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Lo Iacono M, Corrao S, Alberti G, Amico G, Timoneri F, Russo E, Cucina A, Indelicato S, Rappa F, Corsello T, Saieva S, Di Stefano A, Di Gaudio F, Conaldi PG, La Rocca G. Characterization and Proteomic Profiling of Hepatocyte-like Cells Derived from Human Wharton's Jelly Mesenchymal Stromal Cells: De Novo Expression of Liver-Specific Enzymes. BIOLOGY 2025; 14:124. [PMID: 40001892 PMCID: PMC11851833 DOI: 10.3390/biology14020124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025]
Abstract
End-stage liver disease (ESLD), affecting millions worldwide, represents a challenging issue for clinical research and global public health. Liver transplantation is the gold standard therapeutic approach but shows some drawbacks. Hepatocyte transplantation could be a reliable alternative for patient treatment. Mesenchymal stromal cells derived from Wharton's jelly of the umbilical cord (WJ-MSCs) can differentiate into hepatocyte-like cells (HLCs) and show immunomodulatory functions. Due to the increasing demand for fully characterized cell therapy vehicles warranting both the safety and efficacy of treatments, in this work, we extensively characterized WJ-MSCs before and after the application of a hepatocyte-directed differentiation protocol. HLCs exhibited a morphology resembling that of hepatocytes, expressed early and late hepatic markers (α-fetoprotein, albumin, CK18, HNF4-α), and acquired hepatic functions (glycogen synthesis, xenobiotics detoxification), as also revealed by the shotgun proteomics approach. HLCs maintained the same pattern of immunomodulatory molecule expression and mesenchymal markers, other than displaying specific enzymes, suggesting these cells as promising candidates for cellular therapy of ESLD. Our work shed new light on the basic biology of HLCs, suggesting new therapeutic approaches to treat ESLD.
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Affiliation(s)
- Melania Lo Iacono
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (G.A.); (F.R.)
| | - Simona Corrao
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy;
| | - Giusi Alberti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (G.A.); (F.R.)
| | - Giandomenico Amico
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (G.A.); (F.T.); (P.G.C.)
- Unit of Regenerative Medicine and Immunotherapy, Ri.MED Foundation, 90133 Palermo, Italy
| | - Francesca Timoneri
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (G.A.); (F.T.); (P.G.C.)
- Unit of Regenerative Medicine and Immunotherapy, Ri.MED Foundation, 90133 Palermo, Italy
| | - Eleonora Russo
- Departmental Faculty of Medicine, Saint Camillus International University of Health Sciences, 00131 Rome, Italy;
| | - Annamaria Cucina
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) University of Palermo, 90127 Palermo, Italy; (A.C.); (S.I.); (F.D.G.)
| | - Sergio Indelicato
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) University of Palermo, 90127 Palermo, Italy; (A.C.); (S.I.); (F.D.G.)
| | - Francesca Rappa
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (G.A.); (F.R.)
- The Institute of Translational Pharmacology, National Research Council of Italy (CNR), 90146 Palermo, Italy
| | - Tiziana Corsello
- Department of Pediatrics, Division of Clinical and Experimental Immunology and Infectious Diseases (CEIID), University of Texas Medical Branch, Galveston, TX 77550, USA;
| | - Salvatore Saieva
- Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Antonino Di Stefano
- Laboratory of Cardio-Respiratory Apparatus Cytoimmunopathology, “S. Maugeri” Foundation, IRCCS, Medical Center of Veruno, 281010 Novara, Italy;
| | - Francesca Di Gaudio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) University of Palermo, 90127 Palermo, Italy; (A.C.); (S.I.); (F.D.G.)
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (G.A.); (F.T.); (P.G.C.)
| | - Giampiero La Rocca
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (G.A.); (F.R.)
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Ishii R, Ohnishi S, Hojo M, Ishikawa K, Funayama E, Miura T, Okubo N, Okada K, Yamamoto Y, Maeda T. Hypoxic culture enhances the antimicrobial activity of amnion-derived mesenchymal stem cells, thereby reducing bacterial load and promoting wound healing in diabetic mice. Biochem Biophys Res Commun 2024; 739:150903. [PMID: 39531904 DOI: 10.1016/j.bbrc.2024.150903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Conditioned medium from amnion-derived mesenchymal stem cells (AMSCs) enhances wound healing, a process that is further improved under hypoxic culture conditions. Diabetic foot ulcers are difficult to treat and are frequently complicated by a high rate of bacterial infections, mainly Staphylococcus aureus, which can lead to limb amputation and death. Here, we topically applied conditioned medium from AMSCs cultured under hypoxic conditions to S. aureus-infected wounds in diabetic mice to investigate its effect on bacterial counts and wound healing. METHODS We prepared conditioned medium by culturing AMSCs under 21 % or 1 % O2 and investigated its effects on S. aureus. We infected skin wounds of diabetic mice with S. aureus and treated these with hydrogels containing the conditioned medium to examine its effect on bacterial inhibition and wound healing. RESULTS Conditioned medium from AMSCs cultured under 1 % O2 contained higher levels of the antimicrobial peptide LL-37. It significantly inhibited S. aureus growth in vitro, reduced bacterial counts in infected wounds, and facilitated wound closure in diabetic mice. CONCLUSIONS Hydrogels containing conditioned medium from hypoxically cultured AMSCs inhibited the growth of S. aureus and promoted wound healing in a mouse model of diabetic wounds.
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Affiliation(s)
- Riku Ishii
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masahiro Hojo
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kosuke Ishikawa
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Emi Funayama
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takahiro Miura
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Naoto Okubo
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kazufumi Okada
- Data Science Center, Promotion Unit, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yuhei Yamamoto
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Taku Maeda
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
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Eivazi Zadeh Z, Nour S, Kianersi S, Jonidi Shariatzadeh F, Williams RJ, Nisbet DR, Bruggeman KF. Mining human clinical waste as a rich source of stem cells for neural regeneration. iScience 2024; 27:110307. [PMID: 39156636 PMCID: PMC11326931 DOI: 10.1016/j.isci.2024.110307] [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: 08/20/2024] Open
Abstract
Neural diseases are challenging to treat and are regarded as one of the major causes of disability and morbidity in the world. Stem cells can provide a solution, by offering a mechanism to replace damaged circuitry. However, obtaining sufficient cell sources for neural regeneration remains a significant challenge. In recent years, waste-derived stem(-like) cells (WDS-lCs) extracted from both prenatal and adult clinical waste tissues/products, have gained increasing attention for application in neural tissue repair and remodeling. This often-overlooked pool of cells possesses favorable characteristics; including self-renewal, neural differentiation, secretion of neurogenic factors, cost-effectiveness, and low ethical concerns. Here, we offer a perspective regarding the biological properties, extraction protocols, and preclinical and clinical treatments where prenatal and adult WDS-lCs have been utilized for cell replacement therapy in neural applications, and the challenges involved in optimizing these approaches toward patient led therapies.
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Affiliation(s)
- Zahra Eivazi Zadeh
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
| | - Shirin Nour
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- Polymer Science Group, Department of Chemical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
| | - Sogol Kianersi
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences, University of Galway, Galway, Ireland
| | | | - Richard J. Williams
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- iMPACT, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | - David R. Nisbet
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, ANU College of Health & Medicine, Canberra, ACT, Australia
- Research School of Chemistry, ANU College of Science, Canberra, ACT, Australia
- Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
- Founder and Scientific Advisory of Nano Status, Building 137, Sullivans Creek Rd, ANU, Acton, Canberra, ACT, Australia
| | - Kiara F. Bruggeman
- Laboratory of Advanced Biomaterials Research, School of Engineering, Australian National University, Canberra, ACT, Australia
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Wu Y, Wang Y, Gan W, Jiang W. The biological characteristics of chicken embryo mesenchymal stem cells isolated from chorioallantoic membrane. Genesis 2024; 62:e23592. [PMID: 38587195 DOI: 10.1002/dvg.23592] [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: 12/02/2022] [Revised: 02/28/2024] [Accepted: 03/17/2024] [Indexed: 04/09/2024]
Abstract
Mesenchymal stem cells (MSCs) derived from fetal membranes (FMs) have the potential to exhibit immunosuppression, improve blood flow, and increase capillary density during transplantation. In the field of medicine, opening up new avenues for disease treatment. Chicken embryo chorioallantoic membrane (CAM), as an important component of avian species FM structure, has become a stable tissue engineering material in vivo angiogenesis, drug delivery, and toxicology studies. Although it has been confirmed that chorionic mesenchymal stem cells (Ch-MSCs) can be isolated from the outer chorionic layer of FM, little is known about the biological characteristics of MSCs derived from chorionic mesodermal matrix of chicken embryos. Therefore, we evaluated the characteristics of MSCs isolated from chorionic tissues of chicken embryos, including cell proliferation ability, stem cell surface antigen, genetic stability, and in vitro differentiation potential. Ch-MSCs exhibited a broad spindle shaped appearance and could stably maintain diploid karyotype proliferation to passage 15 in vitro. Spindle cells were positive for multifunctional markers of MSCs (CD29, CD44, CD73, CD90, CD105, CD166, OCT4, and NANOG), while hematopoietic cell surface marker CD34, panleukocyte marker CD45, and epithelial cell marker CK19 were negative. In addition, chicken Ch-MSC was induced to differentiate into four types of mesodermal cells in vitro, including osteoblasts, chondrocytes, adipocytes, and myoblasts. Therefore, the differentiation potential of chicken Ch-MSC in vitro may have great potential in tissue engineering. In conclusion, chicken Ch-MSCs may be an excellent model cell for stem cell regenerative medicine and chorionic tissue engineering.
