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Gao P, Kajiya M, Motoike S, Ikeya M, Yang J. Application of mesenchymal stem/stromal cells in periodontal regeneration: Opportunities and challenges. JAPANESE DENTAL SCIENCE REVIEW 2024; 60:95-108. [PMID: 38314143 PMCID: PMC10837070 DOI: 10.1016/j.jdsr.2024.01.001] [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: 08/08/2023] [Revised: 12/06/2023] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Guided tissue regeneration (GTR) has been widely used in the periodontal treatment of intrabony and furcation defects for nearly four decades. The treatment outcomes have shown effectiveness in reducing pocket depth, improving attachment gain and bone filling in periodontal tissue. Although applying GTR could reconstruct the periodontal tissue, the surgical indications are relatively narrow, and some complications and race ethic problems bring new challenges. Therefore, it is challenging to achieve a consensus concerning the clinical benefits of GTR. With the appearance of stem cell-based regenerative medicine, mesenchymal stem/stromal cells (MSCs) have been considered a promising cell resource for periodontal regeneration. In this review, we highlight preclinical and clinical periodontal regeneration using MSCs derived from distinct origins, including non-odontogenic and odontogenic tissues and induced pluripotent stem cells, and discuss the transplantation procedures, therapeutic mechanisms, and concerns to evaluate the effectiveness of MSCs.
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Affiliation(s)
- Pan Gao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Souta Motoike
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Makoto Ikeya
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
| | - Jingmei Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
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Hegde M, Singh AK, Kannan S, Kolkundkar U, Seetharam RN. Therapeutic Applications of Engineered Mesenchymal Stromal Cells for Enhanced Angiogenesis in Cardiac and Cerebral Ischemia. Stem Cell Rev Rep 2024; 20:2138-2154. [PMID: 39305405 PMCID: PMC11554727 DOI: 10.1007/s12015-024-10787-3] [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] [Accepted: 08/31/2024] [Indexed: 11/12/2024]
Abstract
Ischemic diseases are characterized by obstruction of blood flow to the respective organs, of which ischemia of the heart and brain are the most prominent manifestations with shared pathophysiological mechanisms and risk factors. While most revascularization therapies aim to restore blood flow, this can be challenging due to the limited therapeutic window available for treatment approaches. For a very long time, mesenchymal stromal cells have been used to treat cerebral and cardiac ischemia. However, their application is restricted either by inefficient mode of delivery or the low cell survival rates following implantation into the ischemic microenvironment. Nonetheless, several studies are currently focusing on using of mesenchymal stromal cells engineered to overexpress therapeutic genes as a cell-based gene therapy to restore angiogenesis. This review delves into the utilization of MSCs for angiogenesis and the applications of engineered MSCs for the treatment of cardiac and cerebral ischemia. Moreover, the safety issues related to the genetic modification of MSCs have also been discussed.
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Affiliation(s)
- Madhavi Hegde
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Suresh Kannan
- Stempeutics Research Pvt. Ltd., 3rd Floor, Manipal Hospitals Whitefield #143, EPIP Industrial Area, ITPL Main Road, Bangalore, 560 048, India
| | - Udaykumar Kolkundkar
- Stempeutics Research Pvt. Ltd., 3rd Floor, Manipal Hospitals Whitefield #143, EPIP Industrial Area, ITPL Main Road, Bangalore, 560 048, India
| | - Raviraja N Seetharam
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India.
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Huang LY, Sun X, Pan HX, Wang L, He CQ, Wei Q. Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges. World J Stem Cells 2023; 15:385-399. [PMID: 37342219 PMCID: PMC10277963 DOI: 10.4252/wjsc.v15.i5.385] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/17/2023] [Accepted: 03/21/2023] [Indexed: 05/26/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating condition with complex pathological mechanisms that lead to sensory, motor, and autonomic dysfunction below the site of injury. To date, no effective therapy is available for the treatment of SCI. Recently, bone marrow-derived mesenchymal stem cells (BMMSCs) have been considered to be the most promising source for cellular therapies following SCI. The objective of the present review is to summarize the most recent insights into the cellular and molecular mechanism using BMMSC therapy to treat SCI. In this work, we review the specific mechanism of BMMSCs in SCI repair mainly from the following aspects: Neuroprotection, axon sprouting and/or regeneration, myelin regeneration, inhibitory microenvironments, glial scar formation, immunomodulation, and angiogenesis. Additionally, we summarize the latest evidence on the application of BMMSCs in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.
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Affiliation(s)
- Li-Yi Huang
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Xin Sun
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Hong-Xia Pan
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Lu Wang
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Cheng-Qi He
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Quan Wei
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu 610044, Sichuan Province, China
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Naqvi RA, Naqvi A. Co-transplantation with mesenchymal stem cells and endothelial cells improvise islet engraftment and survival in STZ treated hyperglycemic mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525444. [PMID: 36747732 PMCID: PMC9900768 DOI: 10.1101/2023.01.24.525444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Though intra-portal islet transplantation demonstrated as best suited strategy for the reversal of hyperglycemia without the threat of iatrogenic hyperglycemia in type 1 diabetes (T1D) in patients, the inferior quality of post-transplantation (tx) vascularization needs to be addressed for the maximization of post-tx islet survival. Therefore, in this study, we have first generated MSCs and endothelial progenitor cells (EPC) from mice bone marrow by in house optimized protocol and then 3-D co-cultured them with mice islets. Secretion of in the culture supernatant suggested the pro-angiogenic nature of 3D cultured mice islets. After 5 days post-tx of these pro-angiogenic islets in the omental pouch of syngeneic mice led to: 1) restoration of normoglycemia, 2) secretion of mouse C-peptide and 3) induction of angiogenic factors after 3 days of post-tx. The induction of angiogenic factors was done by RT-qPCR of omental biopsies. Importantly, pro-angiogenic islet recipient mice also demonstrated the clearance of glucose within 75 min, reflecting their efficient function and engraftment. Our results highlights needs of 3-D co-culture islets for superior quality post-tx islet vasculature and better engraftment â€" crux to improvise the challenges associated with post-tx islet vascularization and functions.
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Brown SV, Dewitt S, Clayton A, Waddington RJ. Identifying the Efficacy of Extracellular Vesicles in Osteogenic Differentiation: An EV-Lution in Regenerative Medicine. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.849724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have long been the focus for regenerative medicine and the restoration of damaged or aging cells throughout the body. However, the efficacy of MSCs in cell-based therapy still remains unpredictable and carries with it enumerable risks. It is estimated that only 3-10% of MSCs survive transplantation, and there remains undefined and highly variable heterogeneous biological potency within these administered cell populations. The mode of action points to secreted factors produced by MSCs rather than the reliance on engraftment. Hence harnessing such secreted elements as a replacement for live-cell therapies is attractive. Extracellular vesicles (EVs) are heterogenous lipid bounded structures, secreted by cells. They comprise a complex repertoire of molecules including RNA, proteins and other factors that facilitate cell-to-cell communication. Described as protected signaling centers, EVs can modify the cellular activity of recipient cells and are emerging as a credible alternative to cell-based therapies. EV therapeutics demonstrate beneficial roles for wound healing by preventing apoptosis, moderating immune responses, and stimulating angiogenesis, in addition to promoting cell proliferation and differentiation required for tissue matrix synthesis. Significantly, EVs maintain their signaling function following transplantation, circumventing the issues related to cell-based therapies. However, EV research is still in its infancy in terms of their utility as medicinal agents, with many questions still surrounding mechanistic understanding, optimal sourcing, and isolation of EVs for regenerative medicine. This review will consider the efficacy of using cell-derived EVs compared to traditional cell-based therapies for bone repair and regeneration. We discuss the factors to consider in developing productive lines of inquiry and establishment of standardized protocols so that EVs can be harnessed from optimal secretome production, to deliver reproducible and effective therapies.
