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Mahjoor M, Nobakht M, Ataei Kachouei F, Zalpoor H, Heidari F, Yari A, Joulai Veijouye S, Nazari H, Sajedi N. In Vitro differentiation of hair-follicle bulge stem cells into synaptophysin-expressing neurons: a potential new approach for neuro-regeneration. Hum Cell 2024; 38:19. [PMID: 39546092 DOI: 10.1007/s13577-024-01146-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 10/09/2024] [Indexed: 11/17/2024]
Abstract
Stem cells, particularly bulge hair follicle stem cells (HFSCs), have recently attracted significant interest due to their potential for tissue repair and regeneration. These cells, marked by their expression of Nestin (a neural stem cell marker), suggest the possibility of neural differentiation into neurons. This study investigated the use of retinoic acid (RA) and epidermal growth factor (EGF) to induce HFSC transformation into mature neurons, identified by synaptophysin expression. Rat whisker follicles were cultured in a medium suitable for HFSC survival and proliferation. Immunostaining techniques were used to identify HFSCs and assess their differentiation into neural cells. The addition of RA and EGF to the culture medium aimed to induce this differentiation. Findings demonstrate that HFSCs expressed Nestin, indicating their pluripotent nature. Treatment with RA and EGF resulted in synaptophysin expression, a marker of mature neurons, which was absent in the control group. However, this treatment group also displayed a decrease in the expression of other neural markers (βIII tubulin and NeuN). This study suggests that a combination of RA and EGF can accelerate HFSC differentiation into synaptophysin-positive cells in vitro. This research paves the way for further exploration of its potential application in neuro-regeneration.
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Affiliation(s)
- Mohamad Mahjoor
- Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom, Iran
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maliheh Nobakht
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Education & Research Network (USERN), Universal Scientific, Tehran, Iran.
| | - Fatemeh Heidari
- Department of Anatomy, Faculty of Medicine, Qum University of Medical Sciences, Qom, Iran
| | - Abazar Yari
- Department of Anatomy, School of Medicine, Alborz University of Medical Science, Karaj, Iran
| | | | - Hojjatollah Nazari
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydney, NSW, Australia
| | - Nayereh Sajedi
- Department of Anatomy, Faculty of Medicine, Qom Medical Sciences, Islamic Azad University, Qom, Iran.
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Kim NY, Choi YY, Kim TH, Ha JH, Kim TH, Kang T, Chung BG. Synergistic Effect of Electrical and Biochemical Stimulation on Human iPSC-Derived Neural Differentiation in a Microfluidic Electrode Array Chip. ACS APPLIED MATERIALS & INTERFACES 2024; 16:15730-15740. [PMID: 38527279 DOI: 10.1021/acsami.3c17108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Neural differentiation is crucial for advancing our understanding of the nervous system and developing treatments for neurological disorders. The advanced methods and the ability to manipulate the alignment, proliferation, and differentiation of stem cells are essential for studying neuronal development and synaptic interactions. However, the utilization of human induced pluripotent stem cells (iPSCs) for disease modeling of neurodegenerative conditions may be constrained by the prolonged duration and uncontrolled cell differentiation required for functional neural cell differentiation. Here, we developed a microfluidic chip to enhance the differentiation and maturation of specific neural lineages by placing aligned microelectrodes on the glass surface to regulate the neural differentiation of human iPSCs. The utilization of electrical stimulation (ES) in conjunction with neurotrophic factors (NF) significantly enhanced the efficiency in generating functional neurons from human iPSCs. We also observed that the simultaneous application of NF and ES to human iPSCs promoted their differentiation and maturation into functional neurons while increasing synaptic interactions. Our research demonstrated the effect of combining NF and ES on human iPSC-derived neural differentiation.
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Affiliation(s)
- Na Yeon Kim
- Department of Biomedical Engineering, Sogang University, Seoul 04107, Korea
| | - Yoon Young Choi
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
| | - Tae Hyeon Kim
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
| | - Jang Ho Ha
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
| | - Tae-Hyung Kim
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Korea
| | - Taewook Kang
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
- Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 04107, Korea
| | - Bong Geun Chung
- Department of Biomedical Engineering, Sogang University, Seoul 04107, Korea
- Institute of Integrated Biotechnology, Sogang University, Seoul 04107, Korea
- Department of Mechanical Engineering, Sogang University, Seoul 04107, Korea
- Institute of Smart Biosensor, Sogang University, Seoul 04107, Korea
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Exposing intracellular molecular changes during the differentiation of human-induced pluripotent stem cells into erythropoietin-producing cells using Raman spectroscopy and imaging. Sci Rep 2022; 12:20454. [PMID: 36443362 PMCID: PMC9705388 DOI: 10.1038/s41598-022-24725-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
The objective of this study was to explore intracellular molecular changes during the differentiation of human-induced pluripotent stem cells (iPSCs) into erythropoietin (EPO)-producing cells using Raman spectroscopy and imaging. Raman imaging data of fixed cells at four stages of cell differentiation were analyzed by a partial least squares (PLS) regression model, and the variations in the intracellular molecular compositions with cell differentiation were investigated. As a result, three biomarkers characterizing the cell phases were identified: dimethyl sulfoxide (DMSO), fatty acids with a low grade of unsaturation, and glycoproteins. The uptake of DMSO by EPO-producing cells, which was added into a culture medium as an inducer for cell differentiation, was detected, and the increase in unsaturated fatty acid concentrations was revealed that lipid metabolism changed over the course of cell differentiation. The decrease in the glycoprotein concentration after the cell phase during which iPSCs differentiated into EPO-producing cells was also made clear. Raman imaging successfully visualized chemical images of these three biomarkers in two dimensions, where the biomarker concentrations independently varied during cell differentiation. These results demonstrated the application potential of the proposed method to regenerative medicine for monitoring cell differentiation and discriminating cell maturation in situ at the molecular level.
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Zhou JF, Xiong Y, Kang X, Pan Z, Zhu Q, Goldbrunner R, Stavrinou L, Lin S, Hu W, Zheng F, Stavrinou P. Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update. Stem Cell Res Ther 2022; 13:281. [PMID: 35765072 PMCID: PMC9241288 DOI: 10.1186/s13287-022-02965-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/19/2022] [Indexed: 12/14/2022] Open
Abstract
Non-traumatic intracerebral hemorrhage is a highly destructive intracranial disease with high mortality and morbidity rates. The main risk factors for cerebral hemorrhage include hypertension, amyloidosis, vasculitis, drug abuse, coagulation dysfunction, and genetic factors. Clinically, surviving patients with intracerebral hemorrhage exhibit different degrees of neurological deficits after discharge. In recent years, with the development of regenerative medicine, an increasing number of researchers have begun to pay attention to stem cell and exosome therapy as a new method for the treatment of intracerebral hemorrhage, owing to their intrinsic potential in neuroprotection and neurorestoration. Many animal studies have shown that stem cells can directly or indirectly participate in the treatment of intracerebral hemorrhage through regeneration, differentiation, or secretion. However, considering the uncertainty of its safety and efficacy, clinical studies are still lacking. This article reviews the treatment of intracerebral hemorrhage using stem cells and exosomes from both preclinical and clinical studies and summarizes the possible mechanisms of stem cell therapy. This review aims to provide a reference for future research and new strategies for clinical treatment.