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Affiliation(s)
- Yue Wu
- Guangdong Yunfu Vocational College of Chinese Medicine, Yunfu, Guangdong Province, China
| | - Yunan Wang
- Health Committee of Huanggang, Huanggang, Hubei Province, China
| | - Weijun Gan
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Wei Jiang
- Health Committee of Huanggang, Huanggang, Hubei Province, China
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Huang QM, Long YL, Wang JN, Wu J, Tang WL, Wang XY, Zhang ZH, Zhuo YQ, Guan XH, Deng KY, Xin HB. Human amniotic MSCs-mediated anti-inflammation of CD206 hiIL-10 hi macrophages alleviates isoproterenol-induced ventricular remodeling in mice. Int Immunopharmacol 2024; 129:111660. [PMID: 38350357 DOI: 10.1016/j.intimp.2024.111660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/28/2024] [Accepted: 02/04/2024] [Indexed: 02/15/2024]
Abstract
BACKGROUND Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammation which makes them suitable for the treatment of various diseases. OBJECTIVE This study aimed to explore the therapeutic effect and molecular mechanism of hAMSCs in ventricular remodeling (VR). METHODS hAMSCs were characterized by a series of experiments such as flow cytometric analysis, immunofluorescence, differentiative induction and tumorigenicity. Mouse VR model was induced by isoproterenol (ISO) peritoneally, and the therapeutic effects and the potential mechanisms of hAMSCs transplantation were evaluated by echocardiography, carboxy fluorescein diacetate succinimidyl ester (CFSE) labeled cell tracing, histochemistry, qRT-PCR and western blot analysis. The co-culturing experiments were carried out for further exploring the mechanisms of hAMSCs-derived conditioned medium (CM) on macrophage polarization and fibroblast fibrosis in vitro. RESULTS hAMSCs transplantation significantly alleviated ISO-induced VR including cardiac hypertrophy and fibrosis with the improvements of cardiac functions. CFSE labeled hAMSCs kept an undifferentiated state in heart, indicating that hAMSCs-mediated the improvement of ISO-induced VR might be related to their paracrine effects. hAMSCs markedly inhibited ISO-induced inflammation and fibrosis, seen as the increase of M2 macrophage infiltration and the expressions of CD206 and IL-10, and the decreases of CD86, iNOS, COL3 and αSMA expressions in heart, suggesting that hAMSCs transplantation promoted the polarization of M2 macrophages and inhibited the polarization of M1 macrophages. Mechanically, hAMSCs-derived CM significantly increased the expressions of CD206, IL-10, Arg-1 and reduced the expressions of iNOS and IL-6 in RAW264.7 macrophages in vitro. Interestingly, RAW264.7-CM remarkably promoted the expressions of anti-inflammatory factors such as IL-10, IDO, and COX2 in hAMSCs. Furthermore, the CM derived from hAMSCs pretreated with RAW264.7-CM markedly inhibited the expressions of fibrogenesis genes such as αSMA and COL3 in 3T3 cells. CONCLUSION Our results demonstrated that hAMSCs effectively alleviated ISO-induced cardiac hypertrophy and fibrosis, and improved the cardiac functions in mice, and the underlying mechanisms might be related to inhibiting the inflammation and fibrosis during the ventricular remodeling through promoting the polarization of CD206hiIL-10hi macrophages in heart tissues. Our study strongly suggested that by taking the advantages of the potent immunosuppressive and anti-inflammatory effects, hAMSCs may provide an alternative therapeutic approach for prevention and treatment of VR clinically.
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Affiliation(s)
- Qi-Ming Huang
- College of Life Science, Nanchang University, Nanchang 330031, Jiangxi, China; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Ying-Lin Long
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Jia-Nan Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Jie Wu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Wen-Long Tang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Xiao-Yu Wang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, Nanchang 330031, Jiangxi, China
| | - Zhou-Hang Zhang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China
| | - You-Qiong Zhuo
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China; School of Food Science and Technology, Nanchang University, Nanchang 330052, Jiangxi, China
| | - Xiao-Hui Guan
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China.
| | - Ke-Yu Deng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China.
| | - Hong-Bo Xin
- College of Life Science, Nanchang University, Nanchang 330031, Jiangxi, China; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, Jiangxi, China.
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Holroyd NA, Walsh C, Gourmet L, Walker-Samuel S. Quantitative Image Processing for Three-Dimensional Episcopic Images of Biological Structures: Current State and Future Directions. Biomedicines 2023; 11:909. [PMID: 36979887 PMCID: PMC10045950 DOI: 10.3390/biomedicines11030909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/03/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Episcopic imaging using techniques such as High Resolution Episcopic Microscopy (HREM) and its variants, allows biological samples to be visualized in three dimensions over a large field of view. Quantitative analysis of episcopic image data is undertaken using a range of methods. In this systematic review, we look at trends in quantitative analysis of episcopic images and discuss avenues for further research. Papers published between 2011 and 2022 were analyzed for details about quantitative analysis approaches, methods of image annotation and choice of image processing software. It is shown that quantitative processing is becoming more common in episcopic microscopy and that manual annotation is the predominant method of image analysis. Our meta-analysis highlights where tools and methods require further development in this field, and we discuss what this means for the future of quantitative episcopic imaging, as well as how annotation and quantification may be automated and standardized across the field.
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Affiliation(s)
| | - Claire Walsh
- Centre for Computational Medicine, University College London, London WC1E 6DD, UK
- Department of Mechanical Engineering, University College London, London WC1E 7JE, UK
| | - Lucie Gourmet
- Centre for Computational Medicine, University College London, London WC1E 6DD, UK
| | - Simon Walker-Samuel
- Centre for Computational Medicine, University College London, London WC1E 6DD, UK
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Lu Y, Zhang J, Zeng F, Wang P, Guo X, Wang H, Qin Z, Tao T. Human PMSCs-derived small extracellular vesicles alleviate neuropathic pain through miR-26a-5p/Wnt5a in SNI mice model. J Neuroinflammation 2022; 19:221. [PMID: 36071475 PMCID: PMC9450435 DOI: 10.1186/s12974-022-02578-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 08/27/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSCs)-derived small Extracellular Vesicles (sEVs) are considered as a new cell-free therapy for pain caused by nerve injury, but whether human placental mesenchymal stem cell-derived sEVs relieve pain in sciatic nerve injury and its possible mechanism are still unclear. In this study, we investigated the roles of hPMSCs-derived sEVs and related mechanisms in neuropathic pain. METHODS The spared nerve injury (SNI) mouse model was employed. Intrathecal injection of sEVs or miR-26a-5p agomir was performed on the seventh day of modeling, to study its anti-nociceptive effect. sEVs' miRNA sequencing (miRNA-Seq) and bioinformatics analysis were performed to study the downstream mechanisms of miRNAs. RT-qPCR, protein assay and immunofluorescence were used for further validation. RESULTS A single intrathecal injection of sEVs durably reversed mechanical hypersensitivity in the left hind paw of mice with partial sciatic nerve ligation. Immunofluorescence studies found that PKH26-labeled sEVs were visible in neurons and microglia in the dorsal horn of the ipsilateral L4/5 spinal cord and more enriched in the ipsilateral. According to miRNA-seq results, we found that intrathecal injection of miR-26a-5p agomir, the second high counts microRNA in hPMSCs derived sEVs, significantly suppressed neuropathic pain and neuroinflammation in SNI mice. Bioinformatics analysis and dual-luciferase reporter gene analysis identified Wnt5a as a direct downstream target gene of miR-26a-5p. The results showed that overexpression of miR-26a-5p in vivo could significantly reduce the expression level of Wnt5a. In addition, Foxy5, a mimetic peptide of Wnt5a, can significantly reverse the inhibitory effect of miR-26a-5p on neuroinflammation and neuropathic pain, and at the same time, miR-26a-5p can rescue the effect of Foxy5 by overexpression. CONCLUSIONS We reported that hPMSCs derived sEVs as a promising therapy for nerve injury induced neuropathic pain. In addition, we showed that the miR-26a-5p in the sEVs regulated Wnt5a/Ryk/CaMKII/NFAT partly take part in the analgesia through anti-neuroinflammation, which suggests an alleviating pain effect through non-canonical Wnt signaling pathway in neuropathic pain model in vivo.
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Affiliation(s)
- Yitian Lu
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.,Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jintao Zhang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.,Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Fanning Zeng
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Peng Wang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Xiangna Guo
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Haitao Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
| | - Tao Tao
- Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.
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Moonshi SS, Adelnia H, Wu Y, Ta HT. Placenta‐Derived Mesenchymal Stem Cells for Treatment of Diseases: A Clinically Relevant Source. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202200054] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Shehzahdi S. Moonshi
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
| | - Hossein Adelnia
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
- Australian Institute for Bioengineering and Nanotechnology University of Queensland St Lucia Queensland 4072 Australia
| | - Yuao Wu
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
| | - Hang T. Ta
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
- Bioscience Discipline School of Environment and Science Griffith University Nathan Queensland 4111 Australia
- Australian Institute for Bioengineering and Nanotechnology University of Queensland St Lucia Queensland 4072 Australia
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Yang G, Fan X, Mazhar M, Yang S, Xu H, Dechsupa N, Wang L. Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage. Front Cell Neurosci 2022; 16:898497. [PMID: 35769327 PMCID: PMC9234141 DOI: 10.3389/fncel.2022.898497] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10–15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Acupuncture and Rehabilitation, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Houping Xu
- Preventive Treatment Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- *Correspondence: Nathupakorn Dechsupa,
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
- Li Wang,
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10
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Gong M, Wang M, Xu J, Yu B, Wang YG, Liu M, Ashraf M, Xu M. Nano-Sized Extracellular Vesicles Secreted from GATA-4 Modified Mesenchymal Stem Cells Promote Angiogenesis by Delivering Let-7 miRNAs. Cells 2022; 11:1573. [PMID: 35563879 PMCID: PMC9104414 DOI: 10.3390/cells11091573] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
We demonstrated previously that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) play a critical role in angiogenesis. Here, we examine whether this pro-angiogenic efficacy is enhanced in EVs derived from MSCs overexpressing GATA-4 (MSCGATA-4). Methods and Results. EVs were isolated from MSCGATA-4 (EVGATA-4) and control MSCs transduced with an empty vector (EVnull). EVs from both cell types were of the same size and displayed similar molecular markers. Compared with EVnull, EVGATA-4 increased both a tube-like structure formation and spheroid-based sprouting of human umbilical vein endothelial cells (HUVECs). The EVGATA-4 increased the numbers of CD31-positive cells and hemoglobin content inside Matrigel plugs subcutaneously transplanted into mice for 2 weeks. Moreover, EVGATA-4 encapsulated higher levels of let-7 family miRs compared to EVnull. The transfer of exosomal let-7 miRs into HUVECs was recorded with an accompanied down-regulation of thrombospondin-1 (THBS1) expression, a major endogenous angiogenesis inhibitor. The loss-and-gain of function studies of let-7 miRs showed that let-7f knockdown significantly decreased EVGATA-4-mediated vascularization inside Matrigel plugs. In contrast, let-7f overexpression promoted HUVEC migration and tube formation. Conclusion. Our results indicate that EVs derived from genetically modified MSCs with GATA-4 overexpression had increased pro-angiogenic capacity due to the delivery of let-7 miRs that targeted THBS1 in endothelial cells.
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Affiliation(s)
- Min Gong
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
- Department of Neonatology, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou 215025, China
| | - Min Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA
| | - Jie Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
| | - Bin Yu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
| | - Yi-Gang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
| | - Muhammad Ashraf
- Department of Medicine, Cardiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (M.G.); (M.W.); (J.X.); (B.Y.); (Y.-G.W.); (M.L.)
