Cell Response: The Importance of the IL-10/CD210 Axis. Stem Cell Rev Rep 2015; 11:442-452. [PMID: 25326368 DOI: 10.1007/s12015-014-9567-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Bone marrow mesenchymal stromal cells (BM-MSCs) display immunomodulatory features, representing a promising tool for cell-based therapies. However, the mechanisms used by MSCs to regulate T cell fate remain unclear. AIMS We investigated the potential of BM-MSCs to modulate T cell activation, proliferation, cytokine secretion and immunophenotype. MATERIALS AND METHODS T cells were co-cultured with BM-MSCs to assess their immunomodulatory impact. T cell characterization was performed using cell tracing, ELISA, intracellular and surface staining, flow cytometry analysis and qPCR. RESULTS The activation and proliferation of T cells were downregulated during coculture with BM-MSCs. We also observed that BM-MSCs upregulated IL-10 secretion as well as the expression of its receptor CD210 on T cells, thus creating a loop favoring the expansion of IL-10-producing T cells. IL-10 neutralization restored T cell proliferation, demonstrating that IL-10 is functionally relevant during immunomodulation. Moreover, BM-MSCs differently modulated CD4 and CD8 T-cell immunophenotype by inducing broad changes in their molecular pattern. CONCLUSIONS We provide a comprehensive functional and molecular characterization of T cells that are immunomodulated by BM-MSCs. Indeed, a better understanding of the immunological interplay between T cells and MSCs will facilitate the development of new efficient approaches to improve cell-based immune therapies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institute Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Bâtiment de Transfusion (Level +1), Route de Lennik n° 808, 1070, Brussels, Belgium,
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50
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Rodríguez TM, Saldías A, Irigo M, Zamora JV, Perone MJ, Dewey RA. Effect of TGF-β1 Stimulation on the Secretome of Human Adipose-Derived Mesenchymal Stromal Cells. Stem Cells Transl Med 2015; 4:894-8. [PMID: 26025982 DOI: 10.5966/sctm.2015-0012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/08/2015] [Indexed: 12/27/2022] Open
Abstract
Adipose tissue is an attractive source of mesenchymal stromal cells (MSCs) owing to the relative ease of obtaining large volumes with more MSC abundance compared with other sources. Increasing evidence supports the fact that trophic factors secreted by MSCs play a pivotal therapeutic role. Several strategies in regenerative medicine use MSCs, mainly exploiting their immunosuppressive effect and homing capacity to sites of damage. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that, depending on the cell niche, can display either anti-inflammatory or proinflammatory effects. TGF-β1 expression increases in various tissues with damage, especially when accompanied by inflammation. Thus, we analyzed the effect of TGF-β1 on the secretion by adipose-derived mesenchymal stromal cells (ASCs) of a panel of 80 cytokines/chemokines using an antibody array. To avoid a possible effect of fetal bovine serum (FBS) on ASCs secretion, we performed our analysis by culturing cells in FBS-free conditions, only supplemented with 0.1% of bovine serum albumin. We report the cytokine profile secreted by ASCs. We also found that TGF-β1 exposure modulates 8 chemokines and 18 cytokines, including TGF-β1 and -β2, and other important cytokines involved in immunosuppression, allergic responses, and bone resorption.
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Affiliation(s)
- Tania M Rodríguez
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Alejandro Saldías
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Marcelo Irigo
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Jorge Velasco Zamora
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Marcelo J Perone
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Ricardo A Dewey
- Laboratorio de Terapia Génica y Células Madre, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Consejo Nacional de Investigaciones Científicas y Técnicas-Universidad Nacional de San Martín, Chascomús, Argentina; Servicio de Cirugía Plástica, Estética y Reparadora, Hospital Italiano de La Plata, Buenos Aires, Argentina; Centro de Enfermedades Reumáticas/Fundación Articular, Quilmes, Argentina; Instituto de Investigación en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Partner Institute of the Max Planck Society, Buenos Aires, Argentina
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