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Byun KA, Kim HM, Oh S, Batsukh S, Lee S, Oh M, Lee J, Lee R, Kim JW, Oh SM, Kim J, Kim G, Park HJ, Hong H, Lee J, An SH, Oh SS, Jung YS, Son KH, Byun K. High-Intensity Focused Ultrasound Increases Facial Adipogenesis in a Swine Model via Modulation of Adipose-Derived Stem Cell Cilia. Int J Mol Sci 2024; 25:7648. [PMID: 39062891 PMCID: PMC11277104 DOI: 10.3390/ijms25147648] [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: 06/22/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Decreased medial cheek fat volume during aging leads to loss of a youthful facial shape. Increasing facial volume by methods such as adipose-derived stem cell (ASC) injection can produce facial rejuvenation. High-intensity focused ultrasound (HIFU) can increase adipogenesis in subcutaneous fat by modulating cilia on ASCs, which is accompanied by increased HSP70 and decreased NF-κB expression. Thus, we evaluated the effect of HIFU on increasing facial adipogenesis in swine (n = 2) via modulation of ASC cilia. Expression of CD166, an ASC marker, differed by subcutaneous adipose tissue location. CD166 expression in the zygomatic arch (ZA) was significantly higher than that in the subcutaneous adipose tissue in the mandible or lateral temporal areas. HIFU was applied only on the right side of the face, which was compared with the left side, where HIFU was not applied, as a control. HIFU produced a significant increase in HSP70 expression, decreased expression of NF-κB and a cilia disassembly factor (AURKA), and increased expression of a cilia increasing factor (ARL13B) and PPARG and CEBPA, which are the main regulators of adipogenesis. All of these changes were most prominent at the ZA. Facial adipose tissue thickness was also increased by HIFU. Adipose tissue volume, evaluated by magnetic resonance imaging, was increased by HIFU, most prominently in the ZA. In conclusion, HIFU increased ASC marker expression, accompanied by increased HSP70 and decreased NF-κB expression. Additionally, changes in cilia disassembly and length and expression of adipogenesis were observed. These results suggest that HIFU could be used to increase facial volume by modulating adipogenesis.
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Affiliation(s)
- Kyung-A Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- LIBON Inc., Incheon 22006, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Hyoung Moon Kim
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Maylin Clinic, Goyang 10391, Republic of Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sosorburam Batsukh
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sangsu Lee
- Mirabel Clinic, Seoul 04596, Republic of Korea
| | - Myungjune Oh
- GangnamON Clinic, Seoul 06129, Republic of Korea
| | | | - Ran Lee
- Ezen Clinic, Cheonan 31090, Republic of Korea
| | - Jae Woo Kim
- Lienjang Clinic, Seoul 04536, Republic of Korea
| | - Seung Min Oh
- GangnamON Clinic, Seoul 06129, Republic of Korea
| | - Jisun Kim
- MH Clinic, Seoul 06010, Republic of Korea
| | - Geebum Kim
- Misogain Dermatology Clinic, Gimpo 10108, Republic of Korea
| | - Hyun Jun Park
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Maylin Clinic the Cheongdam, Seoul 06091, Republic of Korea
| | - Hanbit Hong
- Lux Well Clinic, Cheongju 28424, Republic of Korea
| | - Jehyuk Lee
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Doctorbom Clinic, Seoul 06614, Republic of Korea
| | - Sang-Hyun An
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Sung Suk Oh
- Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Yeon-Seop Jung
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health & Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea
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Gholami Farashah MS, Mohammadi A, Javadi M, Soleimani Rad J, Shakouri SK, Meshgi S, Roshangar L. Bone marrow mesenchymal stem cells' osteogenic potential: superiority or non-superiority to other sources of mesenchymal stem cells? Cell Tissue Bank 2023; 24:663-681. [PMID: 36622494 DOI: 10.1007/s10561-022-10066-w] [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: 06/02/2022] [Accepted: 12/14/2022] [Indexed: 01/10/2023]
Abstract
Skeletal problems are an increasing issue due to the increase in the global aging population. Different statistics reports show that today, the global population is aging that results in skeletal problems, increased health system costs, and even higher mortality associated with skeletal problems. Common treatments such as surgery and bone grafts are not always effective and in some cases, they can even cause secondary problems such as infections or improper repair. Cell therapy is a method that can be utilized along with common treatments independently. Mesenchymal stem cells (MSCs) are a very important and efficient source in terms of different diseases, especially bone problems. These cells are present in different tissues such as bone marrow, adipose tissue, umbilical cord, placenta, dental pulp, peripheral blood, amniotic fluid and others. Among the types of MSCs, bone marrow mesenchymal stem cells (BMMSCs) are the most widely used source of these cells, which have appeared to be very effective and promising in terms of skeletal diseases, especially compared to the other sources of MSCs. This study focuses on the specific potential and content of BMMSCs from which the specific capacity of these cells originates, and compares their osteogenic potential with other types of MSCs, and also the future directions in the application of BMMSCs as a source for cell therapy.