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11
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Velarde F, Ezquerra S, Delbruyere X, Caicedo A, Hidalgo Y, Khoury M. Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact. Cell Mol Life Sci 2022; 79:177. [PMID: 35247083 PMCID: PMC11073024 DOI: 10.1007/s00018-022-04207-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/27/2022] [Accepted: 02/11/2022] [Indexed: 12/13/2022]
Abstract
There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for therapeutic purposes represents an innovative approach to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the intercellular mitochondrial transfer, of the metabolic and pro-inflammatory profile, opens new avenues to the understanding of diseases' etiology, their relation to both systemic and local risk factors, and also leads to new therapeutic tools for the control of inflammatory and degenerative diseases. To this end, we illustrate in this review, the triggers and mechanisms behind the transfer of mitochondria employed by MSCs and the underlying benefits as well as the possible adverse effects of MSCs mitochondrial exchange. We relay the rationale and opportunities for the use of these organelles in the clinic as cell-based product.
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Affiliation(s)
- Francesca Velarde
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Sarah Ezquerra
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Xavier Delbruyere
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Andres Caicedo
- Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador
- Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina iBioMed, Quito, Ecuador
- Mito-Act Research Consortium, Quito, Ecuador
- Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Yessia Hidalgo
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile.
| | - Maroun Khoury
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile.
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12
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13
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Qin L, Zhang J, Xiao Y, Liu K, Cui Y, Xu F, Ren W, Yuan Y, Jiang C, Ning S, Ye X, Zeng M, Qian H, Bian A, Li F, Yang G, Tang S, Zhang Z, Dai J, Guo J, Wang Q, Sun B, Ge Y, Ouyang C, Xu X, Wang J, Huang Y, Cui H, Zhou J, Wang M, Su Z, Lu Y, Wu D, Shi J, Liu W, Dong L, Pan Y, Zhao B, Cui Y, Gao X, Gao Z, Ma X, Chen A, Wang J, Cao M, Cui Q, Chen L, Chen F, Yu Y, Ji Q, Zhang Z, Gu M, Zhuang X, Lv X, Wang H, Pan Y, Wang L, Xu X, Zhao J, Wang X, Liu C, Liang N, Xing C, Liu J, Wang N. A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism. J Mol Cell Biol 2022; 14:6526318. [PMID: 35142858 PMCID: PMC9205756 DOI: 10.1093/jmcb/mjac010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 11/23/2021] [Accepted: 02/07/2022] [Indexed: 11/12/2022] Open
Abstract
Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Pre-clinical release inspections of hAMSCs, efficacy, and safety assessment including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the pre-clinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature non-calcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization, and restoration of integrity.
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Affiliation(s)
- Lianju Qin
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jing Zhang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yujie Xiao
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Kang Liu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yugui Cui
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Fangyan Xu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Wenkai Ren
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yanggang Yuan
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Chunyan Jiang
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Song Ning
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xiaoxue Ye
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Ming Zeng
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Hanyang Qian
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Anning Bian
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Fan Li
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Guang Yang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Shaowen Tang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jing Guo
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Qiang Wang
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Bin Sun
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yifei Ge
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Chun Ouyang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xueqiang Xu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jing Wang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yaoyu Huang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Hongqing Cui
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jing Zhou
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Meilian Wang
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Zhonglan Su
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yan Lu
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Di Wu
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jingping Shi
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Wei Liu
- Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Li Dong
- Department of Infection, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yinbing Pan
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Baiqiao Zhao
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Department of Nephrology, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Ying Cui
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Department of Nephrology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Xueyan Gao
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Department of General Medicine, Geriatric Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanhui Gao
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.,Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Xiang Ma
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Aiqin Chen
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jie Wang
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Meng Cao
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Qian Cui
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Li Chen
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Feng Chen
- Department of Forensic Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Youjia Yu
- Department of Forensic Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Qiang Ji
- Department of Forensic Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Zhiwei Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Mufeng Gu
- Department of Human Anatomy, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiaojun Zhuang
- Department of Human Anatomy, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiaolin Lv
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Hui Wang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Yanyan Pan
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Ling Wang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xianrong Xu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jing Zhao
- Department of Outpatient Treatment Clinic, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xiuqin Wang
- Department of International Cooperation, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Cuiping Liu
- Department of Biological Specimen Repository, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Ningxia Liang
- Academy of Clinical and Translational Research, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Changying Xing
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Jiayin Liu
- State Key Laboratory of Reproductive Medicine, Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Ningning Wang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
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14
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Shariatzadeh S, Shafiee S, Zafari A, Tayebi T, Yazdanpanah G, Majd A, Haj-Mirzaian A, Bahrami S, Niknejad H. Developing a pro-angiogenic placenta derived amniochorionic scaffold with two exposed basement membranes as substrates for cultivating endothelial cells. Sci Rep 2021; 11:22508. [PMID: 34795361 PMCID: PMC8602627 DOI: 10.1038/s41598-021-01922-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 11/08/2021] [Indexed: 12/13/2022] Open
Abstract
Decellularized and de-epithelialized placenta membranes have widely been used as scaffolds and grafts in tissue engineering and regenerative medicine. Exceptional pro-angiogenic and biomechanical properties and low immunogenicity have made the amniochorionic membrane a unique substrate which provides an enriched niche for cellular growth. Herein, an optimized combination of enzymatic solutions (based on streptokinase) with mechanical scrapping is used to remove the amniotic epithelium and chorion trophoblastic layer, which resulted in exposing the basement membranes of both sides without their separation and subsequent damages to the in-between spongy layer. Biomechanical and biodegradability properties, endothelial proliferation capacity, and in vivo pro-angiogenic capabilities of the substrate were also evaluated. Histological staining, immunohistochemistry (IHC) staining for collagen IV, and scanning electron microscope demonstrated that the underlying amniotic and chorionic basement membranes remained intact while the epithelial and trophoblastic layers were entirely removed without considerable damage to basement membranes. The biomechanical evaluation showed that the scaffold is suturable. Proliferation assay, real-time polymerase chain reaction for endothelial adhesion molecules, and IHC demonstrated that both side basement membranes could support the growth of endothelial cells without altering endothelial characteristics. The dorsal skinfold chamber animal model indicated that both side basement membranes could promote angiogenesis. This bi-sided substrate with two exposed surfaces for cultivating various cells would have potential applications in the skin, cardiac, vascularized composite allografts, and microvascular tissue engineering.
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Affiliation(s)
- Siavash Shariatzadeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepehr Shafiee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Zafari
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Tayebi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghasem Yazdanpanah
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Alireza Majd
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arvin Haj-Mirzaian
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Pichlsberger M, Jerman UD, Obradović H, Tratnjek L, Macedo AS, Mendes F, Fonte P, Hoegler A, Sundl M, Fuchs J, Schoeberlein A, Kreft ME, Mojsilović S, Lang-Olip I. Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing. Front Bioeng Biotechnol 2021; 9:742858. [PMID: 34631683 PMCID: PMC8498585 DOI: 10.3389/fbioe.2021.742858] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022] Open
Abstract
Knowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing.
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Affiliation(s)
- Melanie Pichlsberger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Urška Dragin Jerman
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Hristina Obradović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Larisa Tratnjek
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Sofia Macedo
- LAQV, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Francisca Mendes
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Pedro Fonte
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Center for Marine Sciences (CCMar), Faculty of Sciences and Technology, University of Algarve, Faro, Portugal.,Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, Faro, Portugal
| | - Anja Hoegler
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Monika Sundl
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Julia Fuchs
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Mateja Erdani Kreft
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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16
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Zhou S, Wang Q, Huang A, Fan H, Yan S, Zhang Q. Advances in Skin Wound and Scar Repair by Polymer Scaffolds. Molecules 2021; 26:6110. [PMID: 34684690 PMCID: PMC8541489 DOI: 10.3390/molecules26206110] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/25/2021] [Accepted: 10/06/2021] [Indexed: 12/24/2022] Open
Abstract
Scars, as the result of abnormal wound-healing response after skin injury, may lead to loss of aesthetics and physical dysfunction. Current clinical strategies, such as surgical excision, laser treatment, and drug application, provide late remedies for scarring, yet it is difficult to eliminate scars. In this review, the functions, roles of multiple polymer scaffolds in wound healing and scar inhibition are explored. Polysaccharide and protein scaffolds, an analog of extracellular matrix, act as templates for cell adhesion and migration, differentiation to facilitate wound reconstruction and limit scarring. Stem cell-seeded scaffolds and growth factors-loaded scaffolds offer significant bioactive substances to improve the wound healing process. Special emphasis is placed on scaffolds that continuously release oxygen, which greatly accelerates the vascularization process and ensures graft survival, providing convincing theoretical support and great promise for scarless healing.
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Affiliation(s)
| | | | | | | | - Shuqin Yan
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, School of Textile Science and Engineering, Wuhan Textile University, Wuhan 430200, China; (S.Z.); (Q.W.); (A.H.); (H.F.)
| | - Qiang Zhang
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, School of Textile Science and Engineering, Wuhan Textile University, Wuhan 430200, China; (S.Z.); (Q.W.); (A.H.); (H.F.)
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17
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Sierra-Sánchez Á, Kim KH, Blasco-Morente G, Arias-Santiago S. Cellular human tissue-engineered skin substitutes investigated for deep and difficult to heal injuries. NPJ Regen Med 2021; 6:35. [PMID: 34140525 PMCID: PMC8211795 DOI: 10.1038/s41536-021-00144-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 05/25/2021] [Indexed: 02/05/2023] Open
Abstract
Wound healing is an important function of skin; however, after significant skin injury (burns) or in certain dermatological pathologies (chronic wounds), this important process can be deregulated or lost, resulting in severe complications. To avoid these, studies have focused on developing tissue-engineered skin substitutes (TESSs), which attempt to replace and regenerate the damaged skin. Autologous cultured epithelial substitutes (CESs) constituted of keratinocytes, allogeneic cultured dermal substitutes (CDSs) composed of biomaterials and fibroblasts and autologous composite skin substitutes (CSSs) comprised of biomaterials, keratinocytes and fibroblasts, have been the most studied clinical TESSs, reporting positive results for different pathological conditions. However, researchers' purpose is to develop TESSs that resemble in a better way the human skin and its wound healing process. For this reason, they have also evaluated at preclinical level the incorporation of other human cell types such as melanocytes, Merkel and Langerhans cells, skin stem cells (SSCs), induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs). Among these, MSCs have been also reported in clinical studies with hopeful results. Future perspectives in the field of human-TESSs are focused on improving in vivo animal models, incorporating immune cells, designing specific niches inside the biomaterials to increase stem cell potential and developing three-dimensional bioprinting strategies, with the final purpose of increasing patient's health care. In this review we summarize the use of different human cell populations for preclinical and clinical TESSs under research, remarking their strengths and limitations and discuss the future perspectives, which could be useful for wound healing purposes.
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Affiliation(s)
- Álvaro Sierra-Sánchez
- Cell Production and Tissue Engineering Unit, Virgen de las Nieves University Hospital, Andalusian Network of Design and Translation of Advanced Therapies, Granada, Spain.
- Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.
| | - Kevin H Kim
- Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Department of Dermatology, Virgen de las Nieves University Hospital, Granada University, Granada, Spain
| | - Gonzalo Blasco-Morente
- Department of Dermatology, Virgen de las Nieves University Hospital, Granada University, Granada, Spain
| | - Salvador Arias-Santiago
- Cell Production and Tissue Engineering Unit, Virgen de las Nieves University Hospital, Andalusian Network of Design and Translation of Advanced Therapies, Granada, Spain
- Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain
- Department of Dermatology, Virgen de las Nieves University Hospital, Granada University, Granada, Spain
- Department of Dermatology, Faculty of Medicine, University of Granada, Granada, Spain
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18
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Pethe P, Kale V. Placenta: A gold mine for translational research and regenerative medicine. Reprod Biol 2021; 21:100508. [PMID: 33930790 DOI: 10.1016/j.repbio.2021.100508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
Stem cell therapy has gained much impetus in regenerative medicine due to some of the encouraging results obtained in the laboratory as well as in translational/clinical studies. Although stem cells are of various types and their therapeutic potential has been documented in several studies, mesenchymal stromal/stem cells (MSCs) have an edge, as in addition to being multipotent, these cells are easy to obtain and expand, pose fewer ethical issues, and possess immense regenerative potential when used in a scientifically correct manner. Currently, MSCs are being sourced from various tissues such as bone marrow, cord, cord blood, adipose tissue, dental tissue, etc., and, quite often, the choice depends on the availability of the source. One such rich source of tissue suitable for obtaining good quality MSCs in large numbers is the placenta obtained in a full-term delivery leading to a healthy child's birth. Several studies have demonstrated the regenerative potential of human placenta-derived MSCs (hPMSC), and most show that these MSCs possess comparable, in some instances, even better, therapeutic potential as that shown by human bone marrow-derived (hBMSC) or human umbilical cord-derived (hUC-MSC) MSCs. The placenta can be easily sourced from the OB/GYN department of any hospital, and if its derivatives such as hPMSC or their EVs are produced under GMP conditions, it could serve as a gold mine for translational/clinical research. Here, we have reviewed recent studies revealing the therapeutic potential of hPMSC and their extracellular vesicles (EVs) published over the past three years.
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Affiliation(s)
- Prasad Pethe
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India.
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19
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Topical Application of Conditioned Medium from Hypoxically Cultured Amnion-Derived Mesenchymal Stem Cells Promotes Wound Healing in Diabetic Mice. Plast Reconstr Surg 2021; 147:1342-1352. [PMID: 34019504 DOI: 10.1097/prs.0000000000007993] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Mesenchymal stem cells or their conditioned medium improve chronic wound healing, and their effect is enhanced by hypoxia. Diabetic foot ulcers are chronic wounds characterized by abnormal and delayed healing, which frequently require amputation. The authors evaluated the effect of topical application of conditioned medium from hypoxically cultured amnion-derived mesenchymal stem cells on wound healing in diabetic mice. METHODS Amnion-derived mesenchymal stem cells were cultured under 21% oxygen to prepare normoxic conditioned medium and under 1% oxygen to prepare hypoxic conditioned medium. Hydrogels containing standard medium, normoxic conditioned medium, or hypoxic conditioned medium were topically applied to excisional wounds of mice with streptozotocin-induced diabetes. Ulcer tissues were harvested on day 9; immunohistochemical and quantitative polymerase chain reaction analyses were performed to analyze angiogenesis, inflammatory cell infiltration, and expression levels of inflammation-related genes. RESULTS Hypoxic conditioned medium significantly enhanced wound closure, increased capillary density and epithelization, and reduced macrophage infiltration. It also tended to reduce the infiltration of neutrophils and enhance the infiltration of regulatory T cells; it showed a tendency to downregulate the expression of the inflammation-related genes interleukin-1β, interleukin-6, chemokine ligand 1, and chemokine ligand 2. Normoxic conditioned medium exhibited similar effects, although they were of lesser magnitude than those of hypoxic conditioned medium. CONCLUSIONS Hydrogels containing hypoxically cultured, amnion-derived mesenchymal stem cell conditioned medium accelerated wound healing in diabetic mice by enhancing angiogenesis, accelerating epithelization, and suppressing inflammation. Therefore, topical application of amnion mesenchymal stem cell-derived hypoxic conditioned medium could be a novel treatment for diabetic foot ulcers.
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20
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Li J, Xiao L, He D, Luo Y, Sun H. Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage. Front Aging Neurosci 2021; 13:632054. [PMID: 33927608 PMCID: PMC8078548 DOI: 10.3389/fnagi.2021.632054] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/18/2021] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.
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Affiliation(s)
- Jing Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linglong Xiao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Dian He
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yunhao Luo
- Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of The Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
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21
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Sierra-Sánchez Á, Montero-Vilchez T, Quiñones-Vico MI, Sanchez-Diaz M, Arias-Santiago S. Current Advanced Therapies Based on Human Mesenchymal Stem Cells for Skin Diseases. Front Cell Dev Biol 2021; 9:643125. [PMID: 33768095 PMCID: PMC7985058 DOI: 10.3389/fcell.2021.643125] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Skin disease may be related with immunological disorders, external aggressions, or genetic conditions. Injuries or cutaneous diseases such as wounds, burns, psoriasis, and scleroderma among others are common pathologies in dermatology, and in some cases, conventional treatments are ineffective. In recent years, advanced therapies using human mesenchymal stem cells (hMSCs) from different sources has emerged as a promising strategy for the treatment of many pathologies. Due to their properties; regenerative, immunomodulatory and differentiation capacities, they could be applied for the treatment of cutaneous diseases. In this review, a total of thirteen types of hMSCs used as advanced therapy have been analyzed, considering the last 5 years (2015-2020). The most investigated types were those isolated from umbilical cord blood (hUCB-MSCs), adipose tissue (hAT-MSCs) and bone marrow (hBM-MSCs). The most studied diseases were wounds and ulcers, burns and psoriasis. At preclinical level, in vivo studies with mice and rats were the main animal models used, and a wide range of types of hMSCs were used. Clinical studies analyzed revealed that cell therapy by intravenous administration was the advanced therapy preferred except in the case of wounds and burns where tissue engineering was also reported. Although in most of the clinical trials reviewed results have not been posted yet, safety was high and only local slight adverse events (mild nausea or abdominal pain) were reported. In terms of effectiveness, it was difficult to compare the results due to the different doses administered and variables measured, but in general, percentage of wound's size reduction was higher than 80% in wounds, Psoriasis Area and Severity Index and Severity Scoring for Atopic Dermatitis were significantly reduced, for scleroderma, parameters such as Modified Rodnan skin score (MRSC) or European Scleroderma Study Group activity index reported an improvement of the disease and for hypertrophic scars, Vancouver Scar Scale (VSS) score was decreased after applying these therapies. On balance, hMSCs used for the treatment of cutaneous diseases is a promising strategy, however, the different experimental designs and endpoints stablished in each study, makes necessary more research to find the best way to treat each patient and disease.
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Affiliation(s)
- Álvaro Sierra-Sánchez
- Cell Production and Tissue Engineering Unit, Andalusian Network of Design and Translation of Advanced Therapies, Virgen de las Nieves University Hospital, Granada, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain
| | - Trinidad Montero-Vilchez
- Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.,Department of Dermatology, Virgen de las Nieves University Hospital, Granada, Spain
| | - María I Quiñones-Vico
- Cell Production and Tissue Engineering Unit, Andalusian Network of Design and Translation of Advanced Therapies, Virgen de las Nieves University Hospital, Granada, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.,Department of Dermatology, Faculty of Medicine, University of Granada, Granada, Spain
| | - Manuel Sanchez-Diaz
- Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.,Department of Dermatology, Virgen de las Nieves University Hospital, Granada, Spain
| | - Salvador Arias-Santiago
- Cell Production and Tissue Engineering Unit, Andalusian Network of Design and Translation of Advanced Therapies, Virgen de las Nieves University Hospital, Granada, Spain.,Biosanitary Institute of Granada (ibs.GRANADA), Granada, Spain.,Department of Dermatology, Virgen de las Nieves University Hospital, Granada, Spain.,Department of Dermatology, Faculty of Medicine, University of Granada, Granada, Spain
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22
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Yu S, You X, Liang H, Li Y, Fu Y, Zhang X, Hu X, An J, Xu Y, Li F. First trimester placental mesenchymal stem cells improve cardiac function of rat after myocardial infarction via enhanced neovascularization. Heliyon 2021; 7:e06120. [PMID: 33553765 PMCID: PMC7855719 DOI: 10.1016/j.heliyon.2021.e06120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/10/2020] [Accepted: 01/25/2021] [Indexed: 01/10/2023] Open
Abstract
Acute myocardial infarction (AMI) is the most critical heart disease. Mesenchymal stem cells (MSCs) have been widely used as a therapy for AMI for several years. The human placenta has emerged as a valuable source of transplantable cells of mesenchymal origin that can be used for multiple cytotherapeutic purposes. However, the different abilities of first trimester placental chorion mesenchymal stem cells (FCMSCs) and third trimester placental chorion mesenchymal stem cells (TCMSCs) have not yet been explored. In this study, we aimed to compare the effectiveness of FCMSCs and TCMSCs on the treatment of AMI. FCMSCs and TCMSCs were isolated and characterized, and then they were subjected to in vitro endothelial cell (EC) differentiation induction and tube formation to evaluate angiogenic ability. Moreover, the in vivo effects of FCMSCs and TCMSCs on cardiac improvement were also evaluated in a rat MI model. Both FCSMCs and TCMSCs expressed a series of MSCs surface markers. After differentiation induction, FCMSCs-derived EC (FCMSCs-EC) exhibited morphology that was more similar to that of ECs and had higher CD31 and vWF levels than TCMSCs-EC. Furthermore, tube formation could be achieved by FCMSCs-EC that was significantly better than that of TCMSCs-EC. Especially, FCMSCs-EC expressed higher levels of pro-angiogenesis genes, PDGFD, VEGFA, and TNC, and lower levels of anti-angiogenesis genes, SPRY1 and ANGPTL1. In addition, cardiac improvement, indicated by left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF), could be observed following treatment with FCMSCs, and it was superior to that of TCMSCs and Bone marrow MSCs (BMSCs). FCMSCs exhibited a superior ability to generate EC differentiation, as evidenced by in vitro morphology, angiogenic potential and in vivo cardiac function improvement; further, increased levels of expression of pro-angiogenesis genes may be the mechanism by which this effect occurred.