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Mathen C, Ghag Sawant M, Gupta R, Dsouza W, Krishna SG. Evaluation of Potential Application of Wharton's Jelly-Derived Human Mesenchymal Stromal Cells and its Conditioned Media for Dermal Regeneration using Rat Wound Healing Model. Cells Tissues Organs 2021; 210:31-44. [PMID: 33873188 DOI: 10.1159/000513895] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/18/2020] [Indexed: 11/19/2022] Open
Abstract
Mesenchymal stromal cells and the derived conditioned media represent an area of tremendous medical interest and, among other clinical applications, are currently being extensively explored for wound healing. The aim of this study was to comparatively evaluate the wound healing potential of xeno-free human umbilical cord-derived mesenchymal stromal cells (MSCs) and the conditioned media (CM) in a full-thickness excision wound model in rats. The evaluation parameters included rate of wound healing, serum cytokine analyses, collagen content, histopathology, and hyperspectral imaging as an independent qualitative and quantitative tool. Both the cell-based and cell-free approaches scored better in lower inflammation, as evidenced in lower IL-10 and stable IL-6 levels, and improved rate of wound healing (p < 0.0001). More importantly, no adverse reaction or rejection was observed although human MSCs and CM were used in a xenogeneic model. The presence of hFGF, hHGF, hGCSF, hIL-1Ra, hVEGF, and hIL-6 in the secretome may elucidate the regenerative potential of the xeno-free cell-based and cell-free approaches which have translational value for advanced wound care. The results revealed the therapeutic potential of both the cell-based and cell-free approaches for wound healing.
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Affiliation(s)
- Caroline Mathen
- Clinical R & D, OCT Therapies and Research Pvt Ltd, Mumbai, India
| | - Mrunal Ghag Sawant
- Department of Zoonosis, Haffkine Institute for Training, Research and Testing, Mumbai, India
| | | | - Wilfrid Dsouza
- Clinical R & D, OCT Therapies and Research Pvt Ltd, Mumbai, India
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Xu L, Willumeit-Römer R, Luthringer-Feyerabend BJC. Mesenchymal Stem Cell and Oxygen Modulate the Cocultured Endothelial Cells in the Presence of Magnesium Degradation Products. ACS APPLIED BIO MATERIALS 2021; 4:2398-2407. [DOI: 10.1021/acsabm.0c01289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Lei Xu
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht 21502, Germany
| | - Regine Willumeit-Römer
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht 21502, Germany
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Potential Therapeutic Effects of Exosomes in Regenerative Endodontics. Arch Oral Biol 2020; 120:104946. [PMID: 33129129 DOI: 10.1016/j.archoralbio.2020.104946] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/07/2020] [Accepted: 10/04/2020] [Indexed: 02/05/2023]
Abstract
OBJECTIVE This review aims to describe the basic characteristics of exosomes, and summarize their possible source and potential biological effects in pulp regeneration, providing new insights into the therapeutic role of exosomes for regenerative endodontics in the future. DESIGN A comprehensive review of scientific literature related to exosomes potentially used for pulp regeneration was conducted. RESULTS Dental mesenchymal stem cells (MSCs) play an important role in dental pulp regeneration. MSC-derived exosomes, as important biotransmitters in intercellular communication, have been shown to replicate the therapeutic effects of their parental cells. These exosomes have better stability, lower immunogenicity, higher safety and clinical efficiency, making it possible to apply them in pulp regeneration. Existing research suggests that exosomes could trigger the regeneration of dentin/pulp-like tissue in vivo, which may attribute to their role in promoting pulp angiogenesis, regulating dental cell proliferation, migration and differentiation, and providing neuroprotection. CONCLUSIONS The applications of exosomes in the treatment of pulp regeneration have great potential, and exosomes may become ideal therapeutic biomaterial in regenerative endodontics.
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Zahorec P, Sarkozyova N, Ferancikova N, Bukovcan P, Danisovic L, Bohac M, Tomas M, Koller J. Autologous mesenchymal stem cells application in post-burn scars treatment: a preliminary study. Cell Tissue Bank 2020; 22:39-46. [PMID: 32862394 DOI: 10.1007/s10561-020-09862-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 08/26/2020] [Indexed: 01/19/2023]
Abstract
Mesenchymal stem cells (MSCs) are multi-potent cells characterized by long term self-renewal and by potential for differentiation into cells of different mesenchymal tissue types such as fibroblasts, osteocytes, chondrocytes, and adipocytes. Their unique properties offer broad therapeutic potentials. Bone marrow has been used as the most common MSCs source, but it is gradually going to be replaced by adipose tissue which showed to contain more MSCs per unit than the bone marrow and clinical application of MSCs procured from the adipose tissue have been demonstrating at least similar results. Post-burn scars result frequently in severe both functional and aesthetic impairments in restitution and rehabilitation periods of the burn disease. Despite extensive research in the last decades, the exact mechanisms of scar formation remains unclear. The development of post-burn scars is influenced by multiple factors such as initial depth of the burn, methods of burn wound therapy, duration of the open wound until final wound closure, burn wound infection, genetic predisposition, and many others in both acute and rehabilitation periods. The aim of this study was to point out versatility of the implementation of this method with respect to different types of scars (atrophic scars, hypertrophic scars, keloids). Autologous adipose tissue derived MSCs were applied to post-burn scars in all 8 patients undergoing surgical scar reconstructions at the Department of Burns and Reconstructive Surgery of the University Hospital in Bratislava. The study was approved by Ethical Committee of Ruzinov Hospital. The procedures used for scar reconstructions included dermabrasion, scar excisions, contractures corrections and local plasties combined by lipografting of lipoaspirate containing parenchymal adipocytes and stromal vascular fraction including MSCs, or application of separated autologous MSCs isolated from lipoaspirates. Based on desired result one of these MSCs application methods was selected depending on characteristics of reconstructed scar and required volume of transferred fat. Isolation of MSCs following procurement was provided by the Central Tissue Bank cell culture laboratory which is one of the parts of the burn department. The average time of scars duration was 79 months, ranging from 6 to 216 months. The postburns scars were assessed clinically according to Vancouver Scar Scale (VSS) prior to surgery, including photo documentation, and re-evaluated after 6 months following MSCs application. As the results have shown, the average VSS score before treatment was 7.88 points ranging from 4 to 11 points. The average VSS 6 months after surgical procedure and MSCs application was 2.34 points ranging from 1 to 4 points. According to the results obtained, the favourable effect of adipose tissue derived autologous MSCs application on scar remodelling following surgical reconstruction of post-burn scars could be promising.
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Affiliation(s)
- Peter Zahorec
- Department of Burns and Reconstructive Surgery, Faculty of Medicine, Comenius University, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia.
| | - Nina Sarkozyova
- Department of Burns and Reconstructive Surgery, Faculty of Medicine, Comenius University, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia
| | - Nikola Ferancikova
- Department of Burns and Reconstructive Surgery, Faculty of Medicine, Comenius University, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia
| | - Peter Bukovcan
- Department of Burns and Reconstructive Surgery, Faculty of Medicine, Comenius University, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia
| | - Martin Bohac
- Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Comenius University in Bratislava, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia
| | - Miroslav Tomas
- Department of Surgical Oncology, National Cancer Institute Bratislava, Klenová 1, 833 10, Bratislava, Slovakia
| | - Jan Koller
- Department of Burns and Reconstructive Surgery, Faculty of Medicine, Comenius University, University Hospital, Pazitkova 4, 821 01, Bratislava, Slovakia
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Merckx G, Tay H, Lo Monaco M, van Zandvoort M, De Spiegelaere W, Lambrichts I, Bronckaers A. Chorioallantoic Membrane Assay as Model for Angiogenesis in Tissue Engineering: Focus on Stem Cells. TISSUE ENGINEERING PART B-REVIEWS 2020; 26:519-539. [PMID: 32220219 DOI: 10.1089/ten.teb.2020.0048] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tissue engineering aims to structurally and functionally regenerate damaged tissues, which requires the formation of new blood vessels that supply oxygen and nutrients by the process of angiogenesis. Stem cells are a promising tool in regenerative medicine due to their combined differentiation and paracrine angiogenic capacities. The study of their proangiogenic properties and associated potential for tissue regeneration requires complex in vivo models comprising all steps of the angiogenic process. The highly vascularized extraembryonic chorioallantoic membrane (CAM) of fertilized chicken eggs offers a simple, easy accessible, and cheap angiogenic screening tool compared to other animal models. Although the CAM assay was initially primarily performed for evaluation of tumor growth and metastasis, stem cell studies using this model are increasing. In this review, a detailed summary of angiogenic observations of different mesenchymal, cardiac, and endothelial stem cell types and derivatives in the CAM model is presented. Moreover, we focus on the variation in experimental setup, including the benefits and limitations of in ovo and ex ovo protocols, diverse biological and synthetic scaffolds, imaging techniques, and outcome measures of neovascularization. Finally, advantages and disadvantages of the CAM assay as a model for angiogenesis in tissue engineering in comparison with alternative in vivo animal models are described. Impact statement The chorioallantoic membrane (CAM) assay is an easy and cheap screening tool for the angiogenic properties of stem cells and their associated potential in the tissue engineering field. This review offers an overview of all published angiogenic studies of stem cells using this model, with emphasis on the variation in used experimental timeline, culture protocol (in ovo vs. ex ovo), stem cell type (derivatives), scaffolds, and outcome measures of vascularization. The purpose of this overview is to aid tissue engineering researchers to determine the ideal CAM experimental setup based on their specific study goals.