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Affiliation(s)
- Jian-Feng Zhou
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Yu Xiong
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Xiaodong Kang
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Zhigang Pan
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Qiangbin Zhu
- Department of Neurosurgery, Hui'an County Hospital of Fujian Province, Quanzhou, Fujian, China
| | - Roland Goldbrunner
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany
| | - Lampis Stavrinou
- 2nd Department of Neurosurgery, Athens Medical School, "Attikon" University Hospital, National and Kapodistrian University, Athens, Greece
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Weipeng Hu
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Feng Zheng
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Pantelis Stavrinou
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany.,Neurosurgery, Metropolitan Hospital, Athens, Greece
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Gulzar A, Yıldız E, Kaleli HN, Nazeer MA, Zibandeh N, Malik AN, Taş AY, Lazoğlu I, Şahin A, Kizilel S. Ruthenium-induced corneal collagen crosslinking under visible light. Acta Biomater 2022; 147:198-208. [PMID: 35643198 DOI: 10.1016/j.actbio.2022.05.040] [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: 02/11/2022] [Revised: 04/25/2022] [Accepted: 05/20/2022] [Indexed: 11/01/2022]
Abstract
Corneal collagen crosslinking (CXL) is a commonly used minimally invasive surgical technique to prevent the progression of corneal ectasias, such as keratoconus. Unfortunately, riboflavin/UV-A light-based CXL procedures have not been successfully applied to all patients, and result in frequent complications, such as corneal haze and endothelial damage. We propose a new method for corneal crosslinking by using a Ruthenium (Ru) based water-soluble photoinitiator and visible light (430 nm). Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) and sodium persulfate (SPS) mixture covalently crosslinks free tyrosine, histidine, and lysine groups under visible light (400-450 nm), which prevents UV-A light-induced cytotoxicity in an efficient and time saving collagen crosslinking procedure. In this study, we investigated the effects of the Ru/visible blue light procedure on the viability and toxicity of human corneal epithelium, limbal, and stromal cells. Then bovine corneas crosslinked with ruthenium mixture and visible light were characterized, and their biomechanical properties were compared with the customized riboflavin/UV-A crosslinking approach in the clinics. Crosslinked corneas with a ruthenium-based CXL approach showed significantly higher young's modulus compared to riboflavin/UV-A light-based method applied to corneas. In addition, crosslinked corneas with both methods were characterized to evaluate the hydrodynamic behavior, optical transparency, and enzymatic resistance. In all biomechanical, biochemical, and optical tests used here, corneas that were crosslinked with ruthenium-based approach demonstrated better results than that of corneas crosslinked with riboflavin/ UV-A. This study is promising to be translated into a non-surgical therapy for all ectatic corneal pathologies as a result of mild conditions introduced here with visible light exposure and a nontoxic ruthenium-based photoinitiator to the cornea. STATEMENT OF SIGNIFICANCE: Keratoconus, one of the most frequent corneal diseases, could be treated with riboflavin and ultraviolet light-based photo-crosslinking application to the cornea of the patients. Unfortunately, this method has irreversible side effects and cannot be applied to all keratoconus patients. In this study, we exploited the photoactivation behavior of an organoruthenium compound to achieve corneal crosslinking. Ruthenium-based organic complex under visible light demonstrated significantly better biocompatibility and superior biomechanical results than riboflavin and ultraviolet light application. This study promises to translate into a new fast, efficient non-surgical therapy option for all ectatic corneal pathologies.
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Lenz J, Konecna P, Tichy F, Machacova D, Fiala L, Hurnik P, Kyllar M. Unique expression patterns of the embryonal stem cell marker SOX2 and hormone receptors suggest the existence of a subpopulation of epithelial stem/progenitor cells in porcine and bovine endometrium. Vet Med Sci 2022; 8:1489-1501. [PMID: 35561288 PMCID: PMC9297784 DOI: 10.1002/vms3.802] [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] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND There are currently insufficient data on the population of endometrial epithelial stem/progenitor cells in farm animals. OBJECTIVES With the aim of identifying a potential population of epithelial stem/progenitor cells in the porcine and bovine endometrium, this study immunohistochemically examined the expression patterns of the oestrogen and progesterone receptors, as well as that of the embryonal stem cell marker SOX2. METHODS A total of 24 endometrial tissue samples obtained from cycling pigs (n = 12) and cows (n = 12) were included in our study. Each endometrium was divided into basal, middle and luminal portions. The percentage of marker-positive cells and the intensity of the immunoreaction in each portion of the endometrium were determined. RESULTS Inverse expression patterns of SOX2 and progesterone receptors were found in both animal species throughout the oestrous cycle. Strong diffuse SOX2 expression was detected in the basal portions of the glands, while a significant decrease in positivity and a weak immunoreaction were found in the luminal two thirds of the glandular epithelium. Strong progesterone receptor expression was observed in at least 90% of glandular cells in the middle and luminal portions, whereas weak staining and significant decrease in positivity were detected in the basal portions of the glands. One oestrogen receptor expression pattern resembled that of progesterone receptors. CONCLUSION The inverse expression patterns of SOX2 and hormone (especially progesterone) receptors suggest that endometrial epithelial stem/progenitor cells represent a subset of cells that reside in the basal portions of the endometrial glands in both the bovine and porcine endometrium.
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Affiliation(s)
- Jiri Lenz
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic.,Department of Pathology, Znojmo Hospital, Znojmo, Czech Republic.,Cytohisto s.r.o., Břeclav, Czech Republic
| | - Petra Konecna
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Frantisek Tichy
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Dominika Machacova
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Ludek Fiala
- Cytohisto s.r.o., Břeclav, Czech Republic.,Department of Sexology, Psychiatric Clinic, Faculty of Medicine, Charles University Pilsen, Pilsen, Czech Republic.,Institute of Sexology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
| | | | - Michal Kyllar
- Department of Pathobiology, Institute of Morphology, University of Veterinary Medicine Vienna, Vienna, Austria
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7
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Mohammedsaleh ZM. The use of patient-specific stem cells in different autoimmune diseases. Saudi J Biol Sci 2022; 29:3338-3346. [PMID: 35844404 PMCID: PMC9280249 DOI: 10.1016/j.sjbs.2022.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/27/2022] [Accepted: 02/06/2022] [Indexed: 10/31/2022] Open
Abstract
Autoimmune diseases are developed when the immune system mistakenly attacks the body’s cells. These inflammatory disorders can be inherited or triggered by external forces, such as type 1 diabetes, which is caused by the immune system's destruction of pancreatic beta cells. So far, stem cells such as hESC and iPSC have been used to treat autoimmune disorders such as type 1 diabetes, rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE), although these procedures have certain ethical concerns. On the other hand, bone marrow-derived mesenchymal stem cells (BM-MSC) are thought to be the best source of stem cells. Later, it was shown that mesenchymal stem cells produced from autologous adipose tissues have a great potential for producing huge volumes of stem cells. In-vitro and in-vivo investigations using autologous hematopoietic stem cells and autologous mesenchymal stem cells have been carried out on various rodent and human models, while clinical trials for inflammatory diseases such as multiple sclerosis and diabetes mellitus have yielded promising results. We attempted to summarise the usage of diverse stem cells in the therapy of various autoimmune disorders in this review. Shortly, we expect that the use of autologous stem cells will provide a new perspective on the treatment of autoimmune disorders.
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8
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Rodríguez Escobar MI, Cadena E, Nhu TT, Cooreman-Algoed M, De Smet S, Dewulf J. Analysis of the Cultured Meat Production System in Function of Its Environmental Footprint: Current Status, Gaps and Recommendations. Foods 2021; 10:2941. [PMID: 34945492 PMCID: PMC8701123 DOI: 10.3390/foods10122941] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/27/2022] Open
Abstract
Cultured meat has been presented as an environmentally friendlier option to conventional meat, but due to the limited data, the studies related to its performance are scarce and based on hypothetical production processes. This work provides a short literature review of the published environmental assessments of cultured meat. The main findings of this critical analysis showed that the lack of real data related to cultured meat decreased the level of accuracy of each study. The missing environmental profile of the process itself, including the proliferation and differentiation phases in bioreactors, along with key ingredients such as growth factors and other recombinant proteins, increase the difficulty of achieving reliable conclusions. In order to bridge the highlighted gaps, a complete production system is modelled and analysed from an engineering and life-cycle perspective. Furthermore, an overview of the supply chains of different products used in the process is provided, together with recommendations on how they should be considered in future life-cycle assessments. In essence, this work provides a structured pathway for upcoming consistent environmental assessments in this field, with the objective of setting the basis to understand the potential of cultured meat.
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Affiliation(s)
- María Ignacia Rodríguez Escobar
- Research Group Sustainable Systems Engineering (STEN), Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium; (E.C.); (T.T.N.); (M.C.-A.); (J.D.)
| | - Erasmo Cadena
- Research Group Sustainable Systems Engineering (STEN), Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium; (E.C.); (T.T.N.); (M.C.-A.); (J.D.)
| | - Trang T. Nhu
- Research Group Sustainable Systems Engineering (STEN), Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium; (E.C.); (T.T.N.); (M.C.-A.); (J.D.)
| | - Margot Cooreman-Algoed
- Research Group Sustainable Systems Engineering (STEN), Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium; (E.C.); (T.T.N.); (M.C.-A.); (J.D.)
| | - Stefaan De Smet
- Laboratory for Animal Nutrition and Animal Product Quality, Department of Animal Sciences and Aquatic Ecology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium;
| | - Jo Dewulf
- Research Group Sustainable Systems Engineering (STEN), Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium; (E.C.); (T.T.N.); (M.C.-A.); (J.D.)