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Affiliation(s)
- Shuichang Yu
- Department of Human Anatomy, Histology and Embryology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xinran You
- Department of Nuclear Medicine, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Hansi Liang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ying Li
- Department of Human Anatomy, Histology and Embryology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yi Fu
- Department of Human Anatomy, Histology and Embryology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xia Zhang
- Department of Gynaecology and Obstetrics, TuHa Petroleum Hospital, Xinjiang, China
| | - Xiaohan Hu
- Institute of Pediatrics, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jinnan An
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yunyun Xu
- Institute of Pediatrics, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fang Li
- Department of Human Anatomy, Histology and Embryology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
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23
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Eylert G, Dolp R, Parousis A, Cheng R, Auger C, Holter M, Lang-Olip I, Reiner V, Kamolz LP, Jeschke MG. Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells-a paradigm change. Stem Cell Res Ther 2021; 12:82. [PMID: 33494813 PMCID: PMC7831169 DOI: 10.1186/s13287-020-02131-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/28/2020] [Indexed: 12/16/2022] Open
Abstract
Background Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®. Methods We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin. Result We found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control. Conclusion This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02131-6.
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Affiliation(s)
- Gertraud Eylert
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.,Division of Plastic, Aesthetic, Reconstructive Surgery, Medical University of Graz, Graz, Austria.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Reinhard Dolp
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Department of Psychiatry, Queen's University, Kingston, Canada
| | - Alexandra Parousis
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Richard Cheng
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Christopher Auger
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Magdalena Holter
- Institute of Biostatistics, Medical University of Graz, Graz, Austria
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology, Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Viola Reiner
- Division of Cell Biology, Histology, Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Lars-Peter Kamolz
- Division of Plastic, Aesthetic, Reconstructive Surgery, Medical University of Graz, Graz, Austria.,Coremed- Centre for Regenerative Medicine, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria
| | - Marc G Jeschke
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada. .,Institute of Medical Science, University of Toronto, Toronto, ON, Canada. .,Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Canada. .,Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada. .,Department of Surgery, Division of Plastic Surgery, Department of Immunology, Director Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, M4N 3M5, Canada.
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Miceli V, Bertani A, Chinnici CM, Bulati M, Pampalone M, Amico G, Carcione C, Schmelzer E, Gerlach JC, Conaldi PG. Conditioned Medium from Human Amnion-Derived Mesenchymal Stromal/Stem Cells Attenuating the Effects of Cold Ischemia-Reperfusion Injury in an In Vitro Model Using Human Alveolar Epithelial Cells. Int J Mol Sci 2021; 22:510. [PMID: 33419219 PMCID: PMC7825633 DOI: 10.3390/ijms22020510] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/30/2020] [Accepted: 01/03/2021] [Indexed: 02/07/2023] Open
Abstract
The clinical results of lung transplantation (LTx) are still less favorable than other solid organ transplants in both the early and long term. The fragility of the lungs limits the procurement rate and can favor the occurrence of ischemia-reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) with Steen SolutionTM (SS) aims to address problems, and the implementation of EVLP to alleviate the activation of IRI-mediated processes has been achieved using mesenchymal stromal/stem cell (MSC)-based treatments. In this study, we investigated the paracrine effects of human amnion-derived MSCs (hAMSCs) in an in vitro model of lung IRI that includes cold ischemia and normothermic EVLP. We found that SS enriched by a hAMSC-conditioned medium (hAMSC-CM) preserved the viability and delayed the apoptosis of alveolar epithelial cells (A549) through the downregulation of inflammatory factors and the upregulation of antiapoptotic factors. These effects were more evident using the CM of 3D hAMSC cultures, which contained an increased amount of immunosuppressive and growth factors compared to both 2D cultures and encapsulated-hAMSCs. To conclude, we demonstrated an in vitro model of lung IRI and provided evidence that a hAMSC-CM attenuated IRI effects by improving the efficacy of EVLP, leading to strategies for a potential implementation of this technique.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (M.B.); (P.G.C.)
| | - Alessandro Bertani
- Thoracic Surgery and Lung Transplantation Unit, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, 90127 Palermo, Italy;
| | - Cinzia Maria Chinnici
- Regenerative Medicine Unit, Fondazione Ri.MED, 90127 Palermo, Italy; (C.M.C.); (M.P.); (G.A.); (C.C.)
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS–ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Matteo Bulati
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (M.B.); (P.G.C.)
| | - Mariangela Pampalone
- Regenerative Medicine Unit, Fondazione Ri.MED, 90127 Palermo, Italy; (C.M.C.); (M.P.); (G.A.); (C.C.)
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS–ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Giandomenico Amico
- Regenerative Medicine Unit, Fondazione Ri.MED, 90127 Palermo, Italy; (C.M.C.); (M.P.); (G.A.); (C.C.)
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS–ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Claudia Carcione
- Regenerative Medicine Unit, Fondazione Ri.MED, 90127 Palermo, Italy; (C.M.C.); (M.P.); (G.A.); (C.C.)
| | - Eva Schmelzer
- Department of Surgery, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA; (E.S.); (J.C.G.)
| | - Jörg C. Gerlach
- Department of Surgery, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA; (E.S.); (J.C.G.)
- Department of Bioengineering, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (M.B.); (P.G.C.)
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Vonbrunn E, Mueller M, Pichlsberger M, Sundl M, Helmer A, Wallner SA, Rinner B, Tuca AC, Kamolz LP, Brislinger D, Glasmacher B, Lang-Olip I. Electrospun PCL/PLA Scaffolds Are More Suitable Carriers of Placental Mesenchymal Stromal Cells Than Collagen/Elastin Scaffolds and Prevent Wound Contraction in a Mouse Model of Wound Healing. Front Bioeng Biotechnol 2020; 8:604123. [PMID: 33425870 PMCID: PMC7793771 DOI: 10.3389/fbioe.2020.604123] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/25/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) exert beneficial effects during wound healing, and cell-seeded scaffolds are a promising method of application. Here, we compared the suitability of a clinically used collagen/elastin scaffold (Matriderm) with an electrospun Poly(ε-caprolactone)/poly(l-lactide) (PCL/PLA) scaffold as carriers for human amnion-derived MSCs (hAMSCs). We created an epidermal-like PCL/PLA scaffold and evaluated its microstructural, mechanical, and functional properties. Sequential spinning of different PCL/PLA concentrations resulted in a wide-meshed layer designed for cell-seeding and a dense-meshed layer for apical protection. The Matriderm and PCL/PLA scaffolds then were seeded with hAMSCs, with or without Matrigel coating. The quantity and quality of the adherent cells were evaluated in vitro. The results showed that hAMSCs adhered to and infiltrated both scaffold types but on day 3, more cells were observed on PCL/PLA than on Matriderm. Apoptosis and proliferation rates were similar for all carriers except the coated Matriderm, where apoptotic cells were significantly enhanced. On day 8, the number of cells decreased on all carrier types except the coated Matriderm, which had consistently low cell numbers. Uncoated Matriderm had the highest percentage of proliferative cells and lowest apoptosis rate of all carrier types. Each carrier also was topically applied to skin wound sites in a mouse model and analyzed in vivo over 14 days via optical imaging and histological methods, which showed detectable hAMSCs on all carrier types on day 8. On day 14, all wounds exhibited newly formed epidermis, and all carriers were well-integrated into the underlying dermis and showing signs of degradation. However, only wounds treated with uncoated PCL/PLA maintained a round appearance with minimal contraction. Overall, the results support a 3-day in vitro culture of scaffolds with hAMSCs before wound application. The PCL/PLA scaffold showed higher cell adherence than Matriderm, and the effect of the Matrigel coating was negligible, as all carrier types maintained sufficient numbers of transplanted cells in the wound area. The anti-contractive effects of the PCL/PLA scaffold offer potential new therapeutic approaches to wound care.
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Affiliation(s)
- Eva Vonbrunn
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Marc Mueller
- Institute of Multiphase Processes, Leibniz University Hanover, Hannover, Germany
| | - Melanie Pichlsberger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Monika Sundl
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Alexander Helmer
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | | | - Beate Rinner
- Division of Biomedical Research, Medical University of Graz, Graz, Austria
| | - Alexandru-Cristian Tuca
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Lars-Peter Kamolz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria.,COREMED - Cooperative Centre for Regenerative Medicine, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria
| | - Dagmar Brislinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Birgit Glasmacher
- Institute of Multiphase Processes, Leibniz University Hanover, Hannover, Germany
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Peng SY, Wu TH, Lin TY, Hii LY, Chan KS, Fu TY, Chang SC, Shen PC, Liu KY, Shaw SW. Application of cattle placental stem cells for treating ovarian follicular cyst. World J Stem Cells 2020; 12:1366-1376. [PMID: 33312404 PMCID: PMC7705470 DOI: 10.4252/wjsc.v12.i11.1366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/02/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High humidity and temperature in Taiwan have significant effects on the reproductivity of Holstein cattle, resulting in the occurrence of bovine ovarian follicular cyst (OFC). Because of economic loss from OFC, manual rupture and hormone injection have been advocated for the management of OFC. However, these incomplete treatments increase hormone resistance in cattle. Mesenchymal stem cells (MSCs) derived from placental stem cells (PSCs) demonstrate potential properties for the treatment of several diseases via promoting angiogenesis and immune modulation. AIM To establish the possibility of cattle placental stem cells (CPSCs) as a treatment modality for OFC of cows in Taiwan. METHODS The cows with OFC were divided into three groups: control (BC1 and BC2), hormone (H1 and H2), and CPSC (PS1 and PS2) treatment groups. In the hormone treatment group, the cows were given gonadotrophin-releasing hormone (GnRH)-prostaglandin-GnRH intramuscular injection with or without drainage of follicular fluid. In the CPSC treatment group, CPSCs were isolated from the placenta after labor. With the identification of surface antigen on stem cells, the cows were administered ovarian injection of 1 × 106 or 6 × 106 CPSCs with drainage. In all groups, OFC was scanned by ultrasound once a week for a total of seven times. The concentrations of estradiol and progesterone in serum were tested in the same period. The estrus cycle was analyzed by food intake and activity. If estrus was detected, artificial insemination was conducted. Then the cow was monitored by ultrasound for confirmation of pregnancy. RESULTS After 7 d of culture, CPSCs were successfully isolated from placental pieces. CPSCs significantly proliferated every 24 h and had high expression of MSC markers such as cluster of differentiation 44, as determined by flow cytometry. Ultrasound showed lower numbers of OFCs with drainage of follicular fluid. We achieved recovery rates of 0%, 50%, 50%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. Higher concentrations of progesterone were detected in the CPSC treatment groups. However, both hormone and CPSC treatment groups had no significant difference in the concentration of estradiol. The estrus rate was 0%, 100%, 25%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. The two fetuses were born in H2 and PS1. In brief, cows with CPSC injection achieved higher recovery, estrus, and inseminated conception rates. CONCLUSION CPSCs have efficacy in treating cows with OFC, and thus, may serve as an alternative treatment for reproductive disorders.