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Affiliation(s)
- Mohammad Sadegh Gholami Farashah
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mohammadi
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Javadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleimani Rad
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Kazem Shakouri
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Meshgi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ouzin M, Kogler G. Mesenchymal Stromal Cells: Heterogeneity and Therapeutical Applications. Cells 2023; 12:2039. [PMID: 37626848 PMCID: PMC10453316 DOI: 10.3390/cells12162039] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.
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Affiliation(s)
- Meryem Ouzin
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, 40225 Düsseldorf, Germany;
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Kindi H, Willems C, Zhao M, Menzel M, Schmelzer CEH, Herzberg M, Fuhrmann B, Gallego-Ferrer G, Groth T. Metal Ion Doping of Alginate-Based Surface Coatings Induces Adipogenesis of Stem Cells. ACS Biomater Sci Eng 2022; 8:4327-4340. [PMID: 36174215 DOI: 10.1021/acsbiomaterials.2c00444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Metal ions are important effectors of protein and cell functions. Here, polyelectrolyte multilayers (PEMs) made of chitosan (Chi) and alginate (Alg) were doped with different metal ions (Ca2+, Co2+, Cu2+, and Fe3+), which can form bonds with their functional groups. Ca2+ and Fe3+ ions can be deposited in PEM at higher quantities resulting in more positive ζ potentials and also higher water contact angles in the case of Fe3+. An interesting finding was that the exposure of PEM to metal ions decreases the elastic modulus of PEM. Fourier transformed infrared (FTIR) spectroscopy of multilayers provides evidence of interaction of metal ions with the carboxylic groups of Alg but not for hydroxyl and amino groups. The observed changes in wetting and surface potential are partly related to the increased adhesion and proliferation of multipotent C3H10T1/2 fibroblasts in contrast to plain nonadhesive [Chi/Alg] multilayers. Specifically, PEMs doped with Cu2+ and Fe3+ ions greatly promote cell attachment and adipogenic differentiation, which indicates that changes in not only surface properties but also the bioactivity of metal ions play an important role. In conclusion, metal ion-doped multilayer coatings made of alginate and chitosan can promote the differentiation of multipotent cells on implants without the use of other morphogens like growth factors.