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Świerczek-Lasek B, Dudka D, Bauer D, Czajkowski T, Ilach K, Streminska W, Kominek A, Piwocka K, Ciemerych MA, Archacka K. Comparison of Differentiation Pattern and WNT/SHH Signaling in Pluripotent Stem Cells Cultured under Different Conditions. Cells 2021; 10:cells10102743. [PMID: 34685722 PMCID: PMC8534321 DOI: 10.3390/cells10102743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/01/2021] [Accepted: 10/08/2021] [Indexed: 11/16/2022] Open
Abstract
Pluripotent stem cells (PSCs) are characterized by the ability to self-renew as well as undergo multidirectional differentiation. Culture conditions have a pivotal influence on differentiation pattern. In the current study, we compared the fate of mouse PSCs using two culture media: (1) chemically defined, free of animal reagents, and (2) standard one relying on the serum supplementation. Moreover, we assessed the influence of selected regulators (WNTs, SHH) on PSC differentiation. We showed that the differentiation pattern of PSCs cultured in both systems differed significantly: cells cultured in chemically defined medium preferentially underwent ectodermal conversion while their endo- and mesodermal differentiation was limited, contrary to cells cultured in serum-supplemented medium. More efficient ectodermal differentiation of PSCs cultured in chemically defined medium correlated with higher activity of SHH pathway while endodermal and mesodermal conversion of cells cultured in serum-supplemented medium with higher activity of WNT/JNK pathway. However, inhibition of either canonical or noncanonical WNT pathway resulted in the limitation of endo- and mesodermal conversion of PSCs. In addition, blocking WNT secretion led to the inhibition of PSC mesodermal differentiation, confirming the pivotal role of WNT signaling in this process. In contrast, SHH turned out to be an inducer of PSC ectodermal, not mesodermal differentiation.
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Affiliation(s)
- Barbara Świerczek-Lasek
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Damian Dudka
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Damian Bauer
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Tomasz Czajkowski
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Katarzyna Ilach
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Władysława Streminska
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Agata Kominek
- Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.K.); (K.P.)
| | - Katarzyna Piwocka
- Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.K.); (K.P.)
| | - Maria A. Ciemerych
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
| | - Karolina Archacka
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland; (B.Ś.-L.); (D.D.); (D.B.); (T.C.); (K.I.); (W.S.); (M.A.C.)
- Correspondence: ; Tel.: +48-22-55-42-203
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10
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Application of mesenchymal stem cells in corneal regeneration. Tissue Cell 2021; 73:101600. [PMID: 34371292 DOI: 10.1016/j.tice.2021.101600] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/24/2021] [Accepted: 07/25/2021] [Indexed: 12/13/2022]
Abstract
Due to delicate its structure, the cornea is susceptible to physical, chemical, and genetic damages. Corneal transplantation is the main treatment for serious corneal damage, but it faces significant challenges, including donor shortages and severe complications. In recent years, cell therapy is suggested as a novel alternative method for corneal regeneration. Regarding the unique characteristics of Mesenchymal stem cells including the potential to differentiate into discrete cell types, secretion of growth factors, mobilization potency, and availability from different sources; special attention has been paid to these cells in corneal engineering. Differentiation of MSCs into specialized corneal cells such as keratocytes, epithelial and endothelial cells is reported. Potential for Treatment of keratitis, reducing inflammation, and inhibition of neovascularization by MSCs, introducing them as novel agents for corneal repairing. In this review, various types of MSCs used to treat corneal injuries as well as their potential for restoring different corneal layers was investigated.
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11
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Khandpur S, Gupta S, Gunaabalaji DR. Stem cell therapy in dermatology. Indian J Dermatol Venereol Leprol 2021; 87:753-767. [PMID: 34245532 DOI: 10.25259/ijdvl_19_20] [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: 01/01/2020] [Accepted: 01/01/2021] [Indexed: 12/20/2022]
Abstract
Stem cells are precursor cells present in many tissues with ability to differentiate into various types of cells. This interesting property of plasticity can have therapeutic implications and there has been substantial research in this field in last few decades. As a result, stem cell therapy is now used as a therapeutic modality in many conditions, and has made its way in dermatology too. Stem cells can be classified on the basis of their source and differentiating capacity. In skin, they are present in the inter-follicular epidermis, hair follicle, dermis and adipose tissue, which help in maintaining normal skin homeostasis and repair and regeneration during injury. In view of their unique properties, they have been employed in treatment of several dermatoses including systemic sclerosis, systemic lupus erythematosus, scleromyxedema, alopecia, Merkel cell carcinoma, pemphigus vulgaris, psoriasis, wound healing, epidermolysis bullosa and even aesthetic medicine, with variable success. The advent of stem cell therapy has undoubtedly brought us closer to curative treatment of disorders previously considered untreatable. Nevertheless, there are multiple lacunae which need to be addressed including ideal patient selection, timing of intervention, appropriate conditioning regimens, post-intervention care and cost effectiveness. Further research in these aspects would help optimize the results of stem cell therapy.
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Affiliation(s)
- Sujay Khandpur
- Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
| | - Savera Gupta
- Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
| | - D R Gunaabalaji
- Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
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12
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He R, Dantas A, Riabowol K. Histone Acetyltransferases and Stem Cell Identity. Cancers (Basel) 2021; 13:2407. [PMID: 34067525 PMCID: PMC8156521 DOI: 10.3390/cancers13102407] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/02/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.
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Affiliation(s)
- Ruicen He
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (R.H.); (A.D.)
- Department of Molecular Genetics, Temerty School of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Arthur Dantas
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (R.H.); (A.D.)
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Karl Riabowol
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (R.H.); (A.D.)
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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13
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Aghlmandi A, Nikshad A, Safaralizadeh R, Warkiani ME, Aghebati-Maleki L, Yousefi M. Microfluidics as efficient technology for the isolation and characterization of stem cells. EXCLI JOURNAL 2021; 20:426-443. [PMID: 33746671 PMCID: PMC7975637 DOI: 10.17179/excli2020-3028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/15/2021] [Indexed: 01/09/2023]
Abstract
The recent years have been passed with significant progressions in the utilization of microfluidic technologies for cellular investigations. The aim of microfluidics is to mimic small-scale body environment with features like optical transparency. Microfluidics can screen and monitor different cell types during culture and study cell function in response to stimuli in a fully controlled environment. No matter how the microfluidic environment is similar to in vivo environment, it is not possible to fully investigate stem cells behavior in response to stimuli during cell proliferation and differentiation. Researchers have used stem cells in different fields from fundamental researches to clinical applications. Many cells in the body possess particular functions, but stem cells do not have a specific task and can turn into almost any type of cells. Stem cells are undifferentiated cells with the ability of changing into specific cells that can be essential for the body. Researchers and physicians are interested in stem cells to use them in testing the function of the body's systems and solving their complications. This review discusses the recent advances in utilizing microfluidic techniques for the analysis of stem cells, and mentions the advantages and disadvantages of using microfluidic technology for stem cell research.
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Affiliation(s)
- Afsoon Aghlmandi
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Aylin Nikshad
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Majid Ebrahimi Warkiani
- The School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
| | | | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Science, Tabriz, Iran
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14
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Anwar I, Ashfaq UA, Shokat Z. Therapeutic Potential of Umbilical Cord Stem Cells for Liver Regeneration. Curr Stem Cell Res Ther 2020; 15:219-232. [PMID: 32077830 DOI: 10.2174/1568026620666200220122536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/16/2019] [Accepted: 08/08/2019] [Indexed: 01/18/2023]
Abstract
The liver is a vital organ for life and the only internal organ that is capable of natural regeneration. Although the liver has high regeneration capacity, excessive hepatocyte death can lead to liver failure. Various factors can lead to liver damage including drug abuse, some natural products, alcohol, hepatitis, and autoimmunity. Some models for studying liver injury are APAP-based model, Fas ligand (FasL), D-galactosamine/endotoxin (Gal/ET), Concanavalin A, and carbon tetrachloride-based models. The regeneration of the liver can be carried out using umbilical cord blood stem cells which have various advantages over other stem cell types used in liver transplantation. UCB-derived stem cells lack tumorigenicity, have karyotype stability and high immunomodulatory, low risk of graft versus host disease (GVHD), low risk of transmitting somatic mutations or viral infections, and low immunogenicity. They are readily available and their collection is safe and painless. This review focuses on recent development and modern trends in the use of umbilical cord stem cells for the regeneration of liver fibrosis.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Usman A Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Zeeshan Shokat
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
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15
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Perugini V, Santin M. A comparative in vitro study of the effect of biospecific integrin recognition processes and substrate nanostructure on stem cell 3D spheroid formation. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2020; 31:37. [PMID: 32206915 PMCID: PMC7089895 DOI: 10.1007/s10856-020-06373-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 01/23/2020] [Accepted: 03/02/2020] [Indexed: 05/10/2023]
Abstract
The in vitro study of the properties of the human mesenchymal stem cells as well as their manipulation in culture for clinical purposes depends on the elimination of artefacts caused by the lack of their natural environment. It is now widely accepted that mesenchymal stem cells should be studied when they are organised as 3D spheroids rather than fibroblast-like colonies. Although this can be achieved with the use of some extracellular matrix proteins or by non-adherent conditions these suffer of significant limitations. The recent development of synthetic substrates resembling the physicochemical and biochemical properties of the adult stem cell niche has prompted questions about the role played by nanotopography and receptor-mediated adhesion. In the present paper, the influence of two types of substrates bearing the same nanostructure, but exposing either a non-specific or an integrin-specific binding motif was studied. Carboxybetaine-tethered hyperbranched poly(ɛ-lysine) dendrons showed that the hyperbranched structure was fundamental to induce spheroid formation, but these were forming more slowly, were of reduced size and less stable than those growing on substrates based on the same hyperbranched structures that had been functionalised at their uppermost branching generation by a laminin amino acid sequence, i.e. YIGSR. The study shows that both nanostructure and biorecognition need to be combined to achieve a substrate for stem cell spheroid formation as that observed in vivo in the adult stem cell niche.