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Affiliation(s)
- Greet Merckx
- Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Hanna Tay
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Melissa Lo Monaco
- Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.,Department of Veterinary Medicine, Faculty of Sciences, Integrated Veterinary Research Unit-Namur Research Institute for Life Science (IVRU-NARILIS), University of Namur, Namur, Belgium
| | - Marc van Zandvoort
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases CARIM and School for Oncology and Development GROW, Maastricht University, Maastricht, the Netherlands
| | - Ward De Spiegelaere
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - Ivo Lambrichts
- Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Annelies Bronckaers
- Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
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Merckx G, Hosseinkhani B, Kuypers S, Deville S, Irobi J, Nelissen I, Michiels L, Lambrichts I, Bronckaers A. Angiogenic Effects of Human Dental Pulp and Bone Marrow-Derived Mesenchymal Stromal Cells and their Extracellular Vesicles. Cells 2020; 9:cells9020312. [PMID: 32012900 PMCID: PMC7072370 DOI: 10.3390/cells9020312] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/23/2020] [Accepted: 01/25/2020] [Indexed: 12/18/2022] Open
Abstract
Blood vessel formation or angiogenesis is a key process for successful tooth regeneration. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) possess paracrine proangiogenic properties, which are, at least partially, induced by their extracellular vesicles (EVs). However, the isolation of BM-MSCs is associated with several drawbacks, which could be overcome by MSC-like cells of the teeth, called dental pulp stromal cells (DPSCs). This study aims to compare the angiogenic content and functions of DPSC and BM-MSC EVs and conditioned medium (CM). The angiogenic protein profile of DPSC- and BM-MSC-derived EVs, CM and EV-depleted CM was screened by an antibody array and confirmed by ELISA. Functional angiogenic effects were tested in transwell migration and chicken chorioallantoic membrane assays. All secretion fractions contained several pro- and anti-angiogenic proteins and induced in vitro endothelial cell motility. This chemotactic potential was higher for (EV-depleted) CM, compared to EVs with a stronger effect for BM-MSCs. Finally, BM-MSC CM, but not DPSC CM, nor EVs, increased in ovo angiogenesis. In conclusion, we showed that DPSCs are less potent in relation to endothelial cell chemotaxis and in ovo neovascularization, compared to BM-MSCs, which emphasizes the importance of choice of cell type and secretion fraction for stem cell-based regenerative therapies in inducing angiogenesis.
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Affiliation(s)
- Greet Merckx
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Baharak Hosseinkhani
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Sören Kuypers
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Sarah Deville
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
- Flemish Institute for Technological Research (VITO), Health Department, Boeretang, 2400 Mol, Belgium
| | - Joy Irobi
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Inge Nelissen
- Flemish Institute for Technological Research (VITO), Health Department, Boeretang, 2400 Mol, Belgium
| | - Luc Michiels
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Ivo Lambrichts
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
| | - Annelies Bronckaers
- UHasselt - Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
- Correspondence: ; Tel.: +32-(0)-11-26-92-23
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Caseiro AR, Santos Pedrosa S, Ivanova G, Vieira Branquinho M, Almeida A, Faria F, Amorim I, Pereira T, Maurício AC. Mesenchymal Stem/ Stromal Cells metabolomic and bioactive factors profiles: A comparative analysis on the umbilical cord and dental pulp derived Stem/ Stromal Cells secretome. PLoS One 2019; 14:e0221378. [PMID: 31774816 PMCID: PMC6881058 DOI: 10.1371/journal.pone.0221378] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/21/2019] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal Stem/ Stromal Cells assume a supporting role to the intrinsic mechanisms of tissue regeneration, a feature mostly assigned to the contents of their secretome. A comparative study on the metabolomic and bioactive molecules/factors content of the secretome of Mesenchymal Stem/ Stromal Cells derived from two expanding sources: the umbilical cord stroma and the dental pulp is presented and discussed. The metabolic profile (Nuclear Magnetic Resonance Spectroscopy) evidenced some differences in the metabolite dynamics through the conditioning period, particularly on the glucose metabolism. Despite, overall similar profiles are suggested. More prominent differences are highlighted for the bioactive factors (Multiplexing Laser Bear Analysis), in which Follistatin, Growth Regulates Protein, Hepatocyte Growth Factor, Interleukin-8 and Monocyte Chemotactic Protein-1 dominate in Umbilical Cord Mesenchymal Stem/ Stromal Cells secretion, while in Dental Pulp Stem/ Stromal Cells the Vascular Endothelial Growth Factor-A and Follistatin are more evident. The distinct secretory cocktail did not result in significantly different effects on endothelial cell populations dynamics including proliferation, migration, tube formation capacity and in vivo angiogenesis, or in chemotaxis for both Mesenchymal Stem/ Stromal Cells populations.
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Affiliation(s)
- Ana Rita Caseiro
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
- Escola Universitária Vasco da Gama (EUVG), Lordemão, Coimbra, Portugal
| | - Sílvia Santos Pedrosa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
| | - Galya Ivanova
- REQUIMTE- LAQV, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, Porto, Portugal
| | - Mariana Vieira Branquinho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
| | - André Almeida
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
- Indústria Transformadora de Subprodutos—I.T.S, SA, Grupo ETSA, Rua Padre Adriano, Olivais do Machio, Santo Antão do Tojal, Loures, Portugal
| | - Fátima Faria
- Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
| | - Irina Amorim
- Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- i3S - Instituto de Investigação e Inovação da Universidade do Porto, Rua Alfredo Allen, Porto, Portugal
| | - Tiago Pereira
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
| | - Ana Colette Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado, Porto, Portugal
- * E-mail: ,
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Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, Nolta J, Phinney DG, Sensebe L. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy 2019; 21:1019-1024. [PMID: 31526643 DOI: 10.1016/j.jcyt.2019.08.002] [Citation(s) in RCA: 509] [Impact Index Per Article: 84.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023]
Abstract
The International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell (ISCT MSC) committee offers a position statement to clarify the nomenclature of mesenchymal stromal cells (MSCs). The ISCT MSC committee continues to support the use of the acronym "MSCs" but recommends this be (i) supplemented by tissue-source origin of the cells, which would highlight tissue-specific properties; (ii) intended as MSCs unless rigorous evidence for stemness exists that can be supported by both in vitro and in vivo data; and (iii) associated with robust matrix of functional assays to demonstrate MSC properties, which are not generically defined but informed by the intended therapeutic mode of actions.