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Affiliation(s)
- Husnia Kindi
- Institute of Pharmacy, Department Biomedical Materials, Martin Luther University Halle-Wittenberg, Heinrich-Damerow Strasse 4, 06120 Halle (Saale), Germany
| | - Christian Willems
- Institute of Pharmacy, Department Biomedical Materials, Martin Luther University Halle-Wittenberg, Heinrich-Damerow Strasse 4, 06120 Halle (Saale), Germany
| | - Mingyan Zhao
- Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524003, China
| | - Matthias Menzel
- Department of Biological and Macromolecular Materials, Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Walter-Hülse-Strasse 1, 06120 Halle (Saale), Germany
| | - Christian E H Schmelzer
- Department of Biological and Macromolecular Materials, Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Walter-Hülse-Strasse 1, 06120 Halle (Saale), Germany
| | - Martin Herzberg
- Molecular Microbiology, Institute for Biology/Microbiology, Martin-Luther-University, Halle- Wittenberg, Kurt-Mothes-Strasse 3, 06120 Halle (Saale), Germany
| | - Bodo Fuhrmann
- Institute of Physics, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany.,Interdisciplinary Center of Materials Science, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany
| | - Gloria Gallego-Ferrer
- Centre for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.,Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 46022 Valencia, Spain
| | - Thomas Groth
- Institute of Pharmacy, Department Biomedical Materials, Martin Luther University Halle-Wittenberg, Heinrich-Damerow Strasse 4, 06120 Halle (Saale), Germany.,Interdisciplinary Center of Materials Science, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany
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Oh S, Kim HM, Batsukh S, Sun HJ, Kim T, Kang D, Son KH, Byun K. High-Intensity Focused Ultrasound Induces Adipogenesis via Control of Cilia in Adipose-Derived Stem Cells in Subcutaneous Adipose Tissue. Int J Mol Sci 2022; 23:ijms23168866. [PMID: 36012125 PMCID: PMC9408610 DOI: 10.3390/ijms23168866] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 07/30/2022] [Accepted: 08/07/2022] [Indexed: 11/16/2022] Open
Abstract
During skin aging, the volume of subcutaneous adipose tissue (sWAT) and the adipogenesis potential of adipose-derived stem cells (ASCs) decrease. It is known that the shortening of cilia length by pro-inflammatory cytokines is related to the decreased adipogenic differentiation of ASCs via increase in Wnt5a/β-catenin. High-intensity focused ultrasound (HIFU) is known to upregulate heat shock proteins (HSP), which decrease levels of pro-inflammatory cytokines. In this study, we evaluated whether HIFU modulates the cilia of ASCs by upregulating HSP70 and decreasing inflammatory cytokines. HIFU was applied at 0.2 J to rat skin, which was harvested at 1, 3, 7, and 28 days. All results for HIFU-applied animals were compared with control animals that were not treated. HIFU increased expression of HSP70 and decreased expression of NF-κB, IL-6, and TNF-α in sWAT. HIFU decreased the expression of cilia disassembly-related factors (AurA and HDAC9) in ASCs. Furthermore, HIFU increased the expression of cilia assembly-related factors (KIF3A and IFT88), decreased that of WNT5A/β-catenin, and increased that of the adipogenesis markers PPARγ and CEBPα in sWAT. HIFU increased the number of adipocytes in the sWAT and the thickness of sWAT. In conclusion, HIFU could selectively increase sWAT levels by modulating the cilia of ASCs and be used for skin rejuvenation.
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Affiliation(s)
- Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
| | - Hyoung Moon Kim
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
| | - Sosorburam Batsukh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
| | | | | | | | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea
- Correspondence: (K.H.S.); (K.B.); Tel.: +82-32-460-3666 (K.H.S.); +82-32-899-6511 (K.B.)
| | - Kyunghee Byun
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine, Incheon 21999, Korea
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea
- Correspondence: (K.H.S.); (K.B.); Tel.: +82-32-460-3666 (K.H.S.); +82-32-899-6511 (K.B.)
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Olmedo-Moreno L, Aguilera Y, Baliña-Sánchez C, Martín-Montalvo A, Capilla-González V. Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions. Pharmaceutics 2022; 14:1112. [PMID: 35631698 PMCID: PMC9146397 DOI: 10.3390/pharmaceutics14051112] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/12/2022] Open
Abstract
Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. This review dissects the different changes that occur in culture-expanded MSCs and how these modifications alter their therapeutic properties after transplantation. Furthermore, we discuss the current strategies developed to improve the beneficial effects of MSCs for successful clinical implementation, as well as potential therapeutic alternatives.
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Affiliation(s)
| | | | | | | | - Vivian Capilla-González
- Department of Regeneration and Cell Therapy, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, 41092 Seville, Spain; (L.O.-M.); (Y.A.); (C.B.-S.); (A.M.-M.)