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Affiliation(s)
- Shao-Yu Peng
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tsung-Hsin Wu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tzu-Yi Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ling-Yien Hii
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Kok-Seong Chan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Tzu-Yen Fu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Shen-Chang Chang
- Kaohsiung Animal Propagation Station, Livestock Research Institute, Council of Agriculture, Executive Yuan, Pingtung 912, Taiwan
| | - Perng-Chih Shen
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Kang-You Liu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Steven W. Shaw
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
- Prenatal Cell and Gene Therapy Group, Institute for Women's Health, University College London, London WC1E 6HU, United Kingdom.
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Wang J, Gong M, Zuo S, Xu J, Paul C, Li H, Liu M, Wang YG, Ashraf M, Xu M. WNT11-Conditioned Medium Promotes Angiogenesis through the Activation of Non-Canonical WNT-PKC-JNK Signaling Pathway. Genes (Basel) 2020; 11:E1277. [PMID: 33137935 PMCID: PMC7694138 DOI: 10.3390/genes11111277] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/25/2020] [Accepted: 10/26/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We demonstrated that the transduction of Wnt11 into mesenchymal stem cells (MSCs) (MSCWnt11) promotes these cells differentiation into cardiac phenotypes. In the present study, we investigated the paracrine effects of MSCWnt11 on cardiac function and angiogenesis. METHODS AND RESULTS Conditioned medium was collected from MSCWnt11 (CdMWnt11) and their control cells (CdMGFP). CdMWnt11, especially obtained from MSCWnt11 exposed to hypoxia, significantly promoted human umbilical vein endothelial cells (HUVECs) migration and increased capillary-like tube (CLT) formation, which was blocked by Wnt11 neutralizing antibody. Wnt11 protein was significantly higher in CdMWnt11 compared to that in CdMGFP. Directly treating HUVECs with recombinant Wnt11 protein significantly increased CLT formation, which was abrogated by treating cells with the JNK inhibitor SP600125, as well as the PKC inhibitor Calphostin-C. Moreover, the transfection of Wnt11 to HUVECs (HWnt11) significantly increased CLT formation and HUVEC migration, as well as upregulated p-pan-PKC and p-JNK expression. Injection of CdMWnt11 into the peri-infarct region in a rat acute myocardial infarction (AMI) model significantly improved cardiac function, reduced infarct size, and increased myocardial blood flow and blood vessel density in the ischemic area. CONCLUSION Wnt11 released from MSCWnt11 increased angiogenesis and improved cardiac function via non-canonical Wnt-PKC-JNK dependent pathways.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; (J.W.); (M.G.); (S.Z.); (J.X.); (C.P.); (H.L.); (M.L.); (Y.-G.W.); (M.A.)
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Boss AL, Brooks AES, Chamley LW, James JL. Influence of culture media on the derivation and phenotype of fetal-derived placental mesenchymal stem/stromal cells across gestation. Placenta 2020; 101:66-74. [PMID: 32932101 DOI: 10.1016/j.placenta.2020.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/18/2020] [Accepted: 09/01/2020] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Derivation of pure fetal placental mesenchymal stem/stromal cells (pMSCs) is key to understand their role in placental development. However, isolated pMSCs are often contaminated by maternal-derived decidual MSCs (dMSCs). EGM-2 medium promotes the derivation of term fetal pMSCs, but the extent of first-trimester maternal pMSC contamination remains unclear. Culture media can also affect MSC phenotype. Here, we examined the effects of culture media on maternal pMSC contamination and fetal pMSC phenotype across gestation. METHODS pMSCs were derived from first-trimester or term placentae in advanced-DMEM/F12 medium or EGM-2 medium. Proportions of maternal (XX) and fetal (XY) cells in male pMSC cultures were determined by fluorescence in-situ hybridization. pMSC phenotype was analysed by flow cytometry, immunohistochemistry and Alamar blue proliferation assays. RESULTS When derived in advanced-DMEM/F12, all first trimester pMSC isolates exhibited maternal contamination (>72% XX cells, n = 5), whilst 7/9 term pMSC isolates were >98% fetal. When derived in EGM-2, all first trimester (n = 4) and term (n = 9) pMSC isolates contained 95-100% fetal cells. Fetal pMSCs in EGM-2 proliferated 2-fold (first-trimester) or 4-fold (term) faster than those in advanced-DMEM/F12 (p < 0.05, n = 3). Fetal pMSCs in both media expressed the generic MSC marker profile (CD90+, CD105+, CD73+, CD31-, CD34-, CD144-). However, pMSCs transferred from EGM-2 to advanced-DMEM/F12 increased expression of smooth muscle cell markers calponin and α-smooth muscle actin, and decreased expression of the vascular cell marker VEGFR2 (n = 3). CONCLUSIONS Deriving first-trimester pMSC in EGM-2 dramatically reduces maternal dMSC contamination. Media affects fetal pMSC phenotype, and careful consideration should be given to application specific culture conditions.
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Affiliation(s)
- Anna L Boss
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
| | - Anna E S Brooks
- Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
| | - Lawrence W Chamley
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
| | - Joanna L James
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
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Song Y, Zhang TJ, Li Y, Gao Y. Mesenchymal Stem Cells Decrease M1/M2 Ratio and Alleviate Inflammation to Improve Limb Ischemia in Mice. Med Sci Monit 2020; 26:e923287. [PMID: 32860388 PMCID: PMC7477932 DOI: 10.12659/msm.923287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Limb ischemia (LI) is the underlying pathology of peripheral artery disease (PAD). Macrophages play a critical role in inflammation and can contribute to the exacerbation or reduction of inflammation. Transplantation of mesenchymal stem cells (MSCs) is an emerging therapeutic strategy for PAD. However, the mechanism by which human placenta-derived mesenchymal stem cells (PMSCs) regulate macrophage differentiation in ischemic tissue remains unclear. MATERIAL AND METHODS Placentas were obtained from healthy donors with normal 38- to 40-week gestation, and PMSCs were isolated from the placentas and cultured. A mouse model of hind-limb ischemia was established. Ischemic limbs were injected intramuscularly with about 5×10⁶ PMSCs in the PMSCs group or a placebo solution (phosphate-buffered saline) in the control group at 4 different sites 1 day after the procedure. The blood perfusion of hind-limbs and the histological morphology were observed at day 1, 7, and 14 after the surgical procedure. Macrophages were detected by flow cytometry. The expression of serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). The expression of CD31 and smooth muscle alpha-actin (alpha-SMA) in frozen muscle samples were detected by immunofluorescence staining. RESULTS In the PMSCs group, blood perfusion was gradually recovered and ischemic injury was markedly alleviated. The percentage of M2-like macrophages was increased dramatically, while the M1/M2 macrophage ratio was reduced. The expression of TNF-alpha and IL-6 was reduced, while the IL-10 level was elevated. The expression and density of CD31- and alpha-SMA-positive vessels were both significantly increased. CONCLUSIONS Transplanted PMSCs alleviated inflammation, promoted neovascularization, and improved hind limb ischemia through regulating macrophage differentiation toward the M2 phenotype and cytokine secretion. Cytokine manipulation of macrophage phenotypes may have potential therapeutic benefits in injured ischemic limbs.
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Affiliation(s)
- Ye Song
- Department of Ultrasound Medicine, The Affiliated Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China (mainland)
| | - Tian-Jie Zhang
- Shanghai Leren Dongsheng Clinic, Shanghai, China (mainland)
| | - Yuan Li
- Department of Ultrasound Medicine, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China (mainland)
| | - Yuan Gao
- Department of General Surgery, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China (mainland)
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Dabiri B, Kampusch S, Geyer SH, Le VH, Weninger WJ, Széles JC, Kaniusas E. High-Resolution Episcopic Imaging for Visualization of Dermal Arteries and Nerves of the Auricular Cymba Conchae in Humans. Front Neuroanat 2020; 14:22. [PMID: 32477074 PMCID: PMC7236887 DOI: 10.3389/fnana.2020.00022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/27/2020] [Indexed: 12/16/2022] Open
Abstract
Therapeutic applications of auricular vagus nerve stimulation (VNS) have drawn recent attention. Since the targeted stimulation process and parameters depend on the electrode–tissue interaction, the lack of structural anatomical information on innervation and vascularization of the auricle restrain the current optimization of stimulation paradigms. For the first time, we employed high-resolution episcopic imaging (HREM) to generate histologic volume data from donated human cadaver ears. Optimal parameters for specimen preparation were evaluated. Anatomical 3D vascular and nerve structures were reconstructed in one sample of an auricular cymba conchae (CC). The feasibility of HREM to visualize anatomical structures was assessed in that diameters, occupied areas, volumes, and mutual distances between auricular arteries, nerves, and veins were registered. The selected region of CC (3 × 5.5 mm) showed in its cross-sections 21.7 ± 2.7 (mean ± standard deviation) arteries and 14.66 ± 2.74 nerve fibers. Identified nerve diameters were 33.66 ± 21.71 μm, and arteries had diameters in the range of 71.58 ± 80.70 μm. The respective occupied area showed a share of, on average, 2.71% and 0.3% for arteries and nerves, respectively, and similar volume occupancy for arteries and nerves. Inter-centroid minimum distance between arteries and nerves was 274 ± 222 μm. The density of vessels and nerves around a point within CC on a given grid was assessed, showing that 50% of all vessels and nerves were found in a radial distance of 1.6–1.8 mm from any of these points, which is strategically relevant when using stimulation needles in the auricle for excitation of nerves. HREM seems suitable for anatomical studies of the human ear. A 3D model of CC was established in the micrometer scale, which forms the basis for future optimization of the auricular VNS. Obviously, the presented single cadaver study needs to be validated by additional anatomical data on the innervation and vascularization of the auricle.