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Affiliation(s)
- S Viswanathan
- Arthritis Program, University Health Network, Krembil Research Institute, University Health Network, Cell Therapy Program, University Health Network, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.
| | - Y Shi
- The First Affiliated Hospital, Soochow University Institutes for Translational Medicine, Suzhou, China; Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - J Galipeau
- Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - M Krampera
- Section of Hematology, Department of Medicine, University of Verona, Verona, Italy
| | - K Leblanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden
| | - I Martin
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - J Nolta
- Department of Internal Medicine, Stem Cell Program and Institute for Regenerative Cures, University of California Davis, Sacramento, California, USA
| | - D G Phinney
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA
| | - L Sensebe
- UMR5273 STROMALab CNRS/EFS/UPS-INSERM U1031, Toulouse, France
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15
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Hilkens P, Lambrichts I, Bronckaers A. Current and Future Views on Pulpal Angiogenesis. CLINICAL APPROACHES IN ENDODONTIC REGENERATION 2019:37-53. [DOI: 10.1007/978-3-319-96848-3_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Gamble A, Pawlick R, Pepper AR, Bruni A, Adesida A, Senior PA, Korbutt GS, Shapiro AMJ. Improved islet recovery and efficacy through co-culture and co-transplantation of islets with human adipose-derived mesenchymal stem cells. PLoS One 2018; 13:e0206449. [PMID: 30419033 PMCID: PMC6231609 DOI: 10.1371/journal.pone.0206449] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/13/2018] [Indexed: 02/07/2023] Open
Abstract
Islet transplantation is an established clinical procedure for select patients with type 1 diabetes and severe hypoglycemia to stabilize glycemic control. Post-transplant, substantial beta cell mass is lost, necessitating multiple donors to maintain euglycemia. A potential strategy to augment islet engraftment is the co-transplantation of islets with multipotent mesenchymal stem cells to capitalize upon their pro-angiogenic and anti-inflammatory properties. Herein, we examine the in vitro and in vivo effect of co-culturing murine islets with human adipose-derived mesenchymal stem cells (Ad-MSCs). Islets co-cultured with Ad-MSCs for 48 hours had decreased cell death, superior viability as measured by membrane integrity, improved glucose stimulated insulin secretion and reduced apoptosis compared to control islets. These observations were recapitulated with human islets, albeit tested in a limited capacity. Recipients of marginal mouse islet mass grafts, co-transplanted with Ad-MSCs without a co-culture period, did not reverse to normoglycemia as efficiently as islets alone. However, utilizing a 48-hour co-culture period, marginal mouse islets grafts with Ad-MSCs achieved a superior percent euglycemia rate when compared to islets cultured and transplanted alone. A co-culture period of human islets with human Ad-MSCs may have a clinical benefit improving engraftment outcomes.
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Affiliation(s)
- Anissa Gamble
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
| | - Rena Pawlick
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Andrew R. Pepper
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Antonio Bruni
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Adetola Adesida
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Peter A. Senior
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Gregory S. Korbutt
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - A. M. James Shapiro
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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17
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Cao C, Huang Y, Tang Q, Zhang C, Shi L, Zhao J, Hu L, Hu Z, Liu Y, Chen L. Bidirectional juxtacrine ephrinB2/Ephs signaling promotes angiogenesis of ECs and maintains self-renewal of MSCs. Biomaterials 2018; 172:1-13. [PMID: 29709731 DOI: 10.1016/j.biomaterials.2018.04.042] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 04/21/2018] [Indexed: 12/17/2022]
Abstract
Co-transplantation of endothelial cells (ECs) and mesenchymal stem cells (MSCs) is an important strategy for repairing complex and large bone defects. However, the ways in which ECs and MSCs interact remain to be fully clarified. We found that forward ephrinB2/Ephs signaling from hBMSCs to hUVECs promoted the tube formation of hUVECs by activating the PI3K/AKT/mTOR pathway. Reverse ephrinB2/Ephs signaling from hUVECs to hBMSCs promoted the proliferation and maintenance of hBMSCs self-renewal via upregulation of OCT4, SOX2, and YAP1. Subcutaneous co-transplantation of ECs and MSCs in nude mice confirmed that forward ephrinB2/Ephs signaling could increase the cross-sectional area of blood vessels in the transplanted area, and reverse ephrinB2/Ephs signaling could maintain the self-renewal of transplanted hBMSCs in vivo. Based on these results, ephrinB2/Ephs bidirectional juxtacrine regulation between ECs and MSCs plays a pivotal role in improving the healing of bone defects by promoting angiogenesis and achieving a sufficient number of MSCs.
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Affiliation(s)
- Cen Cao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ying Huang
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chenguang Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lei Shi
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Jiajia Zhao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Hu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhewen Hu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yun Liu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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18
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Gharaei MA, Xue Y, Mustafa K, Lie SA, Fristad I. Human dental pulp stromal cell conditioned medium alters endothelial cell behavior. Stem Cell Res Ther 2018; 9:69. [PMID: 29562913 PMCID: PMC5861606 DOI: 10.1186/s13287-018-0815-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/01/2018] [Accepted: 02/22/2018] [Indexed: 12/13/2022] Open
Abstract
Background Angiogenesis is of utmost importance for tissue regeneration and repair. Human dental pulp stromal cells (hDPSCs) possess angiogenic potential, as they secrete paracrine factors that may alter the host microenvironment. However, more insight into how hDPSCs guide endothelial cells (ECs) in a paracrine fashion is yet to be obtained. Therefore, the current study aimed to investigate the effect(s) of conditioned medium derived from hDPSCs (hDPSC-CM) on EC behavior in vitro. Methods hDPSCs were harvested from third molars scheduled for surgical removal under informed consent. The angiogenic profile of hDPSC-CM was identified using human angiogenesis antibody array and enzyme-linked immunosorbent assay (ELISA). Using real-time reverse transcription-polymerase chain reaction (RT-PCR) and ELISA, the mRNA and protein expression level of specific angiogenic biomarkers was determined in human umbilical vein endothelial cells (HUVECs) exposed to hDPSC-CM. The effect of hDPSC-CM on HUVEC attachment, proliferation and migration was evaluated by crystal violet staining, MTT, transwell migration along with real-time cell monitoring assays (xCELLigence; ACEA Biosciences, Inc.). A Matrigel assay was included to examine the influence of hDPSC-CM on HUVEC network formation. Endothelial growth medium (EGM-2) and EGM-2 supplemented with hDPSC-CM served as experimental groups, whereas endothelial basal medium (EBM-2) was set as negative control. Results A wide range of proangiogenic and antiangiogenic factors, including vascular endothelial growth factor, tissue inhibitor of metalloproteinase protein 1, plasminogen activator inhibitor (serpin E1), urokinase plasminogen activator and stromal cell-derived factor 1, was abundantly detected in hDPSC-CM by protein profiling array and ELISA. hDPSC-CM significantly accelerated the adhesion phases, from sedimentation to attachment and spreading, the proliferation rate and migration of HUVECs as shown in both endpoint assays and real-time cell analysis recordings. Furthermore, Matrigel assay demonstrated that hDPSC-CM stimulated tubulogenesis, affecting angiogenic parameters such as the number of nodes, meshes and total tube length. Conclusions The sustained proangiogenic and promaturation effects of hDPSC-CM shown in this in vitro study strongly suggest that the trophic factors released by hDPSCs are able to trigger pronounced angiogenic responses, even beyond EGM-2 considered as an optimal culture condition for ECs.
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Affiliation(s)
- M A Gharaei
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway
| | - Y Xue
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway
| | - K Mustafa
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway
| | - S A Lie
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway
| | - I Fristad
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway.
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19
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Orekhov PY, Konoplyannikov MA, Baklaushev VP, Kalsin VAA, Averyanov AV, Konopliannikov AG, Habazov RI, Troitskiy AV. Bone marrow stem cells for the critical limb ischemia treatment: biological aspects and clinical application. GENES & CELLS 2018; 13:20-34. [DOI: 10.23868/201805002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2025]
Abstract
Cell therapy is one of the most promising directions in the treatment of critical limb ischemia (CLI). In spite of certain advances achieved in this field in the last decades, which are related to application of bone marrow stem cells (BMSC), a large number of problems still remain unsolved. In this review, we discuss the BMSC biology, mechanisms of their therapeutic effect in the CLI treatment and results of the most notable BMSC-based clinical studies in detail.