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Xu J, Liu G, Wang X, Hu Y, Luo H, Ye L, Feng Z, Li C, Kuang M, Zhang L, Zhou Y, Qi X. hUC-MSCs: evaluation of acute and long-term routine toxicity testing in mice and rats. Cytotechnology 2022; 74:17-29. [PMID: 35185283 PMCID: PMC8817012 DOI: 10.1007/s10616-021-00502-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 10/17/2021] [Indexed: 02/03/2023] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are present in human umbilical connective tissue and can differentiate into various cell types. Our previous studies have proved that hUC-MSCs do not lead to allergies and tumorigenesis. In the present study, the acute and long-term toxicity of hUC-MSCs in mice and rats was evaluated. The acute toxicity of hUC-MSCs was assessed in 8-week-old mice receiving two caudal intravenous (i.v.) injections of hUC-MSCs at the maximum tolerated dose of 1.5 × 107 cells/kg with an interval of 8 h and the observation period sustained for 14 days. For the long-term toxicity evaluation, rats were randomly divided into control, low-dose (3.0 × 105 cells/kg), mid-dose (1.5 × 106 cells/kg), and high-dose (7.5 × 106 cells/kg) groups, which were treated with hUC-MSCs via a caudal i.v. injection every 3 days for 90 days. Weight and food intake evaluation was performed for all rats for 2 weeks after the hUC-MSC administration. The animals were then sacrificed for hematological, blood biochemical, and pathological analyses, as well as organ index determination. We observed no obvious acute toxicity of hUC-MSCs in mice at the maximum tolerated dose. Long-term toxicity tests in rats showed no significant differences between HUC-MSC-treated and control groups in the following parameters: body weight, hematological and blood biochemical parameters, and histopathologic changes in the heart, liver, kidneys, and lungs. This study provides evidence of the safety of i.v. hUC-MSCs infusion for future clinical therapies.
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Affiliation(s)
- Jianwei Xu
- grid.413458.f0000 0000 9330 9891National Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Center for Tissue Engineering and Stem Cell Research, Guizhou Province Key Laboratory of Regenerative Medicine, Guizhou Medical University, Guiyang, China ,Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, China ,grid.413458.f0000 0000 9330 9891Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang, China
| | - Gang Liu
- grid.413458.f0000 0000 9330 9891Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang, China
| | - Xianyao Wang
- grid.413458.f0000 0000 9330 9891National Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Center for Tissue Engineering and Stem Cell Research, Guizhou Province Key Laboratory of Regenerative Medicine, Guizhou Medical University, Guiyang, China
| | - Ya’nan Hu
- grid.263761.70000 0001 0198 0694Department of Cell Biology, Medical College of Soochow University, Suzhou, China
| | - Hongyang Luo
- Department of Otorhinolaryngology, People’s Hospital of Wudang District, Guiyang, China
| | - Lan Ye
- grid.413458.f0000 0000 9330 9891Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang, China
| | - Zhanhui Feng
- grid.452244.1Neurological Department, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Chen Li
- Department of Oncology, General Hospital of the Yangtze River Shipping, Wuhan, China
| | - Menglan Kuang
- grid.413458.f0000 0000 9330 9891School of Pharmacy, Guizhou Medical University, Guiyang, China
| | - Lijuan Zhang
- grid.413458.f0000 0000 9330 9891School of Nursing, Guizhou Medical University, Guiyang, China
| | - Yixia Zhou
- grid.443382.a0000 0004 1804 268XSchool of Nursing, Guizhou University of Traditional Chinese Medicine, 9# Beijing Road, Guiyang, China ,grid.452244.1Department of Nursing, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiaolan Qi
- grid.413458.f0000 0000 9330 9891Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, 9# Beijing Road, Guiyang, People’s Republic of China ,grid.413458.f0000 0000 9330 9891Key Laboratory of Medical Molecular Biology (Guizhou Medical University), Guiyang, 550004 People’s Republic of China
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Palmitic Acid Methyl Ester Enhances Adipogenic Differentiation in Rat Adipose Tissue-Derived Mesenchymal Stem Cells through a G Protein-Coupled Receptor-Mediated Pathway. Stem Cells Int 2021; 2021:9938649. [PMID: 34650609 PMCID: PMC8510814 DOI: 10.1155/2021/9938649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/29/2021] [Accepted: 09/11/2021] [Indexed: 11/29/2022] Open
Abstract