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Affiliation(s)
- Valeria Perugini
- Centre for Regenerative Medicine and Devices, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, BN2 4GJ, UK
| | - Matteo Santin
- Centre for Regenerative Medicine and Devices, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, BN2 4GJ, UK.
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16
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Kim MH, Kino-Oka M. Bioengineering Considerations for a Nurturing Way to Enhance Scalable Expansion of Human Pluripotent Stem Cells. Biotechnol J 2020; 15:e1900314. [PMID: 31904180 DOI: 10.1002/biot.201900314] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/11/2019] [Indexed: 12/13/2022]
Abstract
Understanding how defects in mechanotransduction affect cell-to-cell variability will add to the fundamental knowledge of human pluripotent stem cell (hPSC) culture, and may suggest new approaches for achieving a robust, reproducible, and scalable process that result in consistent product quality and yields. Here, the current state of the understanding of the fundamental mechanisms that govern the growth kinetics of hPSCs between static and dynamic cultures is reviewed, the factors causing fluctuations are identified, and culture strategies that might eliminate or minimize the occurrence of cell-to-cell variability arising from these fluctuations are discussed. The existing challenges in the development of hPSC expansion methods for enabling the transition from process development to large-scale production are addressed, a mandatory step for industrial and clinical applications of hPSCs.
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Affiliation(s)
- Mee-Hae Kim
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masahiro Kino-Oka
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
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17
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Matthews H, Noulin F. Unexpected encounter of the parasitic kind. World J Stem Cells 2019; 11:904-919. [PMID: 31768219 PMCID: PMC6851008 DOI: 10.4252/wjsc.v11.i11.904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/10/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some “unexpected encounters”. In this review, we summarise the various links between parasites and stem cells. First, we discuss how parasites’ own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.
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Affiliation(s)
- Holly Matthews
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
| | - Florian Noulin
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
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18
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de Cara SPHM, Origassa CST, de Sá Silva F, Moreira MSNA, de Almeida DC, Pedroni ACF, Carvalho GL, Cury DP, Câmara NOS, Marques MM. Angiogenic properties of dental pulp stem cells conditioned medium on endothelial cells in vitro and in rodent orthotopic dental pulp regeneration. Heliyon 2019; 5:e01560. [PMID: 31183428 PMCID: PMC6488540 DOI: 10.1016/j.heliyon.2019.e01560] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 02/18/2019] [Accepted: 04/18/2019] [Indexed: 12/15/2022] Open
Abstract
Objectives To evaluate the effect of SHED-CM on the proliferation, differentiation, migration ability, cell death, gene expression and production of VEGF of HUVEC in vitro and in a rodent orthotopic dental pulp regeneration. Methods Three culture media [M199, DMEM/Ham's F12 and DMEM/Ham's F12 conditioned by SHEDs] were used as experimental groups. SHED-CM was prepared maintaining confluent cells in culture without serum for 3 days. The proliferation and cell death marker of HUVECs were assessed using flow cytometry. The capacity of formation of vascular-like structures was analyzed in cells grown over Matrigel® in hypoxic condition. HUVECs migration was followed using the scratch test. VEGF-A expression in HUVECs was assessed using real time RT-qPCR; and VEGF synthesis with ELISA test. SHED-CM was also applied in rodent ortotopic model of dental pulp regeneration in rats. The formed tissue was submitted to histological and immunohistochemical analyses. Results SHED-CM promoted significantly lower expression of 7AAD in HUVECs; whereas the expression of the Ki67 was similar in all groups. The vascular-like structures were observed in all groups. Migration of SHED-CM group was faster than DMEM/Ham's F12. SHED-CM induced similar expression of VEGF-A than M199, and higher than DMEM/Ham's F12. SHED-CM induced significantly higher VEGF synthesis than other media. SHED-CM induced formation of a vascularized connective tissue inside the root canal. Conclusion The study showed that SHEDs release angiogenic and cytoprotective factors, which are of great importance for tissue engineering. Clinical significance SHED-CM could be an option to the use of stem cells in tissue engineering.
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Affiliation(s)
| | | | - Fernando de Sá Silva
- Institute of Life Sciences, Universidade Federal de Juiz de Fora (UFJF), Governador Valadares, MG, Brazil
| | | | - Danilo Candido de Almeida
- Departamento de Medicina, Divisão de Nefrologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Ana Clara Fagundes Pedroni
- Department of Restorative Dentistry and Endodontics, School of Dentistry, University of Sao Paulo (USP), Sao Paulo, SP, Brazil
| | - Giovanna Lopes Carvalho
- Department of Restorative Dentistry and Endodontics, School of Dentistry, University of Sao Paulo (USP), Sao Paulo, SP, Brazil
| | | | - Niels Olsen Saraiva Câmara
- Departamento de Medicina, Divisão de Nefrologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Márcia Martins Marques
- Department of Restorative Dentistry and Endodontics, School of Dentistry, University of Sao Paulo (USP), Sao Paulo, SP, Brazil
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19
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Torizal FG, Horiguchi I, Sakai Y. Physiological Microenvironmental Conditions in Different Scalable Culture Systems for Pluripotent Stem Cell Expansion and Differentiation. Open Biomed Eng J 2019. [DOI: 10.2174/1874120701913010041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Human Pluripotent Stem Cells (PSCs) are a valuable cell type that has a wide range of biomedical applications because they can differentiate into many types of adult somatic cell. Numerous studies have examined the clinical applications of PSCs. However, several factors such as bioreactor design, mechanical stress, and the physiological environment have not been optimized. These factors can significantly alter the pluripotency and proliferation properties of the cells, which are important for the mass production of PSCs. Nutritional mass transfer and oxygen transfer must be effectively maintained to obtain a high yield. Various culture systems are currently available for optimum cell propagation by maintaining the physiological conditions necessary for cell cultivation. Each type of culture system using a different configuration with various advantages and disadvantages affecting the mechanical conditions in the bioreactor, such as shear stress. These factors make it difficult to preserve the cellular viability and pluripotency of PSCs. Additional limitations of the culture system for PSCs must also be identified and overcome to maintain the culture conditions and enable large-scale expansion and differentiation of PSCs. This review describes the different physiological conditions in the various culture systems and recent developments in culture technology for PSC expansion and differentiation.
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20
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Christodoulou I, Goulielmaki M, Devetzi M, Panagiotidis M, Koliakos G, Zoumpourlis V. Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review. Stem Cell Res Ther 2018; 9:336. [PMID: 30526687 PMCID: PMC6286545 DOI: 10.1186/s13287-018-1078-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSC) comprise a heterogeneous population of rapidly proliferating cells that can be isolated from adult (e.g., bone marrow, adipose tissue) as well as fetal (e.g., umbilical cord) tissues (termed bone marrow (BM)-, adipose tissue (AT)-, and umbilical cord (UC)-MSC, respectively) and are capable of differentiation into a wide range of non-hematopoietic cell types. An additional, unique attribute of MSC is their ability to home to tumor sites and to interact with the local supportive microenvironment which rapidly conceptualized into MSC-based experimental cancer cytotherapy at the turn of the century. Towards this purpose, both naïve (unmodified) and genetically modified MSC (GM-MSC; used as delivery vehicles for the controlled expression and release of antitumorigenic molecules) have been employed using well-established in vitro and in vivo cancer models, albeit with variable success. The first approach is hampered by contradictory findings regarding the effects of naïve MSC of different origins on tumor growth and metastasis, largely attributed to inherent biological heterogeneity of MSC as well as experimental discrepancies. In the second case, although the anti-cancer effect of GM-MSC is markedly improved over that of naïve cells, it is yet apparent that some protocols are more efficient against some types of cancer than others. Regardless, in order to maximize therapeutic consistency and efficacy, a deeper understanding of the complex interaction between MSC and the tumor microenvironment is required, as well as examination of the role of key experimental parameters in shaping the final cytotherapy outcome. This systematic review represents, to the best of our knowledge, the first thorough evaluation of the impact of experimental anti-cancer therapies based on MSC of human origin (with special focus on human BM-/AT-/UC-MSC). Importantly, we dissect the commonalities and differences as well as address the shortcomings of work accumulated over the last two decades and discuss how this information can serve as a guide map for optimal experimental design implementation ultimately aiding the effective transition into clinical trials.