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20
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Gamble A, Pepper AR, Bruni A, Shapiro AMJ. The journey of islet cell transplantation and future development. Islets 2018; 10:80-94. [PMID: 29394145 PMCID: PMC5895174 DOI: 10.1080/19382014.2018.1428511] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 01/12/2018] [Indexed: 02/06/2023] Open
Abstract
Intraportal islet transplantation has proven to be efficacious in preventing severe hypoglycemia and restoring insulin independence in selected patients with type 1 diabetes. Multiple islet infusions are often required to achieve and maintain insulin independence. Many challenges remain in clinical islet transplantation, including substantial islet cell loss early and late after islet infusion. Contributions to graft loss include the instant blood-mediated inflammatory reaction, potent host auto- and alloimmune responses, and beta cell toxicity from immunosuppressive agents. Protective strategies are being tested to circumvent several of these events including exploration of alternative transplantation sites, stem cell-derived insulin producing cell therapies, co-transplantation with mesenchymal stem cells or exploration of novel immune protective agents. Herein, we provide a brief introduction and history of islet cell transplantation, limitations associated with this procedure and methods to alleviate islet cell loss as a means to improve engraftment outcomes.
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Affiliation(s)
- Anissa Gamble
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Canada
| | - Andrew R. Pepper
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Canada
| | - Antonio Bruni
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Canada
| | - A. M. James Shapiro
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Canada
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21
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Shin SC, Seo Y, Park HY, Jung DW, Shin TH, Son H, Kim YK, Lee JC, Sung ES, Jang JY, Kim HS, Lee BJ. Regenerative potential of tonsil mesenchymal stem cells on surgical cutaneous defect. Cell Death Dis 2018; 9:183. [PMID: 29416004 PMCID: PMC5833728 DOI: 10.1038/s41419-017-0248-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 12/03/2017] [Accepted: 12/18/2017] [Indexed: 12/23/2022]
Abstract
As tissue engineering and regenerative medicine have evolved recently, stem cell therapy has been investigated in the field of impaired wound healing. Several studies have reported that mesenchymal stem cells derived from various tissues including bone marrow and adipose tissue can exert the regenerative efficacy in the wound healing. Previously, we have demonstrated the isolation and characterization of tonsil-derived mesenchymal stem cells (TMSCs) with excellent proliferative property. In the present study, we aimed to evaluate the regenerative efficacy of TMSCs in the wound healing process. Two distinct cutaneous surgical defects were generated in the dorsum of mice. Each wound was treated with TMSCs or phosphate-buffered saline (PBS), respectively. After sacrifice, the skin and subcutaneous tissues around the surgical defect were harvested and assessed for inflammation, re-epithelialization, dermal regeneration, and granulation tissue formation. The administration of TMSCs into wound beds significantly promoted the repair of surgical defects in mice. Especially, TMSCs efficiently contributed to the attenuation of excessive inflammation in the surgical lesion, as well as the augmentation of epidermal and dermal regeneration. To elucidate the underlying mechanisms, TMSCs were analyzed for their potency in immunomodulatory ability on immune cells, stimulatory effect on the proliferation of keratinocytes, and fibroblasts, as well as the regulation of fibroblast differentiation. TMSCs inhibited the non-specific or T-cell-specific proliferation of peripheral blood mononuclear cells, as well as the M1 polarization of macrophage-like cells. Moreover, TMSCs augmented the proliferation of skin-constituting fibroblasts and keratinocytes while they suppressed the differentiation of fibroblasts into myofibroblasts. Taken together, our findings demonstrate the regenerative potential of TMSCs in wound healing process through the regulation on inflammation, proliferation, and remodeling of various skin cells, implying that TMSCs can be a promising alternative for wound repair.
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Affiliation(s)
- Sung-Chan Shin
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Yoojin Seo
- Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Hee Young Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Da-Woon Jung
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Tae-Hoon Shin
- Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Haejin Son
- Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Young Keum Kim
- Department of Pathology, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea
| | - Jin-Choon Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Yangsan Pusan National University Hospital, Yangsan, Republic of Korea
| | - Eui-Suk Sung
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Yangsan Pusan National University Hospital, Yangsan, Republic of Korea
| | - Jeon Yeob Jang
- Department of Otorhinolaryngology-Head and Neck Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyung-Sik Kim
- Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea.
| | - Byung-Joo Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Republic of Korea.
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22
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Navarro-Requena C, Weaver JD, Clark AY, Clift DA, Pérez-Amodio S, Castaño Ó, Zhou DW, García AJ, Engel E. PEG hydrogel containing calcium-releasing particles and mesenchymal stromal cells promote vessel maturation. Acta Biomater 2018; 67:53-65. [PMID: 29246650 PMCID: PMC6534820 DOI: 10.1016/j.actbio.2017.12.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 11/23/2017] [Accepted: 12/05/2017] [Indexed: 12/20/2022]
Abstract
The use of human mesenchymal stromal cells (hMSC) for treating diseased tissues with poor vascularization has received significant attention, but low cell survival has hampered its translation to the clinic. Bioglasses and glass-ceramics have also been suggested as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. In this study, calcium-releasing particles and hMSC were combined within a hydrogel to examine their vasculogenic potential in vitro and in vivo. The particles provided sustained calcium release and showed proangiogenic stimulation in a chorioallantoic membrane (CAM) assay. The number of hMSC encapsulated in a degradable RGD-functionalized PEG hydrogel containing particles remained constant over time and IGF-1 release was increased. When implanted in the epidydimal fat pad of immunocompromised mice, this composite material improved cell survival and stimulated vessel formation and maturation. Thus, the combination of hMSC and calcium-releasing glass-ceramics represents a new strategy to achieve vessel stabilization, a key factor in the revascularization of ischemic tissues. STATEMENT OF SIGNIFICANCE Increasing blood vessel formation in diseased tissues with poor vascularization is a current clinical challenge. Cell therapy using human mesenchymal stem cells has received considerable interest, but low cell survival has hampered its translation to the clinic. Bioglasses and glass-ceramics have been explored as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. By incorporating both human mesenchymal stem cells and glass-ceramic particles in an implantable hydrogel, this study provides insights into the vasculogenic potential in soft tissues of the combined strategies. Enhancement of vessel formation and maturation supports further investigation of this strategy.
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Affiliation(s)
- Claudia Navarro-Requena
- Biomaterials for Regenerative Therapies. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona 08028, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Zaragoza 50018, Spain; Materials Science and Metallurgical Engineering, EEBE, Universitat Politècnica de Catalunya (UPC), Barcelona 08028, Spain
| | - Jessica D Weaver
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Amy Y Clark
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Douglas A Clift
- Biomaterials for Regenerative Therapies. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona 08028, Spain
| | - Soledad Pérez-Amodio
- Biomaterials for Regenerative Therapies. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona 08028, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Zaragoza 50018, Spain; Materials Science and Metallurgical Engineering, EEBE, Universitat Politècnica de Catalunya (UPC), Barcelona 08028, Spain
| | - Óscar Castaño
- Electronics and Biomedical Engineering, Universitat de Barcelona (UB), Barcelona 08028, Spain; Biomaterials for Regenerative Therapies. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona 08028, Spain; Institute of Nanoscience and Nanotechnology, Universitat de Barcelona (UB), Barcelona 08028, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Zaragoza 50018, Spain
| | - Dennis W Zhou
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Elisabeth Engel
- Biomaterials for Regenerative Therapies. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona 08028, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Zaragoza 50018, Spain; Materials Science and Metallurgical Engineering, EEBE, Universitat Politècnica de Catalunya (UPC), Barcelona 08028, Spain.