Adipogenic differentiation from stem cells has become a research target due to the increasing interest in obesity. It has been indicated that adipocytes can secrete palmitic acid methyl ester (PAME), which is able to regulate stem cell proliferation. However, the effects of PAME on adipogenic differentiation in stem cell remain unclear. Here, we present that the adipogenic differentiation medium supplemented with PAME induced the differentiation of rat adipose tissue-derived mesenchymal stem cells (rAD-MSCs) into adipocyte. rAD-MSCs were treated with PAME for 12 days and then subjected to various analyses. The results from the present study show that PAME significantly increased the levels of adipogenic differentiation markers, PPARγ and Gpd1, and enhanced adipogenic differentiation in rAD-MSCs. Furthermore, the level of GPR40/120 protein increased during induction of adipocyte differentiation in rAD-MSCs. Cotreatment with PAME and a GPR40/120 antagonist together inhibited the PAME-enhanced adipogenic differentiation. Moreover, PAME significantly increased phosphorylation of extracellular signal-regulated kinases (ERK), but not AKT and mTOR. Cotreatment with PAME and a GPR40/120 antagonist together inhibited the PAME-enhanced ERK phosphorylation and adipogenic differentiation. PAME also increased the intracellular Ca2+ levels. Cotreatment with PAME and a Ca2+ chelator or a phospholipase C (PLC) inhibitor prevented the PAME-enhanced ERK phosphorylation and adipogenic differentiation. Our data suggest that PAME activated the GPR40/120/PLC-mediated pathway, which in turn increased the intracellular Ca2+ levels, thereby activating the ERK, and eventually enhanced adipogenic differentiation in rAD-MSCs. The findings from the present study might help get insight into the physiological roles and molecular mechanism of PAME in regulating stem cell differentiation.
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PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model. Cells 2021; 10:cells10092420. [PMID: 34572070 PMCID: PMC8466059 DOI: 10.3390/cells10092420] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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11
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Stem cell plasticity and regenerative potential regulation through Ca 2+-mediated mitochondrial nuclear crosstalk. Mitochondrion 2020; 56:1-14. [PMID: 33059088 DOI: 10.1016/j.mito.2020.10.002] [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: 05/31/2020] [Revised: 09/03/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
The multi-lineage differentiation potential is one of the prominent mechanisms through which stem cells can repair damaged tissues. The regenerative potential of stem cells is the manifestation of several changes at the structural and molecular levels in stem cells that are regulated through intricate mitochondrial-nuclear interactions maintained by Ca2+ ion signaling. Despite the exhilarating evidences strengthening the versatile and indispensible role of Ca2+ in regulating mitochondrial-nuclear interactions, the extensive details of signaling mechanisms remains largely unexplored. In this review we have discussed the effect of Ca2+ ion mediated mitochondrial-nuclear interactions participating in stem plasticity and its regenerative potential.
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A Small-Sized Population of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Shows High Stemness Properties and Therapeutic Benefit. Stem Cells Int 2020; 2020:5924983. [PMID: 32399043 PMCID: PMC7204153 DOI: 10.1155/2020/5924983] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 03/11/2020] [Accepted: 03/24/2020] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cells (MSCs) represent a promising means to promote tissue regeneration. However, the heterogeneity of MSCs impedes their use for regenerative medicine. Further investigation of this phenotype is required to develop cell therapies with improved clinical efficacy. Here, a small-sized population of human umbilical cord blood-derived MSCs (UCB-MSCs) was isolated using a filter and centrifuge system to analyze its stem cell characteristics. Consequently, this population showed higher cell growth and lower senescence. Additionally, it exhibited diverse stem cell properties including differentiation, stemness, and adhesion, as compared to those of the population before isolation. Using cell surface protein array or sorting analysis, both EGFR and CD49f were identified as markers associated with the small-sized population. Accordingly, suppression of these surface proteins abolished the superior characteristics of this population. Moreover, compared to that with large or nonisolated populations, the small-sized population showed greater therapeutic efficacy by promoting the engraftment potential of infused cells and reducing lung damage in an emphysema mouse model. Therefore, the isolation of this small-sized population of UCB-MSCs could be a simple and effective way to enhance the efficacy of cell therapy.