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Affiliation(s)
- Ioannis Christodoulou
- Institute of Biological Research and Biotechnology, National Hellenic Research Foundation (NHRF), Konstantinou 48 Av., 116 35, Athens, Greece
| | - Maria Goulielmaki
- Institute of Biological Research and Biotechnology, National Hellenic Research Foundation (NHRF), Konstantinou 48 Av., 116 35, Athens, Greece
| | - Marina Devetzi
- Institute of Biological Research and Biotechnology, National Hellenic Research Foundation (NHRF), Konstantinou 48 Av., 116 35, Athens, Greece
| | | | | | - Vassilis Zoumpourlis
- Institute of Biological Research and Biotechnology, National Hellenic Research Foundation (NHRF), Konstantinou 48 Av., 116 35, Athens, Greece.
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21
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The effect of alginate-gelatin encapsulation on the maturation of human myelomonocytic cell line U937. J Tissue Eng Regen Med 2018; 13:25-35. [DOI: 10.1002/term.2765] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/02/2018] [Accepted: 10/18/2018] [Indexed: 01/04/2023]
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The special stemness functions of Tbx3 in stem cells and cancer development. Semin Cancer Biol 2018; 57:105-110. [PMID: 30268432 DOI: 10.1016/j.semcancer.2018.09.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/13/2018] [Accepted: 09/26/2018] [Indexed: 12/15/2022]
Abstract
The T-box factors belong to an ancient protein family, which comprises a cluster of evolutionarily-conserved transcription factors that regulate gene expression and that are crucial to embryonic development. T-box transcription factor 3 (Tbx3) is a member of this family, is expressed in some tissues, and is a key regulator in many critical organs, including the heart, mammary gland, and limbs. Overexpression of Tbx3 is associated with a number of cancers, including head and neck squamous cell carcinoma, gastric, breast, ovary, cervical, pancreatic, bladder and liver cancers, as well as melanoma. Tbx3 promotes tumor development by modulating cell proliferation, tumor formation, metastasis, cell survival and drug resistance. Moreover, there is strong evidence that Tbx3 regulates stem cell maintenance by controlling stem cell self-renewal and differentiation. Verification of the upstream regulatory factors and potential molecular mechanism of Tbx3, being able to explain the function of Tbx3 in carcinogenic effects and stem cell maintenance, will make a valuable contribution to stem cell and cancer research. This review provides an insight into the current research on Tbx3 and explores the significance of Tbx3 in stem cells and tumorigenesis.
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23
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Alakpa EV, Saeed A, Chung P, Riehle MO, Gadegaard N, Dalby MJ, Cusack M. The Prismatic Topography of Pinctada maxima
Shell Retains Stem Cell Multipotency and Plasticity In Vitro. ACTA ACUST UNITED AC 2018. [DOI: 10.1002/adbi.201800012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Enateri V. Alakpa
- Institution for Integrative Medical Biology; Umeå University; SE901 87 Umeå Sweden
| | - Anwer Saeed
- Division of Biomedical Engineering; School of Engineering; University of Glasgow; Glasgow G12 8LT Scotland UK
| | - Peter Chung
- School of Geographical & Earth Sciences; College of Science & Engineering; Gregory Building; University of Glasgow; Glasgow G12 8QQ UK
| | - Mathis O. Riehle
- Centre for Cell Engineering; Institute of Molecular Cell & Systems Biology; College of Medical; Veterinary & Life Sciences; Joseph Black Building; University of Glasgow; Glasgow G12 8QQ UK
| | - Nikolaj Gadegaard
- Division of Biomedical Engineering; School of Engineering; University of Glasgow; Glasgow G12 8LT Scotland UK
| | - Matthew J. Dalby
- Centre for Cell Engineering; Institute of Molecular Cell & Systems Biology; College of Medical; Veterinary & Life Sciences; Joseph Black Building; University of Glasgow; Glasgow G12 8QQ UK
| | - Maggie Cusack
- Division of Biological & Environmental Sciences; Faculty of Natural Sciences; Cottrell Building; University of Stirling; Stirling FK9 4LA UK
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24
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Long bone mesenchymal stem cells (Lb-MSCs): clinically reliable cells for osteo-diseases. Cell Tissue Bank 2017; 18:489-500. [DOI: 10.1007/s10561-017-9652-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 08/08/2017] [Indexed: 01/24/2023]
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25
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Bastami F, Nazeman P, Moslemi H, Rezai Rad M, Sharifi K, Khojasteh A. Induced pluripotent stem cells as a new getaway for bone tissue engineering: A systematic review. Cell Prolif 2017; 50:e12321. [PMID: 27905670 PMCID: PMC6529104 DOI: 10.1111/cpr.12321] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 10/31/2016] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) are frequently used for bone regeneration, however, they are limited in quantity. Moreover, their proliferation and differentiation capabilities reduce during cell culture expansion. Potential application of induced pluripotent stem cells (iPSCs) has been reported as a promising alternative source for bone regeneration. This study aimed to systematically review the available literature on osteogenic potential of iPSCs and to discuss methods applied to enhance their osteogenic potential. METHODS AND MATERIALS A thorough search of MEDLINE database was performed from January 2006 to September 2016, limited to English-language articles. All in vitro and in vivo studies on application of iPSCs in bone regeneration were included. RESULTS The current review is organized according to the PRISMA statement. Studies were categorized according to three different approaches used for osteo-induction of iPSCs. Data are summarized and reported according to the following variables: types of study, cell sources used for iPSC generation, applied reprogramming methods, applied osteo-induction methods and treatment groups. CONCLUSION According to the articles reviewed, osteo-induced iPSCs revealed osteogenic capability equal to or superior than MSCs; cell sources do not significantly affect osteogenic potential of iPSCs; addition of resveratrol to the osteogenic medium (OM) and irradiatiation after osteogenic induction reduce teratoma formation in animal models; transfection with lentiviral bone morphogenetic protein 2 results in higher mineralization compared to osteo-induction in OM; addition of TGF-β, IGF-1 and FGF-β to OM increases osteogenic capability of iPSCs.
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Affiliation(s)
- Farshid Bastami
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Pantea Nazeman
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Hamidreza Moslemi
- School of DentistryShahid Beheshti University of Medical SciencesTehranIran
| | - Maryam Rezai Rad
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Kazem Sharifi
- Department of BiotechnologySchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Arash Khojasteh
- Department of Tissue EngineeringSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
- Faculty of MedicineUniversity of AntwerpAntwerpBelgium
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26
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Guo R, Pan F, Tian Y, Li H, Li S, Cao C. Down-Regulation of ClC-3 Expression Reduces Epidermal Stem Cell Migration by Inhibiting Volume-Activated Chloride Currents. J Membr Biol 2016; 249:281-92. [DOI: 10.1007/s00232-015-9867-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 12/30/2015] [Indexed: 01/10/2023]
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27
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Induced Pluripotency and Gene Editing in Disease Modelling: Perspectives and Challenges. Int J Mol Sci 2015; 16:28614-34. [PMID: 26633382 PMCID: PMC4691066 DOI: 10.3390/ijms161226119] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/13/2015] [Accepted: 11/24/2015] [Indexed: 02/07/2023] Open
Abstract
Embryonic stem cells (ESCs) are chiefly characterized by their ability to self-renew and to differentiate into any cell type derived from the three main germ layers. It was demonstrated that somatic cells could be reprogrammed to form induced pluripotent stem cells (iPSCs) via various strategies. Gene editing is a technique that can be used to make targeted changes in the genome, and the efficiency of this process has been significantly enhanced by recent advancements. The use of engineered endonucleases, such as homing endonucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Cas9 of the CRISPR system, has significantly enhanced the efficiency of gene editing. The combination of somatic cell reprogramming with gene editing enables us to model human diseases in vitro, in a manner considered superior to animal disease models. In this review, we discuss the various strategies of reprogramming and gene targeting with an emphasis on the current advancements and challenges of using these techniques to model human diseases.
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Sivakumar M, Dineshshankar J, Sunil PM, Nirmal RM, Sathiyajeeva J, Saravanan B, Senthileagappan AR. Stem cells: An insight into the therapeutic aspects from medical and dental perspectives. J Pharm Bioallied Sci 2015; 7:S361-71. [PMID: 26538878 PMCID: PMC4606620 DOI: 10.4103/0975-7406.163453] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The recent advancements in the field of stem cell (SC) biology have increased the hope of achieving the definitive treatments for the diseases which are now considered incurable such as diabetes, Parkinson's disease and other chronic long standing conditions. To achieve this possibility, it is necessary to understand the basic concepts of SC biology to utilize in various advanced techniques of regenerative medicine including tissue engineering and gene therapy. This article highlights the types of SCs available and their therapeutic capacity in regenerative medical and dental fields.