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23
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Guerra AD, Rose WE, Hematti P, Kao WJ. Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells. Stem Cell Res Ther 2017; 8:171. [PMID: 28732530 PMCID: PMC5521110 DOI: 10.1186/s13287-017-0623-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/05/2017] [Accepted: 06/28/2017] [Indexed: 02/06/2023] Open
Abstract
Background Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties due to their anti-inflammatory, angiogenic, and even antibacterial properties. We have shown previously that minocycline enhances the wound healing phenotype of MSCs, and MSCs encapsulated in poly(ethylene glycol) and gelatin-based hydrogels with minocycline have antibacterial properties against Staphylococcus aureus (SA). Here, we investigated the signaling pathway that minocycline modulates in MSCs which results in their enhanced wound healing phenotype and determined whether preconditioning MSCs with minocycline has an effect on antimicrobial activity. We further investigated the in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels in inoculated full-thickness cutaneous wounds. Methods Modulation of cell signaling pathways in MSCs with minocycline was analyzed via western blot, immunofluorescence, and ELISA. Antimicrobial efficacy of MSCs pretreated with minocycline was determined by direct and transwell coculture with SA. MSC viability after SA coculture was determined via a LIVE/DEAD® stain. Internalization of SA by MSCs pretreated with minocycline was determined via confocal imaging. All protein and cytokine analysis was done via ELISA. The in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels was determined in Sprague–Dawley rats inoculated with SA. Two-way ANOVA for multiple comparisons was used with Bonferroni test assessment and an unpaired two-tailed Student’s t test was used to determine p values for all assays with multiple or two conditions, respectively. Results Minocycline leads to the phosphorylation of transcriptional nuclear factor-κB (NFκB), but not c-Jun NH2-terminal kinase (JNK) or mitogen-activated protein kinase (ERK). Inhibition of NFκB activation prevented the minocycline-induced increase in VEGF secretion. Preconditioning of MSCs with minocycline led to a reduced production of the antimicrobial peptide LL-37, but enhanced antimicrobial activity against SA via an increased production of IL-6 and SA internalization. MSC and antibiotic-loaded hydrogels reduced SA bioburden in inoculated wounds over 3 days and accelerated reepithelialization. Conclusions Minocycline modulates the NFκB pathway in MSCs that leads to an enhanced production of IL-6 and internalization of SA. This mechanism may have contributed to the in-vivo antibacterial efficacy of MSC and antibiotic-loaded hydrogels. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0623-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alberto Daniel Guerra
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA
| | - Warren E Rose
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA
| | - Peiman Hematti
- School of Medicine and Public Health, Department of Medicine, Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI, 53705, USA
| | - W John Kao
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA. .,College of Engineering, Department of Biomedical Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, WI, 53706, USA. .,School of Medicine and Public Health, Department of Surgery, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI, 53705, USA. .,Present Address: 10/F Knowles Building, Pokfulam, Hong Kong.
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24
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Chen W, Liu X, Chen Q, Bao C, Zhao L, Zhu Z, Xu HHK. Angiogenic and osteogenic regeneration in rats via calcium phosphate scaffold and endothelial cell co-culture with human bone marrow mesenchymal stem cells (MSCs), human umbilical cord MSCs, human induced pluripotent stem cell-derived MSCs and human embryonic stem cell-derived MSCs. J Tissue Eng Regen Med 2017; 12:191-203. [PMID: 28098961 DOI: 10.1002/term.2395] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 10/03/2016] [Accepted: 01/09/2017] [Indexed: 02/05/2023]
Abstract
Angiogenesis is a limiting factor in regenerating large bone defects. The objective of this study was to investigate angiogenic and osteogenic effects of co-culture on calcium phosphate cement (CPC) scaffold using human umbilical vein endothelial cells (hUVECs) and mesenchymal stem cells (MSCs) from different origins for the first time. hUVECs were co-cultured with four types of cell: human umbilical cord MSCs (hUCMSCs), human bone marrow MSCs (hBMSCs) and MSCs from induced pluripotent stem cells (hiPSC-MSCs) and embryonic stem cells (hESC-MSCs). Constructs were implanted in 8 mm cranial defects of rats for 12 weeks. CPC without cells served as control 1. CPC with hBMSCs served as control 2. Microcapillary-like structures were successfully formed on CPC in vitro in all four co-cultured groups. Microcapillary lengths increased with time (p < 0.05). Osteogenic and angiogenic gene expressions were highly elevated and mineralization by co-cultured cells increased with time (p < 0.05). New bone amount and blood vessel density of co-cultured groups were much greater than controls (p < 0.05) in an animal study. hUVECs co-cultured with hUCMSCs, hiPSC-MSCs and hESC-MSCs achieved new bone and vessel density similar to hUVECs co-cultured with hBMSCs (p > 0.1). Therefore, hUCMSCs, hiPSC-MSCs and hESC-MSCs could serve as alternative cell sources to hBMSCs, which require an invasive procedure to harvest. In conclusion, this study showed for the first time that co-cultures of hUVECs with hUCMSCs, hiPSC-MSCs, hESC-MSCs and hBMSCs delivered via CPC scaffold achieved excellent osteogenic and angiogenic capabilities in vivo. The novel co-culture constructs are promising for bone reconstruction with improved angiogenesis for craniofacial/orthopaedic applications. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Wenchuan Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Biomaterials & Tissue Engineering Division, Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Xian Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Biomaterials & Tissue Engineering Division, Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Qianmin Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Biomaterials & Tissue Engineering Division, Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Liang Zhao
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD, USA.,Department of Orthopaedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhimin Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hockin H K Xu
- Biomaterials & Tissue Engineering Division, Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD, USA.,Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.,University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Mechanical Engineering, University of Maryland at Baltimore County, Baltimore County, MD, USA
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25
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Cho RJ, Kim YS, Kim JY, Oh YM. Human adipose-derived mesenchymal stem cell spheroids improve recovery in a mouse model of elastase-induced emphysema. BMB Rep 2017; 50:79-84. [PMID: 27756443 PMCID: PMC5342870 DOI: 10.5483/bmbrep.2017.50.2.101] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Indexed: 01/24/2023] Open
Abstract
Emphysema, a pathologic component of the chronic obstructive pulmonary disease, causes irreversible destruction of lung. Many researchers have reported that mesenchymal stem cells can regenerate lung tissue after emphysema. We evaluated if spheroid human adipose-derived mesenchymal stem cells (ASCs) showed greater regenerative effects than dissociated ASCs in mice with elastase-induced emphysema. ASCs were administered via an intrapleural route. Mice injected with spheroid ASCs showed improved regeneration of lung tissues, increased expression of growth factors such as fibroblast growth factor-2 (FGF2) and hepatocyte growth factor (HGF), and a reduction in proteases with an induction of protease inhibitors when compared with mice injected with dissociated ASCs. Our findings indicate that spheroid ASCs show better regeneration of lung tissues than dissociated ACSs in mice with elastase-induced emphysema.