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13
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Primary Cilia Mediate Wnt5a/β-catenin Signaling to Regulate Adipogenic Differentiation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Calcium Induction. Tissue Eng Regen Med 2020; 17:193-202. [PMID: 32008170 DOI: 10.1007/s13770-019-00237-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/17/2019] [Accepted: 12/22/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Regeneration of soft tissue defects is essential for adipose tissue pathologies and disease, trauma, or injury-induced damage. Here, we show that umbilical cord blood-derived mesenchymal stem cells could potentially be tailored and used for the reconstruction of specific damaged sites. Adipogenesis can be exploited in soft tissue reconstruction. Also, primary cilia play a role in the control of adipogenesis. METHODS The adipogenic differentiation capacity of mesenchymal stem cells (MSCs) was shown to influence ciliogenesis. MSCs transfected with intraflagellar transport 88 (IFT88) small interfering RNA (siRNA), which blocks the assembly and maintenance of cilia, were examined to confirm the relationship between adipogenesis and ciliogenesis. Also, 1,2-Bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), calcium chelator, inhibited the ciliogenesis of MSCs in adipogenic differentiation. RESULTS IFT88-knockdown led to decreased cilia formation and limitation of cilia elongation in adipogenesis. Additionally, intracellular calcium triggered cilia formation in MSCs adipogenesis. Interestingly, intracellular calcium cannot overcome the inhibition of adipogenesis caused by low numbers of cilia in MSCs. CONCLUSION Our data suggested that ciliogenesis was negatively regulated by Wnt5a/β-catenin signaling during adipogenesis. Thus, we suggest that calcium induction triggers adipogenesis and ciliogenesis.
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14
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Soluble PTX3 of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Attenuates Hyperoxic Lung Injury by Activating Macrophage Polarization in Neonatal Rat Model. Stem Cells Int 2020; 2020:1802976. [PMID: 32399038 PMCID: PMC7204119 DOI: 10.1155/2020/1802976] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/18/2019] [Accepted: 11/27/2019] [Indexed: 12/13/2022] Open
Abstract
Therapeutic treatment of various inflammation-related diseases using mesenchymal stem cells (MSCs) has increased in recent years because of the paracrine action of these cells but shows several limitations. First, MSC-based therapies exhibit varying efficacies; thus, biomarkers should be determined to identify who may benefit from these candidate therapeutic agents. Second, the mechanism underlying the therapeutic effects is poorly understood. To evaluate the effects of human umbilical cord blood-derived MSCs (UCB-MSCs) on macrophages, the macrophage cell line NR8383 stimulated with lipopolysaccharide (LPS) was cocultured by UCB-MSCs. We found that UCB-MSCs mediated changes in macrophage polarization towards M2 from M1 macrophages. To identify the paracrine action underlying the anti-inflammation effect of UCB-MSCs, the secretion of UCB-MSCs exposed to LPS-stimulated NR8383 cells was tested using a biotin label-based 507 antibody array. Among the secreted proteins, we selected pentraxin-related protein PTX3/tumor necrosis factor-inducible gene 14 protein (PTX3) to investigate its association with UCB-MSCs in macrophage polarization. We found that human PTX3 was secreted from UCB-MSCs under inflammation condition and reinforced the M2 macrophage marker via the Dectin-1 receptor by activating MSK1/2 phosphorylation signaling in NR8383 cells. Accordingly, knockdown of PTX3 in UCB-MSCs significantly attenuated their therapeutic effects in a neonatal hyperoxic lung injury resulting in reduced survival, lung alveolarization, M2 marker expression, Dectin-1 levels, anti-inflammatory cytokines, and improved M1 marker expression and inflammatory cytokines compared to control MSC-injected rats. UCB-MSCs show therapeutic potential by controlling macrophage polarization. Interestingly, higher PTX3 levels in UCB-MSCs induced greater improvement in the therapeutic effects than lower PTX3 levels. Collectively, PTX3 is a potential marker with critical paracrine effects for predicting the therapeutic potential of MSC therapy in inflammatory diseases; quality control assessments using PTX3 may be useful for improving the therapeutic effects of UCB-MSCs.