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Affiliation(s)
- Muniapillai Sivakumar
- Department of Oral Pathology and Microbiology, Madha Dental College and Hospital, Chennai, Tamil Nadu, India
| | - Janardhanam Dineshshankar
- Department of Oral Pathology and Microbiology, Vivekanandha Dental College for Women, Tiruchengode, Namakkal, Tamil Nadu, India
| | - P M Sunil
- Department of Oral Pathology and Microbiology, Sree Anjaneya Institute of Dental Sciences, Calicut, Kerala, India
| | - R Madhavan Nirmal
- Department of Oral Pathology and Microbiology, Rajah Muthiah Dental College and Hospital, Annamalai University, Chidambaram, Tamil Nadu, India
| | - J Sathiyajeeva
- Department of Oral Pathology and Microbiology, Thai Moogambigai Dental College and Hospital, Chennai, Tamil Nadu, India
| | - Balasubramanian Saravanan
- Department of Oral and Maxillofacial Surgery, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India
| | - A R Senthileagappan
- Department of Pedodontics, Chettinad Dental College and Research Institute, Chettinad Health City, Chennai, Tamil Nadu, India
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Strategies for stem cell patent applications in the light of recent court cases. Pharm Pat Anal 2015; 4:431-41. [PMID: 26580992 DOI: 10.4155/ppa.15.29] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Stem cells offer the prospect of treatments for diseases and injuries that are currently beyond medical science. Although development of these potential medical marvels has been dogged by their controversial origin, technological developments and guidance from recent judicial decisions have answered and overcome many of these difficulties. In particular, the European Patent Office, United States Patent and Trademark Office, Japan Patent Office and State Intellectual Property Office of China have published guidelines covering patenting of stem cell technologies in the light of recent decisions. We now see a patent landscape where stem cell technologies and related therapies can, with very few exceptions, be protected via patents, provided the appropriate form of claim wording is used.
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Ochiai H, Suga H, Yamada T, Sakakibara M, Kasai T, Ozone C, Ogawa K, Goto M, Banno R, Tsunekawa S, Sugimura Y, Arima H, Oiso Y. BMP4 and FGF strongly induce differentiation of mouse ES cells into oral ectoderm. Stem Cell Res 2015; 15:290-8. [PMID: 26209816 DOI: 10.1016/j.scr.2015.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 06/08/2015] [Accepted: 06/30/2015] [Indexed: 11/30/2022] Open
Abstract
During embryonic development, oral ectoderm differentiates into the adenohypophysis, dental epithelia, salivary glands, and nasal pit. Few reports exist concerning the induction of oral ectoderm from embryonic stem (ES) cells. Generally, any lot differences in fetal bovine serum (FBS) and serum replacer may affect the induction of ES cell-differentiation. Using a previously established culture strategy for differentiation, the proportion of cell aggregates containing Pitx1+ oral ectoderm varied widely between 9-36% when several different lots of FBS or serum replacer were used. We therefore tried to enhance the differentiation method. We found that bone morphogenetic protein (BMP) 4 and fibroblast growth factor (FGF) treatments improved oral ectoderm induction. Such treatment also improved the differentiation of oral ectoderm into the adenohypophysis. Furthermore, increased BMP4 treatment induced dental epithelium and mesenchyme. Such differentiation suggests that the Pitx1+ layer displays similar properties to oral ectoderm, as found in vivo. Differentiation of ES cells into oral ectoderm using different lots of FBS and serum replacer increased 78-90% after treatment with BMP4 and FGF. In summary, we have established a robust strategy for the induction of oral ectoderm differentiation from mouse ES cells.
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Affiliation(s)
- Hiroshi Ochiai
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
| | - Tomiko Yamada
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Mayu Sakakibara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Takatoshi Kasai
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Chikafumi Ozone
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Koichiro Ogawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Motomitsu Goto
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Ryoichi Banno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Shin Tsunekawa
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Yoshihisa Sugimura
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Yutaka Oiso
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
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Zahra SA, Muzavir SR, Ashraf S, Ahmad A. Stem cell research in pakistan; past, present and future. Int J Stem Cells 2015; 8:1-8. [PMID: 26019749 PMCID: PMC4445703 DOI: 10.15283/ijsc.2015.8.1.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 02/02/2015] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Stem cells have proved to have great therapeutic potential as stem cell treatment is replacing traditional ways of treatment in different disorders like cancer, aplastic anemia, stroke, heart disorders. The developed and developing countries are investing differently in this area of research so research output and clinical translation of research greatly vary among developed and developing countries. Present study was done to investigate the current status of stem cells research in Pakistan and ways to improve it. RESULTS Many advanced countries (USA, UK and Canada etc.) are investing heavily in stem cell research and treatment. Different developing countries like Iran, Turkey and India are also following the developed countries and investing a lot in stem cells research. Pakistan is also making efforts in establishing this field to get desired benefits but unfortunately the progress is at very low pace. If Government plays an active role along with private sector, stem cell research in Pakistan can be boosted up. The numbers of publications from Pakistan are very less compared to developed and neighboring countries and Pakistan also has very less number of institutes working in this area of research. CONCLUSIONS Stem cells research is at its initial stages in Pakistan and there is great need to bring Government, academia and industry together so they could make serious efforts to promote research in this very important field. This will help millions of patients suffering from incurable disorders and will also reduce economic loss.
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Affiliation(s)
- Sayeda Anum Zahra
- National Academy of Young Scientists (NAYS), University of the Punjab, Quaid-i-Azam Campus, Lahore,
Pakistan
| | - Sayed Raheel Muzavir
- National Academy of Young Scientists (NAYS), University of the Punjab, Quaid-i-Azam Campus, Lahore,
Pakistan
| | - Sadia Ashraf
- National Academy of Young Scientists (NAYS), University of the Punjab, Quaid-i-Azam Campus, Lahore,
Pakistan
| | - Aftab Ahmad
- National Academy of Young Scientists (NAYS), University of the Punjab, Quaid-i-Azam Campus, Lahore,
Pakistan
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32
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Gelinsky M, Bernhardt A, Milan F. Bioreactors in tissue engineering: Advances in stem cell culture and three-dimensional tissue constructs. Eng Life Sci 2015. [DOI: 10.1002/elsc.201400216] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Michael Gelinsky
- Centre for Translational Bone; Joint and Soft Tissue Research; Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden; Dresden Germany
| | - Anne Bernhardt
- Centre for Translational Bone; Joint and Soft Tissue Research; Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden; Dresden Germany
| | - Falk Milan
- Centre for Translational Bone; Joint and Soft Tissue Research; Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden; Dresden Germany
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Martin-Manso G, Hanley PJ. Using the quantum cell expansion system for the automated expansion of clinical-grade bone marrow-derived human mesenchymal stromal cells. Methods Mol Biol 2015; 1283:53-63. [PMID: 25523809 DOI: 10.1007/7651_2014_164] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Bone marrow-derived human mesenchymal stromal cells (hMSCs) constitute a promising therapeutic approach. However, the extremely low frequency of hMSCs in bone marrow makes the translation of these regulatory cells to clinical therapies difficult for large patient populations. Here, we describe a good manufacturing practices-compliant procedure for the expansion of hMSCs using the Quantum Cell Expansion System. This closed and automated system allows the large-scale expansion of hMSCs while maintaining their multipotency, immunophenotype, morphology, and karyotype.