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Affiliation(s)
- Ryeon Jin Cho
- University of Ulsan College of Medicine, Seoul 05505, Korea
| | - You-Sun Kim
- University of Ulsan College of Medicine, Seoul 05505; Asan Institute for Life Science, Seoul 05505, Korea
| | - Ji-Young Kim
- Asan Institute for Life Science, Seoul 05505, Korea
| | - Yeon-Mok Oh
- University of Ulsan College of Medicine, Seoul 05505; Asan Institute for Life Science, Seoul 05505; Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Disease, Asan Medical Center, Seoul 05505, Korea
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26
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Katagiri W, Kawai T, Osugi M, Sugimura-Wakayama Y, Sakaguchi K, Kojima T, Kobayashi T. Angiogenesis in newly regenerated bone by secretomes of human mesenchymal stem cells. Maxillofac Plast Reconstr Surg 2017; 39:8. [PMID: 28405581 PMCID: PMC5366987 DOI: 10.1186/s40902-017-0106-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 02/14/2017] [Indexed: 12/21/2022] Open
Abstract
Background For an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors. We previously reported that the secretomes of bone marrow-derived mesenchymal stem cells (MSC-CM) contain numerous growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which can affect the cellular characteristics and behavior of regenerating bone cells. We hypothesized that angiogenesis is an important step for bone regeneration, and VEGF is one of the crucial factors in MSC-CM that would enhance its osteogenic potential. In the present study, we focused on VEGF in MSC-CM and evaluated the angiogenic and osteogenic potentials of MSC-CM for bone regeneration. Methods Cytokines in MSC-CM were measured by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were cultured with MSC-CM or MSC-CM with anti-VEGF antibody (MSC-CM + anti-VEGF) for neutralization, and tube formation was evaluated. For the evaluation of bone and blood vessel formation with micro-computed tomography (micro-CT) and for the histological and immunohistochemical analyses, a rat calvarial bone defect model was used. Results The concentrations of IGF-1, VEGF, and TGF-β1 in MSC-CM were 1515.6 ± 211.8 pg/mL, 465.8 ± 108.8 pg/mL, and 339.8 ± 14.4 pg/mL, respectively. Tube formation of HUVECs, bone formation, and blood vessel formation were increased in the MSC-CM group but decreased in the MSC-CM + anti-VEGF group. Histological findings suggested that new bone formation in the entire defect was observed in the MSC-CM group although it was decreased in the MSC-CM + anti-VEGF group. Immunohistochemistry indicated that angiogenesis and migration of endogenous stem cells were much more abundant in the MSC-CM group than in the MSC-CM + anti-VEGF group. Conclusions VEGF is considered a crucial factor in MSC-CM, and MSC-CM is proposed to be an adequate therapeutic agent for bone regeneration with angiogenesis.
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Affiliation(s)
- Wataru Katagiri
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.,Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Takamasa Kawai
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Masashi Osugi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Yukiko Sugimura-Wakayama
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Kohei Sakaguchi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Taku Kojima
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tadaharu Kobayashi
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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27
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Guerra AD, Rose WE, Hematti P, Kao WJ. Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels. Acta Biomater 2017; 51:184-196. [PMID: 28069512 PMCID: PMC5704963 DOI: 10.1016/j.actbio.2017.01.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 01/04/2017] [Accepted: 01/05/2017] [Indexed: 01/12/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties including an anti-inflammatory cytokine profile and the promotion of angiogenesis via expression of growth factors in pre-clinical models. MSCs encapsulated in poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) crosslinked hydrogels have led to controlled cellular presentation at wound sites with favorable wound healing outcomes. However, the therapeutic potential of MSC-loaded hydrogels may be limited by non-specific protein adsorption on the delivery matrix that could facilitate the initial adhesion of microorganisms and subsequent virulent biofilm formation. Antimicrobials loaded concurrently in the hydrogels with MSCs could reduce microbial bioburden and promote healing, but the antimicrobial effect on the MSC wound healing capacity and the antibacterial efficacy of the hydrogels is unknown. We demonstrate that minocycline specifically induces a favorable change in MSC migration capacity, proliferation, gene expression, extracellular matrix (ECM) attachment, and adhesion molecule and growth factor release with subsequent increased angiogenesis. We then demonstrate that hydrogels loaded with MSCs, minocycline, vancomycin, and linezolid can significantly decrease bacterial bioburden. Our study suggests that minocycline can serve as a dual mechanism for the regenerative capacity of MSCs and the reduction of bioburden in triple antimicrobial-loaded hydrogels. STATEMENT OF SIGNIFICANCE Wound healing is a complex biological process that can be hindered by bacterial infection, excessive inflammation, and inadequate microvasculature. In this study, we develop a new formulation of poly(ethylene glycol) diacrylate and thiolated gelatin poly(ethylene glycol) crosslinked hydrogels loaded with minocycline, vancomycin, linezolid, and mesenchymal stromal/stem cells that induces a favorable wound healing phenotype in mesenchymal stromal/stem cells and prevents bacterial bioburden on the hydrogel. This combinatorial approach to biomaterial development has the potential to impact wound healing for contaminated full thickness cutaneous wounds.
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Affiliation(s)
- Alberto Daniel Guerra
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
| | - Warren E Rose
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
| | - Peiman Hematti
- School of Medicine and Public Health, Department of Medicine, Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA.
| | - W John Kao
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; College of Engineering, Department of Biomedical Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, WI 53706, USA; School of Medicine and Public Health, Department of Surgery, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA.
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28
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In Vitro Impact of Conditioned Medium From Demineralized Freeze-Dried Bone on Human Umbilical Endothelial Cells. J Craniofac Surg 2017; 28:440-444. [DOI: 10.1097/scs.0000000000003230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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29
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Sanen K, Martens W, Georgiou M, Ameloot M, Lambrichts I, Phillips J. Engineered neural tissue with Schwann cell differentiated human dental pulp stem cells: potential for peripheral nerve repair? J Tissue Eng Regen Med 2017; 11:3362-3372. [PMID: 28052540 DOI: 10.1002/term.2249] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 06/14/2016] [Accepted: 07/03/2016] [Indexed: 12/18/2022]
Abstract
Despite the spontaneous regenerative capacity of the peripheral nervous system, large gap peripheral nerve injuries (PNIs) require bridging strategies. The limitations and suboptimal results obtained with autografts or hollow nerve conduits in the clinic urge the need for alternative treatments. Recently, we have described promising neuroregenerative capacities of Schwann cells derived from differentiated human dental pulp stem cells (d-hDPSCs) in vitro. Here, we extended the in vitro assays to show the pro-angiogenic effects of d-hDPSCs, such as enhanced endothelial cell proliferation, migration and differentiation. In addition, for the first time we evaluated the performance of d-hDPSCs in an in vivo rat model of PNI. Eight weeks after transplantation of NeuraWrap™ conduits filled with engineered neural tissue (EngNT) containing aligned d-hDPSCs in 15-mm rat sciatic nerve defects, immunohistochemistry and ultrastructural analysis revealed ingrowing neurites, myelinated nerve fibres and blood vessels along the construct. Although further research is required to optimize the delivery of this EngNT, our findings suggest that d-hDPSCs are able to exert a positive effect in the regeneration of nerve tissue in vivo. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Kathleen Sanen
- Biophysics Group, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590, Diepenbeek, Belgium
| | - Wendy Martens
- Morphology Group, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590, Diepenbeek, Belgium
| | - Melanie Georgiou
- Advanced Centre for Biochemical Engineering, University College London, Bernard Katz Building, Gordon Street, London, WC1H 0AH, UK
| | - Marcel Ameloot
- Biophysics Group, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Morphology Group, Biomedical Research Institute, Hasselt University, Agoralaan Building C, 3590, Diepenbeek, Belgium
| | - James Phillips
- Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, University College London, 256 Gray's Inn Road, London, WC1X 8LD, UK
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30
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Ribot J, Caliaperoumal G, Paquet J, Boisson-Vidal C, Petite H, Anagnostou F. Type 2 diabetes alters mesenchymal stem cell secretome composition and angiogenic properties. J Cell Mol Med 2016; 21:349-363. [PMID: 27641937 PMCID: PMC5264143 DOI: 10.1111/jcmm.12969] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 08/06/2016] [Indexed: 01/09/2023] Open
Abstract
This study aimed at characterizing the impact of type 2 diabetes mellitus (T2DM) on the bone marrow mesenchymal stem cell (BMMSC) secretome and angiogenic properties. BMMSCs from Zucker diabetic fatty rats (ZDF) (a T2DM model) and Zucker LEAN littermates (control) were cultured. The supernatant conditioned media (CM) from BMMSCs of diabetic and control rats were collected and analysed. Compared to results obtained using CM from LEAN‐BMMSCs, the bioactive content of ZDF‐BMMSC CM (i) differently affects endothelial cell (HUVEC) functions in vitro by inducing increased (3.5‐fold; P < 0.01) formation of tubule‐like structures and migration of these cells (3‐fold; P < 0.001), as well as promotes improved vascular formation in vivo, and (ii) contains different levels of angiogenic factors (e.g. IGF1) and mediators, such as OSTP, CATD, FMOD LTBP1 and LTBP2, which are involved in angiogenesis and/or extracellular matrix composition. Addition of neutralizing antibodies against IGF‐1, LTBP1 or LTBP2 in the CM of BMMSCs from diabetic rats decreased its stimulatory effect on HUVEC migration by approximately 60%, 40% or 40%, respectively. These results demonstrate that BMMSCs from T2DM rats have a unique secretome with distinct angiogenic properties and provide new insights into the role of BMMSCs in aberrant angiogenesis in the diabetic milieu.