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15
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Kanojia D, Dakle P, Mayakonda A, Parameswaran R, Puhaindran ME, Min VLK, Madan V, Koeffler P. Identification of somatic alterations in lipoma using whole exome sequencing. Sci Rep 2019; 9:14370. [PMID: 31591430 PMCID: PMC6779901 DOI: 10.1038/s41598-019-50805-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 09/19/2019] [Indexed: 01/09/2023] Open
Abstract
Lipomas are benign fatty tumors with a high prevalence rate, mostly found in adults but have a good prognosis. Until now, reason for lipoma occurrence not been identified. We performed whole exome sequencing to define the mutational spectrum in ten lipoma patients along with their matching control samples. We presented genomic insight into the development of lipomas, the most common benign tumor of soft tissue. Our analysis identified 412 somatic variants including missense mutations, splice site variants, frameshift indels, and stop gain/lost. Copy number variation analysis highlighted minor aberrations in patients. Kinase genes and transcriptions factors were among the validated mutated genes critical for cell proliferation and survival. Pathway analysis revealed enrichment of calcium, Wnt and phospholipase D signaling in patients. In conclusion, whole exome sequencing in lipomas identified mutations in genes with a possible role in development and progression of lipomas.
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Affiliation(s)
- Deepika Kanojia
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
| | - Pushkar Dakle
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Anand Mayakonda
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rajeev Parameswaran
- Division of Surgical Oncology, National University Cancer Institute, Singapore, Singapore
| | - Mark E Puhaindran
- Department of Hand and Reconstructive Microsurgery, National University Hospital, Singapore, Singapore
| | | | - Vikas Madan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA
- National University Cancer Institute, National University Hospital, Singapore, Singapore
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16
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Zhou S, Chen S, Jiang Q, Pei M. Determinants of stem cell lineage differentiation toward chondrogenesis versus adipogenesis. Cell Mol Life Sci 2019; 76:1653-1680. [PMID: 30689010 PMCID: PMC6456412 DOI: 10.1007/s00018-019-03017-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 12/10/2018] [Accepted: 01/15/2019] [Indexed: 12/12/2022]
Abstract
Adult stem cells, also termed as somatic stem cells, are undifferentiated cells, detected among differentiated cells in a tissue or an organ. Adult stem cells can differentiate toward lineage specific cell types of the tissue or organ in which they reside. They also have the ability to differentiate into mature cells of mesenchymal tissues, such as cartilage, fat and bone. Despite the fact that the balance has been comprehensively scrutinized between adipogenesis and osteogenesis and between chondrogenesis and osteogenesis, few reviews discuss the relationship between chondrogenesis and adipogenesis. In this review, the developmental and transcriptional crosstalk of chondrogenic and adipogenic lineages are briefly explored, followed by elucidation of signaling pathways and external factors guiding lineage determination between chondrogenic and adipogenic differentiation. An in-depth understanding of overlap and discrepancy between these two mesenchymal tissues in lineage differentiation would benefit regeneration of high-quality cartilage tissues and adipose tissues for clinical applications.
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Affiliation(s)
- Sheng Zhou
- Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, 64 Medical Center Drive, PO Box 9196, Morgantown, WV, 26506-9196, USA
- Department of Sports Medicine and Adult Reconstructive Surgery, School of Medicine, Drum Tower Hospital, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Song Chen
- Department of Orthopaedics, Chengdu Military General Hospital, Chengdu, 610083, Sichuan, People's Republic of China
| | - Qing Jiang
- Department of Sports Medicine and Adult Reconstructive Surgery, School of Medicine, Drum Tower Hospital, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Ming Pei
- Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, 64 Medical Center Drive, PO Box 9196, Morgantown, WV, 26506-9196, USA.
- Robert C. Byrd Health Sciences Center, WVU Cancer Institute, West Virginia University, Morgantown, WV, 26506, USA.
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