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Affiliation(s)
- Gema Martin-Manso
- Program for Cell Enhancement and Technologies for Immunotherapy, Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA
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34
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Sun B. Proteomics and glycoproteomics of pluripotent stem-cell surface proteins. Proteomics 2014; 15:1152-63. [DOI: 10.1002/pmic.201400300] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/07/2014] [Accepted: 09/08/2014] [Indexed: 12/19/2022]
Affiliation(s)
- Bingyun Sun
- Department of Chemistry and Department of Molecular Biology and Biochemistry, Simon Fraser University; Burnaby British Columbia Canada
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35
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Chen G, Xu X, Zhang L, Fu Y, Wang M, Gu H, Xie X. Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming. Cell Res 2014; 24:1121-36. [PMID: 25145356 PMCID: PMC4152737 DOI: 10.1038/cr.2014.112] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/16/2014] [Accepted: 06/02/2014] [Indexed: 12/21/2022] Open
Abstract
Maintaining the self-renewal of embryonic stem cells (ESCs) could be achieved by activating the extrinsic signaling, i.e., the use of leukemia inhibitory factor (LIF), or blocking the intrinsic differentiation pathways, i.e., the use of GSK3 and MEK inhibitors (2i). Here we found that even in medium supplemented with LIF, mESCs still tend to differentiate toward meso-endoderm lineages after long-term culture and the culture spontaneously secretes vascular endothelial growth factors (VEGFs). Blocking VEGF signaling with sunitinib, an anti-cancer drug and a receptor tyrosine kinase (RTK) inhibitor mainly targeting VEGF receptors (VEGFRs), is capable of maintaining the mESCs in the undifferentiated state without the need for feeder cells or LIF. Sunitinib facilitates the derivation of mESCs from blastocysts, and the mESCs maintained in sunitinib-containing medium remain pluripotent and are able to contribute to chimeric mice. Sunitinib also promotes iPSC generation from MEFs with only Oct4. Knocking down VEGFR2 or blocking it with neutralizing antibody mimicks the effect of sunitinib, indicating that blocking VEGF/VEGFR signaling is indeed beneficial to the self-renewal of mESCs. We also found that hypoxia-inducible factor alpha (HIF1α) and endoplasmic reticulum (ER) stress are involved in the production of VEGF in mESCs. Blocking both pathways inhibits the expression of VEGF and prevents spontaneous differentiation of mESCs. Interestingly, LIF may also exert its effect by downregulating HIF1α and ER stress pathways and subsequent VEGF expression. These results indicate the existence of an intrinsic differentiation pathway in mESCs by activating the autocrine VEGF signaling. Blocking VEGF signaling with sunitinib or other small molecules help to maintain the mESCs in the ground state of pluripotency.
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Affiliation(s)
- Guofang Chen
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China
| | - Xinxiu Xu
- 1] CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China [2] Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Lihong Zhang
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China
| | - Yanbin Fu
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Min Wang
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China
| | - Haifeng Gu
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China
| | - Xin Xie
- 1] CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China [2] Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
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Efficient derivation of osteoprogenitor cells from induced pluripotent stem cells for bone regeneration. INTERNATIONAL ORTHOPAEDICS 2014; 38:1779-85. [DOI: 10.1007/s00264-014-2440-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 06/20/2014] [Indexed: 10/25/2022]
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Oliveira MB, Neto AI, Correia CR, Rial-Hermida MI, Alvarez-Lorenzo C, Mano JF. Superhydrophobic chips for cell spheroids high-throughput generation and drug screening. ACS APPLIED MATERIALS & INTERFACES 2014; 6:9488-9495. [PMID: 24865973 DOI: 10.1021/am5018607] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
We suggest the use of biomimetic superhydrophobic patterned chips produced by a benchtop methodology as low-cost and waste-free platforms for the production of arrays of cell spheroids/microtissues by the hanging drop methodology. Cell spheroids have a wide range of applications in biotechnology fields. For drug screening, they allow studying 3D models in structures resembling real living tissues/tumors. In tissue engineering, they are suggested as building blocks of bottom-up fabricated tissues. We used the wettability contrast of the chips to fix cell suspension droplets in the wettable regions and evaluated on-chip drug screening in 3D environment. Cell suspensions were patterned in the wettable spots by three distinct methods: (1) by pipetting the cell suspension directly in each individual spot, (2) by the continuous dragging of a cell suspension on the chip, and (3) by dipping the whole chip in a cell suspension. These methods allowed working with distinct throughputs and degrees of precision. The platforms were robust, and we were able to have static or dynamic environments in each droplet. The access to cell culture media for exchange or addition/removal of components was versatile and opened the possibility of using each spot of the chip as a mini-bioreactor. The platforms' design allowed for samples visualization and high-content image-based analysis on-chip. The combinatorial analysis capability of this technology was validated by following the effect of doxorubicin at different concentrations on spheroids formed using L929 and SaOs-2 cells.
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Affiliation(s)
- Mariana B Oliveira
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine , AvePark, 4806-909 Taipas, Guimarães, Portugal
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38
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Ebrahimkhani S, Farjadian S, Ebrahimi M. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity? ACTA ACUST UNITED AC 2014; 41:134-8. [PMID: 24847189 DOI: 10.1159/000357997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 09/03/2013] [Indexed: 11/19/2022]
Abstract
BACKGROUND Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. METHODS From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. RESULTS The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 10(7)-107 × 10(7). The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). CONCLUSIONS Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future.
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Affiliation(s)
- Saeideh Ebrahimkhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shirin Farjadian
- Department of Immunology, Shiraz University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran ; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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39
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Comparison of different protocols for neural differentiation of human induced pluripotent stem cells. Mol Biol Rep 2014; 41:1713-21. [DOI: 10.1007/s11033-014-3020-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 01/02/2014] [Indexed: 12/27/2022]
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Abstract
Dental pulp stem cells (DPSC) have been proposed as an alternative to pluripotent stem cells to study multilineage differentiation in vitro and for therapeutic application. Standard culture media for isolation and expansion of stem cells includes animal sera or animal-derived matrix components (e.g., Matrigel(®)). However, animal-derived reagents raise significant concerns with respect to the translational ability of these cells due to the possibility of infection and/or severe immune reaction. For these reasons clinical grade substitutes to animal components are needed in order for stem cells to reach their full therapeutic potential. In this chapter we detail a method for isolation and proliferation of DPSC in a chemically defined medium containing a low percentage of human serum. We demonstrate that in this defined culture medium a 1.25 % human serum component sufficiently replaces fetal bovine serum. This method allows for isolation of a morphologically and phenotypically uniform population of DPSCs from dental pulp tissue. DPSCs represent a rapidly proliferating cell population that readily differentiates into the osteoblastic, neuronal, myocytic, and hepatocytic lineages. This multilineage capacity of these DPSCs suggests that they may have a more broad therapeutic application than lineage-restricted adult stem cell populations such as mesenchymal stem cells. Further the culture protocol presented here makes these cells more amenable to human application than current expansion techniques for other pluripotent stem cells (embryonic stem cell lines or induced pluripotent stem cells).
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41
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Fan L, Hu K, Ji K, Sun Q, Xiong J, Yang L, Liu H. Directed differentiation of aged human bone marrow multipotent stem cells effectively generates dopamine neurons. In Vitro Cell Dev Biol Anim 2013; 50:304-12. [PMID: 24163158 DOI: 10.1007/s11626-013-9701-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 09/27/2013] [Indexed: 12/11/2022]
Abstract
This study aimed to isolate aged human bone marrow multipotent stem cells (hAMSCs) with the potential for multilineage differentiation and to directly induce the cells to generate dopamine neurons, which could be used for Parkinson's disease therapy. We compared different culture methods for stem cells from aged human bone marrow and identified hAMSCs that could proliferate in vitro for at least 60 doubling times. Using RT-PCR and IHC, we found that these hAMSCs expressed pluripotent genes, such as Oct4, Sox2, and Nanog. In vitro studies also proved that hAMSCs could differentiate into three germ layer-derived cell types, such as osteogenic, chondrogenic, adipogenic, and hepatocyte-liked cells. After induction for more than 20 d in vitro with retinoic acid, basic fibroblast growth factor, and sonic hedgehog using a two-step method and withdrawal of serum, hAMSCs could differentiate into dopamine neurons at the positive ratio of 70%, which showed DA secretion function upon depolarization. In conclusion, we suggest that hAMSCs can be used as cell sources to develop medical treatments to prevent the progression of Parkinson's disease, especially in aged persons.