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Affiliation(s)
- Babak Dabiri
- Institute of Electrodynamics, Microwave and Circuit Engineering, Vienna University of Technology, Vienna, Austria
| | - Stefan Kampusch
- Institute of Electrodynamics, Microwave and Circuit Engineering, Vienna University of Technology, Vienna, Austria.,SzeleSTIM GmbH, Vienna, Austria
| | - Stefan H Geyer
- Division of Anatomy, MIC, Medical University of Vienna, Vienna, Austria
| | - Van Hoang Le
- Institute of Electrodynamics, Microwave and Circuit Engineering, Vienna University of Technology, Vienna, Austria
| | | | - Jozsef Constantin Széles
- Department for Vascular Surgery, University Clinic for Surgery, Medical University of Vienna, Vienna, Austria
| | - Eugenijus Kaniusas
- Institute of Electrodynamics, Microwave and Circuit Engineering, Vienna University of Technology, Vienna, Austria.,SzeleSTIM GmbH, Vienna, Austria
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Velarde F, Castañeda V, Morales E, Ortega M, Ocaña E, Álvarez-Barreto J, Grunauer M, Eguiguren L, Caicedo A. Use of Human Umbilical Cord and Its Byproducts in Tissue Regeneration. Front Bioeng Biotechnol 2020; 8:117. [PMID: 32211387 PMCID: PMC7075856 DOI: 10.3389/fbioe.2020.00117] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 02/06/2020] [Indexed: 12/13/2022] Open
Abstract
The fresh or cryopreserved human umbilical cord (HUC) and its byproducts, such as cells and extracts, have different uses in tissue regeneration. Defining what HUC byproduct is more effective in a particular application is a challenge. Furthermore, the methods of isolation, culture and preservation, may affect cell viability and regenerative properties. In this article, we review the HUC and its byproducts' applications in research and clinical practice. We present our results of successful use of HUC as a patch to treat gastroschisis and its potential to be applied in other conditions. Our in vitro results show an increase in proliferation and migration of human fibroblasts by using an acellular HUC extract. Our goal is to promote standardization of procedures and point out that applications of HUC and its byproducts, as well as the resulting advances in regenerative medicine, will depend on rigorous quality control and on more research in this area.
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Affiliation(s)
- Francesca Velarde
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito, Quito, Ecuador
| | - Verónica Castañeda
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito, Quito, Ecuador
- Colegio de Ciencias Biológicas y Ambientales, Escuela de Biotecnología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Emilia Morales
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito, Quito, Ecuador
- Colegio de Ciencias Biológicas y Ambientales, Escuela de Biotecnología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Mayra Ortega
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito, Quito, Ecuador
- Colegio de Ciencias Biológicas y Ambientales, Escuela de Biotecnología, Universidad San Francisco de Quito, Quito, Ecuador
| | - Edwin Ocaña
- Hospital Carlos Andrade Marín, Quito, Ecuador
| | - Jose Álvarez-Barreto
- Instituto para el Desarrollo de Energías y Materiales Alternativos (IDEMA), Colegio de Ciencias e Ingenierías (Politécnico), Universidad San Francisco de Quito, Quito, Ecuador
| | - Michelle Grunauer
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Unidad de Cuidados Intensivos Pediátricos, Hospital de los Valles, Quito, Ecuador
| | - Luis Eguiguren
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Sistemas Médicos, SIME, Universidad San Francisco de Quito, Quito, Ecuador
| | - Andrés Caicedo
- Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito, Quito, Ecuador
- Instituto de Investigaciones en Biomedicina, Universidad San Francisco de Quito, Quito, Ecuador
- Sistemas Médicos, SIME, Universidad San Francisco de Quito, Quito, Ecuador
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Klama-Baryła A, Rojczyk E, Kitala D, Łabuś W, Smętek W, Wilemska-Kucharzewska K, Kucharzewski M. Preparation of placental tissue transplants and their application in skin wound healing and chosen skin bullous diseases - Stevens-Johnson syndrome and toxic epidermal necrolysis treatment. Int Wound J 2020; 17:491-507. [PMID: 31943788 DOI: 10.1111/iwj.13305] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022] Open
Abstract
Unique properties of amniotic membrane make it a promising source for tissue engineering and a clinically useful alternative for patients suffering from chronic wounds including, for example, ulcers, burns, ocular surface damages and wounds occurring in the course of bullous diseases like stevens-johnson syndrome and toxic epidermal necrolysis. Its use has many advantages over standard wound care, as it contains pluripotent cells, nutrients, anti-fibrotic and anti-inflammatory cytokines, growth factors and extracellular matrix (ECM) proteins. Placental tissues can be prepared as a medical component, an advanced therapy medicinal product or a tissue graft. In addition to basic preparation procedures such as washing, rinsing, cutting, drying and sterilisation, there are many optional steps such as perforation, crosslinking and decellularisation. Finally, transplants should be properly stored-in cryopreserved or dehydrated form. In recent years, many studies including basic science and clinical trials have proven the potential to expand the use of amniotic membrane and amnion-derived cells to the fields of orthopaedics, dentistry, surgery, urology, vascular tissue engineering and even oncology. In this review, we discuss the role of placental tissues in skin wound healing and in the treatment of various diseases, with particular emphasis on bullous diseases. We also describe some patented procedures for placental tissue grafts preparation.
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Affiliation(s)
- Agnieszka Klama-Baryła
- The Burn Centre of Stanisław Sakiel in Siemianowice Śląskie, Siemianowice Śląskie, Poland
| | - Ewa Rojczyk
- Department of Descriptive and Topographic Anatomy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Zabrze, Poland
| | - Diana Kitala
- The Burn Centre of Stanisław Sakiel in Siemianowice Śląskie, Siemianowice Śląskie, Poland
| | - Wojciech Łabuś
- The Burn Centre of Stanisław Sakiel in Siemianowice Śląskie, Siemianowice Śląskie, Poland
| | - Wojciech Smętek
- The Burn Centre of Stanisław Sakiel in Siemianowice Śląskie, Siemianowice Śląskie, Poland
| | | | - Marek Kucharzewski
- Department of Descriptive and Topographic Anatomy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Zabrze, Poland
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High-Resolution Episcopic Microscopy (HREM): Looking Back on 13 Years of Successful Generation of Digital Volume Data of Organic Material for 3D Visualisation and 3D Display. APPLIED SCIENCES-BASEL 2019. [DOI: 10.3390/app9183826] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
High-resolution episcopic microscopy (HREM) is an imaging technique that permits the simple and rapid generation of three-dimensional (3D) digital volume data of histologically embedded and physically sectioned specimens. The data can be immediately used for high-detail 3D analysis of a broad variety of organic materials with all modern methods of 3D visualisation and display. Since its first description in 2006, HREM has been adopted as a method for exploring organic specimens in many fields of science, and it has recruited a slowly but steadily growing user community. This review aims to briefly introduce the basic principles of HREM data generation and to provide an overview of scientific publications that have been published in the last 13 years involving HREM imaging. The studies to which we refer describe technical details and specimen-specific protocols, and provide examples of the successful use of HREM in biological, biomedical and medical research. Finally, the limitations, potentials and anticipated further improvements are briefly outlined.
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Shojaei F, Rahmati S, Banitalebi Dehkordi M. A review on different methods to increase the efficiency of mesenchymal stem cell-based wound therapy. Wound Repair Regen 2019; 27:661-671. [PMID: 31298446 DOI: 10.1111/wrr.12749] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/04/2019] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) accelerate wound healing but the harsh environment of wound site limits the engraftment, retention, and survival rate of transplanted cells. There are multiple approaches that amplify the therapeutic potential of MSCs. The MSCs derived from medical waste material, provide comparable regenerative abilities compared to traditional sources. The application of different scaffolds increases MSC delivery and migration into the wound. The spheroid culture of MSC increases the paracrine effects of the entrapped cells and the secretion of pro-angiogenic and anti-inflammatory cytokines. The MSC pretreating and preconditioning enhances the cell migration, proliferation, and survival rate, which lead to higher angiogenesis, re-epithelialization, wound closure, and granulation tissue formation. Moreover, genetic modification has been performed in order to increase MSC angiogenesis, differentiation potential, as well as the cell life span. Herein, we review the results of aforementioned approaches and provide information accommodating to the continued development of MSC-based wound therapy in the future.
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Affiliation(s)
- Fereshteh Shojaei
- Department of Medical biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Shima Rahmati
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mehdi Banitalebi Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Leng Z, Sun D, Huang Z, Tadmori I, Chiang N, Kethidi N, Sabra A, Kushida Y, Fu YS, Dezawa M, He X, Young W. Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting. Cell Transplant 2019; 28:907-923. [PMID: 30997834 PMCID: PMC6719495 DOI: 10.1177/0963689719844260] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are a population of pluripotent stage-specific embryonic antigen 3 (SSEA3)+ mesenchymal stem cells first described by Mari Dezawa in 2010. Although some investigators have reported SSEA3+ mesenchymal cells in umbilical cord tissues, none have quantitatively compared SSEA3+ cells isolated from Wharton’s jelly (WJ) and the cord lining (CL) of human umbilical cords (HUCs). We separated WJ and the CL from HUCs, cultured mesenchymal stromal cells (MSCs) isolated from these two tissues with collagenase, and quantified the percentage of SSEA3+ cells over three passages. The first passage had 5.0% ± 4.3% and 5.3% ± 5.1% SSEA3+ cells from WJ and the CL, respectively, but the percentage of SSEA3+ cells decreased significantly (P < 0.05) between P0 and P2 in the CL group and between P0 and P1 in the WJ group. Magnetic-activated cell sorting (MACS) markedly enriched SSEA3+ cells to 91.4% ± 3.2%. Upon culture of the sorted population, we found that the SSEA3+ percentage ranged from 62.5% to 76.0% in P2–P5 and then declined to 42.0%–54.7% between P6 and P9. At P10, the cultures contained 37.4% SSEA3+ cells. After P10, we resorted the cells and achieved 89.4% SSEA3+ cells in culture. The procedure for MACS-based enrichment of SSEA3+ cells, followed by expansion in culture and a re-enrichment step, allows the isolation of many millions of SSEA3+ cells in relatively pure culture. When cultured, the sorted SSEA3+ cells differentiated into embryoid spheres and survived 4 weeks after transplant into a contused Sprague-Dawley rat spinal cord. The transplanted SSEA3+ cells migrated into the injury area from four injection points around the contusion site and did not produce any tumors. The umbilical cord is an excellent source of fetal Muse cells, and our method allows the practical and efficient isolation and expansion of relatively pure populations of SSEA3+ Muse cells that can be matched by human leukocyte antigen for transplantation in human trials.
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Affiliation(s)
- Zikuan Leng
- 1 Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Dongming Sun
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Zihao Huang
- 3 Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei
| | - Iman Tadmori
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Ning Chiang
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Nikhit Kethidi
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Ahmed Sabra
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Yoshihiro Kushida
- 4 Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yu-Show Fu
- 3 Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei
| | - Mari Dezawa
- 4 Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Xijing He
- 1 Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wise Young
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
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Miceli V, Pampalone M, Vella S, Carreca AP, Amico G, Conaldi PG. Comparison of Immunosuppressive and Angiogenic Properties of Human Amnion-Derived Mesenchymal Stem Cells between 2D and 3D Culture Systems. Stem Cells Int 2019; 2019:7486279. [PMID: 30911299 PMCID: PMC6397962 DOI: 10.1155/2019/7486279] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/15/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
Abstract
The secretion of potential therapeutic factors by mesenchymal stem cells (MSCs) has aroused much interest given the benefits that it can bring in the field of regenerative medicine. Indeed, the in vitro multipotency of these cells and the secretive capacity of both angiogenic and immunomodulatory factors suggest a role in tissue repair and regeneration. However, during culture, MSCs rapidly lose the expression of key transcription factors associated with multipotency and self-renewal, as well as the ability to produce functional paracrine factors. In our study, we show that a three-dimensional (3D) culture method is effective to induce MSC spheroid formation, to maintain the multipotency and to improve the paracrine activity of a specific population of human amnion-derived MSCs (hAMSCs). The regenerative potential of both 3D culture-derived conditioned medium (3D CM) and their exosomes (EXO) was assessed against 2D culture products. In particular, tubulogenesis assays revealed increased capillary maturation in the presence of 3D CM compared with both 2D CM and 2D EXO. Furthermore, 3D CM had a greater effect on inhibition of PBMC proliferation than both 2D CM and 2D EXO. To support this data, hAMSC spheroids kept in our 3D culture system remained viable and multipotent and secreted considerable amounts of both angiogenic and immunosuppressive factors, which were detected at lower levels in 2D cultures. This work reveals the placenta as an important source of MSCs that can be used for eventual clinical applications as cell-free therapies.