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Affiliation(s)
- Lixing Fan
- Research Center of Developmental Biology, Second Military Medical University, XiangYin road 800, Shanghai, China
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42
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Smeets B, Odenthal T, Tijskens E, Ramon H, Van Oosterwyck H. Quantifying the mechanical micro-environment during three-dimensional cell expansion on microbeads by means of individual cell-based modelling. Comput Methods Biomech Biomed Engin 2013; 16:1071-84. [DOI: 10.1080/10255842.2013.829461] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Kantartzis KL, Moalli PA. Stem Cell Therapy for Female Urinary Incontinence. CURRENT OBSTETRICS AND GYNECOLOGY REPORTS 2013. [DOI: 10.1007/s13669-013-0049-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Sun LY, Pang CY, Li DK, Liao CH, Huang WC, Wu CC, Chou YY, Li WW, Chen SY, Liu HW, Chang YJ, Cheng CF. Antioxidants cause rapid expansion of human adipose-derived mesenchymal stem cells via CDK and CDK inhibitor regulation. J Biomed Sci 2013; 20:53. [PMID: 23915242 PMCID: PMC3751058 DOI: 10.1186/1423-0127-20-53] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Accepted: 07/26/2013] [Indexed: 12/22/2022] Open
Abstract
Background Antioxidants have been shown to enhance the proliferation of adipose-derived mesenchymal stem cells (ADMSCs) in vitro, although the detailed mechanism(s) and potential side effects are not fully understood. In this study, human ADMSCs cultured in ImF-A medium supplemented with antioxidants (N-acetyl-l-cysteine and ascorbic acid-2-phosphate) and fibroblast growth factor 2 (FGF-2) were compared with ADMSCs cultured with FGF-2 alone (ImF) or with FGF-2 under 5% pO2 conditions (ImF-H). Results During log-phase growth, exposure to ImF-A resulted in a higher percentage of ADMSCs in the S phase of the cell cycle and a smaller percentage in G0/G1 phase. This resulted in a significantly reduced cell-doubling time and increased number of cells in the antioxidant-supplemented cultures compared with those supplemented with FGF-2 alone, an approximately 225% higher cell density after 7 days. Western blotting showed that the levels of the CDK inhibitors p21 and p27 decreased after ImF-A treatment, whereas CDK2, CDK4, and CDC2 levels clearly increased. In addition, ImF-A resulted in significant reduction in the expression of CD29, CD90, and CD105, whereas relative telomere length, osteogenesis, adipogenesis, and chondrogenesis were enhanced. The results were similar for ADMSCs treated with antioxidants and those under hypoxic conditions. Conclusion Antioxidant treatment promotes entry of ADMSCs into the S phase by suppressing cyclin-dependent kinase inhibitors and results in rapid cell proliferation similar to that observed under hypoxic conditions.
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Lignin Induces ES Cells to Differentiate into Neuroectodermal Cells through Mediation of the Wnt Signaling Pathway. PLoS One 2013; 8:e66376. [PMID: 23805217 PMCID: PMC3689838 DOI: 10.1371/journal.pone.0066376] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 05/05/2013] [Indexed: 02/06/2023] Open
Abstract
Embryonic stem cells (ES cells) are characterized by their pluripotency and infinite proliferation potential. Ever since ES cells were first established in 1981, there have been a growing number of studies aimed at clinical applications of ES cells. In recent years, various types of differentiation inducement systems using ES cells have been established. Further studies have been conducted to utilize differentiation inducement systems in the field of regenerative medicine. For cellular treatments using stem cells including ES cells, differentiation induction should be performed in a sufficient manner to obtain the intended cell lineages. Lignin is a high-molecular amorphous material that forms plants together with cellulose and hemicelluloses, in which phenylpropane fundamental units are complexly condensed. Lignin derivatives have been shown to have several bioactive functions. In spite of these findings, few studies have focused on the effects of lignin on stem cells. Our study aimed to develop a novel technology using lignin to effectively induce ES cells to differentiate into neuroectodermal cells including ocular cells and neural cells. Since lignin can be produced at a relatively low cost in large volumes, its utilization is expected for more convenient differentiation induction technologies and in the field of regenerative medicine in the future.
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Morphology and growth of mammalian cells in a liquid/liquid culture system supported with oxygenated perfluorodecalin. Biotechnol Lett 2013; 35:1387-94. [PMID: 23666427 PMCID: PMC3730094 DOI: 10.1007/s10529-013-1218-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 04/18/2013] [Indexed: 11/30/2022]
Abstract
Adherent A431, BHK-21, and C2C12 cells were cultured on a flexible interface formed between two immiscible liquid phases: (i) hydrophobic perfluorodecalin (PFD) and (ii) aqueous culture medium (DMEM). BHK-21 cells formed multicellular aggregates characterized by irregular shapes. A431, as well as C2C12 cells, grew as tight multicellular sheets of 3-D cells. Enhanced mass transfer and facilitated access of the cells to the O2 dissolved in PFD/DMEM by approx. 250 % and thereby increased the density of BHK-21 cells. Thus the liquid/liquid system is a simple, ready-to-use, and fully scalable (independent of vessel shapes); consequently it is a method for 3-D cultures of adherent animal cells in which the growth of anchorage-dependent cells is not limited by confluence effect.
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Salerno S, Piscioneri A, Morelli S, Al-Fageeh MB, Drioli E, De Bartolo L. Membrane Bioreactor for Expansion and Differentiation of Embryonic Liver Cells. Ind Eng Chem Res 2013. [DOI: 10.1021/ie400035d] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Simona Salerno
- Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, Via P. Bucci, cubo 17/C, 87030 Rende (CS),
Italy
| | - Antonella Piscioneri
- Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, Via P. Bucci, cubo 17/C, 87030 Rende (CS),
Italy
| | - Sabrina Morelli
- Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, Via P. Bucci, cubo 17/C, 87030 Rende (CS),
Italy
| | - Mohamed B. Al-Fageeh
- National Centre for Biotechnology, King Abdulaziz City for Science and
Technology, Riyadh 11442 Saudi Arabia
| | - Enrico Drioli
- Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, Via P. Bucci, cubo 17/C, 87030 Rende (CS),
Italy
- Department of Chemical Engineering
and Materials, University of Calabria,
via P. Bucci cubo 45/A, 87030 Rende (CS) Italy
- WCU Energy Engineering Department, Hanyang University, Seoul, S. Korea
| | - Loredana De Bartolo
- Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, Via P. Bucci, cubo 17/C, 87030 Rende (CS),
Italy
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Li R, Wei M, Shao J. Effects of verapamil on the immediate-early gene expression of bone marrow mesenchymal stem cells stimulated by mechanical strain in vitro. Med Sci Monit Basic Res 2013; 19:68-75. [PMID: 23435320 PMCID: PMC3638684 DOI: 10.12659/msmbr.883790] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background To study the effects of verapamil on the immediate-early genes (IEGs) expression of bone marrow mesenchymal stem cells (MSCs) stimulated by cyclic mechanical strain, in order to deduce the role of calcium ion channel in the cell signaling responses of MSCs to mechanical strain. Material/Methods MSCs were isolated and cultured, and the passage of 3–6 MSCs were stimulated by mechanical strain and pretreated with or without verapamil. After that, flow cytometry was used to measure the fluorescence intensity of intracellular Ca2+ immediately. The expression of early-response genes/proteins (c-fos, c-jun and c-myc) were examined by RT-PCR, immunohistochemistry and Western blot. Results Intracellular Ca2+ concentration of MSCs significantly changed when stimulated by cyclic strain, and the expression of c-fos, c-jun and c-myc remarkably increased in both mRNA and protein levels, while verapamil pre-treatment partially inhibited these effects (P<0.01). Conclusions The changes of the intracellular calcium concentration of MSCs induced by mechanical strain, dependent on the regulation of calcium channel activation, might play a role in the early response of MSCs to cyclic strain.
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Affiliation(s)
- Runguang Li
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
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Sarvi F, Arbatan T, Chan PPY, Shen W. A novel technique for the formation of embryoid bodies inside liquid marbles. RSC Adv 2013. [DOI: 10.1039/c3ra40364e] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Vatansever HS, Uluer ET, Aydede H, Ozbilgin MK. Analysis of transferred keratinocyte-like cells derived from mouse embryonic stem cells on experimental surgical skin wounds of mouse. Acta Histochem 2013; 115:32-41. [PMID: 22494612 DOI: 10.1016/j.acthis.2012.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 03/14/2012] [Accepted: 03/15/2012] [Indexed: 10/28/2022]
Abstract
Autologous/allogenic skin grafts constituted from differentiated adult or embryonic stem cells can be used in treatment of skin disorders. In our study we aimed to differentiate keratinocytes from mouse embryonic stem cells and the transfer of viable keratinocyte-like cells to a model of surgical skin wound of mouse. Embryoid bodies, derived from mouse embryonic stem cells, were cultured on basement membrane matrix with added BMP-4 for 10 days. The identification of differentiated keratinocyte-like cells was done by detection of cytokeratin-8 and cytokeratin-14 localization using an indirect immunoperoxidase technique and transmission electron microscopy evaluation. Distribution of BrdU, cytokeratin-8 and cytokeratin-14 were evaluated using an indirect immunoperoxidase technique from the experimental (dressing including BrdU labelled cells applied after the surgical wound was created on mouse), control (only the surgical wound was created on mouse) and sham (only the dressing applied after the surgical wound was created on mouse) in groups after 3, 5 and 7 days. Immunohistochemically and ultrastructurally, cells derived from mouse embryonic stem cells were similar to differentiated keratinocyte-like cells. Differentiated keratinocyte-like cells were demonstrated by positive BrdU, cytokeratin-8 and cytokeratin-14 staining after transfer to the wound area. In the experimental group wound healing was better after transferring differentiated keratinocytes when compared to the sham and control groups. In vivo continuity and usability of derived cells are very important issues. In wound repair mechanisms, keratinocyte-like cells could provide positive effects during the wound healing and could be used in clinical treatments of wound repair process.
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