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Affiliation(s)
- Vitale Miceli
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy
| | - Mariangela Pampalone
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy
- Ri.MED Foundation, Palermo, Italy
| | | | | | - Giandomenico Amico
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy
- Ri.MED Foundation, Palermo, Italy
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Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency. Biomedicines 2019; 7:biomedicines7010007. [PMID: 30669278 PMCID: PMC6466426 DOI: 10.3390/biomedicines7010007] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/06/2019] [Accepted: 01/14/2019] [Indexed: 12/22/2022] Open
Abstract
Background: Premature ovarian insufficiency (POI) is a challenging disease, with limited treatment options at the moment. Umbilical cord blood mesenchymal stem cells (UCMSCs) have demonstrated promising regenerative abilities in several diseases including POI. Materials and Method: A pre-clinical murine case versus vehicle control randomized study. Two experiments ran in parallel in each of the three groups. The first was to prove the ability of UCMSCs in restoring ovarian functions. The second was to prove improved fertility. A total of 36 mice were randomly assigned; 6 mice into each of 3 groups for two experiments. Group 1 (control), group 2 (sham chemotherapy), group 3 (stem cells). Results: In the first experiment, post-UCMSCs treatment (group 3) showed signs of restored ovarian function in the form of increased ovarian weight and estrogen-dependent organs (liver, uterus), increased follicular number, and a significant decrease in FSH serum levels (p < 0.05) compared to group 2, and anti-Mullerian hormone (AMH) serum levels increased (p < 0.05) in group 3 versus group 2. Immuno-histochemistry analysis demonstrated a higher expression of AMH, follicle stimulating hormone receptor (FSHR) and Inhibin A in the growing follicles of group 3 versus group 2. In the second experiment, post-UCMSCs treatment (group 3) pregnancy rates were higher than group 2, however, they were still lower than group 1. Conclusion: We demonstrated the ability of UCMSCs to restore fertility in female cancer survivors with POI and as another source of stem cells with therapeutic potentials.
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Pfeiffer D, Wankhammer K, Stefanitsch C, Hingerl K, Huppertz B, Dohr G, Desoye G, Lang I. Amnion-derived mesenchymal stem cells improve viability of endothelial cells exposed to shear stress in ePTFE grafts. Int J Artif Organs 2018; 42:80-87. [PMID: 30585116 DOI: 10.1177/0391398818815470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE: Blood vessel reconstruction is an increasing need of patients suffering from cardiovascular diseases. For the development of microvascular prostheses, efficient endothelialization is mandatory to prevent graft occlusion. Here, we assessed the impact of amnion-derived mesenchymal stem/stromal cells (hAMSC), known for their important angiogenic potential, on the integrity and stability of endothelial cells exposed to shear stress in vascular grafts. METHODS: Human placental endothelial cells (hPEC) were cultured at the inner surface of an expanded polytetrafluoroethylene (ePTFE) graft positioned within a bioreactor and exposed to a minimal shear stress of 0.015 dyne/cm2 or a physiological shear stress of 0.92 dyne/cm2. hAMSC attached to the outer graft surface were able to interact with human placental endothelial cells by paracrine factors. RESULTS: Microscopical analysis and evaluation of glucose/lactate metabolism evidenced successful cell seeding of the graft: hPEC formed a stable monolayer, hAMSC showed a continuous growth during 72 h incubation. hAMSC improved the viability of hPEC exposed to 0.015 dyne/cm2 as shown by a decreased lactate dehydrogenase release of 13% after 72 h compared to hPEC single culture. The viability-enhancing effect of hAMSC on hPEC was further improved by 13% under physiological shear stress. Angiogenesis array analysis revealed that hPEC exposed to physiological shear stress and hAMSC co-culture reduced the secretion of angiogenin, GRO, MCP-1, and TIMP-2. CONCLUSION: hAMSC exerted best survival-enhancing effects on hPEC under exposure to physiological shear stress and modulated endothelial function by paracrine factors. Our data support further studies on the development of grafts functionalized with hAMSC-derived secretomes to enable fast clinical application.
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Affiliation(s)
- Dagmar Pfeiffer
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Karin Wankhammer
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Christina Stefanitsch
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Kerstin Hingerl
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Berthold Huppertz
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Gottfried Dohr
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Gernot Desoye
- 2 Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Ingrid Lang
- 1 Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Visualising the Cardiovascular System of Embryos of Biomedical Model Organisms with High Resolution Episcopic Microscopy (HREM). J Cardiovasc Dev Dis 2018; 5:jcdd5040058. [PMID: 30558275 PMCID: PMC6306920 DOI: 10.3390/jcdd5040058] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 12/09/2018] [Accepted: 12/11/2018] [Indexed: 12/17/2022] Open
Abstract
The article will briefly introduce the high-resolution episcopic microscopy (HREM) technique and will focus on its potential for researching cardiovascular development and remodelling in embryos of biomedical model organisms. It will demonstrate the capacity of HREM for analysing the cardiovascular system of normally developed and genetically or experimentally malformed zebrafish, frog, chick and mouse embryos in the context of the whole specimen and will exemplarily show the possibilities HREM offers for comprehensive visualisation of the vasculature of adult human skin. Finally, it will provide examples of the successful application of HREM for identifying cardiovascular malformations in genetically altered mouse embryos produced in the deciphering the mechanisms of developmental disorders (DMDD) program.
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40
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Mu Y, Wu X, Hao Z. Comparative evaluation of mesenchymal stromal cells from umbilical cord and amniotic membrane in xeno-free conditions. BMC Cell Biol 2018; 19:27. [PMID: 30545286 PMCID: PMC6293527 DOI: 10.1186/s12860-018-0178-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 11/28/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Within the past years, umbilical cord (UC) and amniotic membrane (AM) expanded in human platelet lysate (PL) have been found to become increasingly candidate of mesenchymal stromal cells (MSCs) in preclinical and clinical studies. Different sources of MSCs have different properties, and lead to different therapeutic applications. However, the similarity and differences between the AMMSCs and UCMSCs in PL remain unclear. RESULTS In this study, we conduct a direct head-to-head comparison with regard to biological characteristics (morphology, immunophenotype, self-renewal capacity, and trilineage differentiation potential) and immunosuppression effects of AMMSCs and UCMSCs expanded in PL. Our results indicated that AMMSCs showed similar morphology, immunophenotype, proliferative capacity and colony efficiency with UCMSCs. Moreover, no significantly differences in osteogenic, chondrogenic and adipogenic differentiation potential were observed between the two types of cells. However, AMMSCs exhibited higher PGE2 expression and IDO activity compared with UCMSCs when primed by IFN-γ and (or) TNF-α induction, and AMMSCs showed a higher inhibitory effect on PBMCs proliferation than UCMSCs. CONCLUSION The results suggest that AMMSCs expanded in PL showed similar morphology, immunophenotype, self-renewal capacity, and trilineage differentiation potential with UCMSCs. However, AMMSCs possessed superior immunosuppression effects in comparison with UCMSCs. These results suggest that AMMSCs in PL might be more suitable than UCMSCs for treatment of immune diseases. This work provides a novel insight into choosing the appropriate source of MSCs for treatment of immune diseases.
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Affiliation(s)
- Yongxu Mu
- Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Pvovince, China.,Department of Interventional Treatment, the First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Xiaoyun Wu
- Department of Technology, Stem Cell Medicine Engineering & Technology Research Center of Inner Mongolia, Huhhot, Inner Mongolia, China.,Department of Research and Development, Beijing Jingmeng Stem Cell Technology. Co. Ltd., Beijing, China
| | - Zhiming Hao
- Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Pvovince, China.
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Human Adipose Mesenchymal Stem Cells Show More Efficient Angiogenesis Promotion on Endothelial Colony-Forming Cells than Umbilical Cord and Endometrium. Stem Cells Int 2018; 2018:7537589. [PMID: 30651736 PMCID: PMC6311802 DOI: 10.1155/2018/7537589] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/11/2018] [Accepted: 09/23/2018] [Indexed: 01/08/2023] Open
Abstract
Angiogenesis is a complicated process in which perivascular cells play important roles. Multipotent mesenchymal stem/stromal cells (MSCs) from distinct tissues have been proved to be proangiogenic and share functional properties and gene expression profiles with perivascular cells. However, different tissues derived MSCs may exhibit different potential for clinical applications. Accordingly, comparative studies on different MSCs are essential. Here, we characterized MSCs from adipose (ADSCs), umbilical cord (UCMSCs), and endometrium (EMSCs) in terms of the surface antigen expression, differentiation ability, and the ability of angiogenesis promotion on endothelial colony-forming cells (ECFCs) both in vitro and in vivo. No significant differences in immunophenotype and differentiation were observed. In addition, three types of MSCs all located around tubular-like structures formed by ECFCs in coculture system on matrigel. But ECFCs seeded on ADSCs monolayer formed more organized capillary-like network than that on UCMSCs or EMSCs. When suspended with ECFCs in matrigel and implanted into nude mice, ADSCs promoted more functional vessel formation after 7 days. Moreover, in murine hindlimb ischemia model, cotransplantation of ECFCs with ADSCs was significantly superior to UCMSCs and EMSCs in promoting perfusion recovery and limb salvage. Furthermore, ADSC-conditioned medium (CM) contained more proangiogenic factors (such as vascular endothelial growth factor-A, platelet-derived growth factor BB, and basic fibroblast growth factor) and less inhibitory factor (such as thrombospondin-1), when compared with UCMSC-CM and EMSC-CM. And ADSC-CM more durably stabilized the vascular-like structures formed by ECFCs on matrigel and promoted ECFCs migration more efficiently. In summary, MSCs from adipose show significantly efficient promotion on angiogenesis both in vitro and in vivo than UCMSCs and EMSCs. Hence, ADSCs may be recommended as a more suitable source for treating hindlimb ischemia.
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