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Affiliation(s)
- Jonathan Ribot
- Laboratory of Bioingénierie et Biomécanique Ostéo-articulaires-UMR CNRS 7052 Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France
| | - Guavri Caliaperoumal
- Laboratory of Bioingénierie et Biomécanique Ostéo-articulaires-UMR CNRS 7052 Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France
| | - Joseph Paquet
- Laboratory of Bioingénierie et Biomécanique Ostéo-articulaires-UMR CNRS 7052 Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France
| | | | - Herve Petite
- Laboratory of Bioingénierie et Biomécanique Ostéo-articulaires-UMR CNRS 7052 Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France
| | - Fani Anagnostou
- Laboratory of Bioingénierie et Biomécanique Ostéo-articulaires-UMR CNRS 7052 Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France.,Department of Periodontology, Service of Odontology, Pitié Salpêtrière Hospital et Hôtel-Dieu Hospital AP-HP, U.F.R. of Odontology Paris 7-Denis Diderot University, Sorbonne Paris Cite, Paris, France
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31
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Li Q, Zhang C, Fu X. Will stem cells bring hope to pathological skin scar treatment? Cytotherapy 2016; 18:943-956. [PMID: 27293205 DOI: 10.1016/j.jcyt.2016.05.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 04/19/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022]
Abstract
Pathological skin scars, such as keloids, aesthetically and psychosocially affect patients. The quest for scar reduction and the increasing recognition of patient satisfaction has led to the continued exploration of scar treatment. Stem cells are a promising source for tissue repair and regeneration. The multi-potency and secretory functions of these cells could offer possible treatments for pathological scars and have been examined in recent studies. Here, we analyze the factors that influence the formation of pathological skin scars, summarize recent research on pathological scar treatment with stem cells and elaborate on the possible mechanisms of this treatment. Additionally, other effects of stem cell treatments are also presented while evaluating potential side effects of stem cell-based pathological scar treatments. Thus, this review may provide meaningful guidance in the clinic for scar treatments with stem cells.
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Affiliation(s)
- Qiankun Li
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
| | - Cuiping Zhang
- Stem Cell and Tissue Regeneration Laboratory, The First Affiliated Hospital, General Hospital of PLA, Beijing, China.
| | - Xiaobing Fu
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China; Stem Cell and Tissue Regeneration Laboratory, The First Affiliated Hospital, General Hospital of PLA, Beijing, China.
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32
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Fanton Y, Houbrechts C, Willems L, Daniëls A, Linsen L, Ratajczak J, Bronckaers A, Lambrichts I, Declercq J, Rummens JL, Hendrikx M, Hensen K. Cardiac atrial appendage stem cells promote angiogenesis in vitro and in vivo. J Mol Cell Cardiol 2016; 97:235-44. [PMID: 27291064 DOI: 10.1016/j.yjmcc.2016.06.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/17/2016] [Accepted: 06/08/2016] [Indexed: 12/23/2022]
Abstract
Cardiac atrial appendage stem cells (CASCs) show extraordinary myocardial differentiation properties, making them ideal candidates for myocardial regeneration. However, since the myocardium is a highly vascularized tissue, revascularization of the ischemic infarct area is essential for functional repair. Therefore, this study assessed if CASCs contribute to cardiac angiogenesis via paracrine mechanisms. First, it was demonstrated that CASCs produce and secrete high levels of numerous angiogenic growth factors, including vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and insulin-like growth factor binding protein 3 (IGFBP-3). Functional in vitro assays with a human microvascular endothelial cell line (HMEC-1) and CASC CM showed that CASCs promote endothelial cell proliferation, migration and tube formation, the most important steps of the angiogenesis process. Addition of inhibitory antibodies against identified growth factors could significantly reduce these effects, indicating their importance in CASC-induced neovascularization. The angiogenic potential of CASCs and CASC CM was also confirmed in a chorioallantoic membrane assay, demonstrating that CASCs promote blood vessel formation in vivo. In conclusion, this study shows that CASCs not only induce myocardial repair by cardiomyogenic differentiation, but also stimulate blood vessel formation by paracrine mechanisms. The angiogenic properties of CASCs further strengthen their therapeutic potential and make them an optimal stem cell source for the treatment of ischemic heart disease.
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Affiliation(s)
- Yanick Fanton
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium.
| | - Cynthia Houbrechts
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Leen Willems
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Annick Daniëls
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium
| | - Loes Linsen
- AC Biobanking, University Hospital Leuven, Leuven, Belgium
| | | | | | - Ivo Lambrichts
- Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - Jeroen Declercq
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Jean-Luc Rummens
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Marc Hendrikx
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium; Department of Cardiothoracic Surgery, Jessa Hospital, Hasselt, Belgium
| | - Karen Hensen
- Laboratory of Experimental Hematology, Jessa Hospital, Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
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Kamprom W, Kheolamai P, U-Pratya Y, Supokawej A, Wattanapanitch M, Laowtammathron C, Issaragrisil S. Effects of mesenchymal stem cell-derived cytokines on the functional properties of endothelial progenitor cells. Eur J Cell Biol 2016; 95:153-63. [PMID: 26899034 DOI: 10.1016/j.ejcb.2016.02.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 12/28/2015] [Accepted: 02/03/2016] [Indexed: 01/10/2023] Open
Abstract
Human mesenchymal stem cell (hMSC) is a potential source for cell therapy due to its property to promote tissue repair. Although, it has been known that hMSCs promote tissue repair via angiogenic cytokines, the interaction between hMSC-derived cytokines and the endothelial progenitor cells (EPCs), which play an important role in tissue neovascularization, is poorly characterized. We investigate the effect of cytokine released from different sources of hMSCs including bone marrow and gestational tissues on the EPC functions in vitro. The migration, extracellular matrix invasion and vessel formation of EPCs were studied in the presence or absence of cytokines released from various sources of hMSCs using transwell culture system. The migration of EPCs was highest when co-culture with secretory factors from placenta-derived hMSCs (PL-hMSCs) compared to those co-culture with other sources of hMSCs. For invasion and vessel formation, secretory factors from bone marrow-derived hMSCs (BM-hMSCs) could produce the maximal enhancement compared to other sources. We further identified the secreted cytokines and found that the migratory-enhancing cytokine from PL-hMSCs was PDGF-BB while the enhancing cytokine from BM-hMSCs on invasion was IGF-1. For vessel formation, the cytokines released from BM-hMSCs were IGF1 and SDF-1. In conclusion, hMSCs can release angiogenic cytokines which increase the migration, invasion and vessel forming capacity of EPCs. We can then use hMSCs as a source of angiogenic cytokines to induce neovascularization in injured/ischemic tissues.
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Affiliation(s)
- Witchayaporn Kamprom
- Department of Immunology, Faculty of Medicine Siriraj hospital, Mahidol University, Bangkok, Thailand; Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pakpoom Kheolamai
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand; Center of Excellence in Stem Cell Research, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Yaowalak U-Pratya
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Methichit Wattanapanitch
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chuti Laowtammathron
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Surapol Issaragrisil
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Amniotic Mesenchymal Stem Cells Can Enhance Angiogenic Capacity via MMPs In Vitro and In Vivo. BIOMED RESEARCH INTERNATIONAL 2015; 2015:324014. [PMID: 26491665 PMCID: PMC4600487 DOI: 10.1155/2015/324014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 12/18/2014] [Accepted: 12/22/2014] [Indexed: 12/27/2022]
Abstract
The aim of this study was to evaluate the angiogenic capacity and proteolytic mechanism of coculture using human amniotic mesenchymal stem cells (hAMSCs) with human umbilical vein endothelial cells (HUVECs) in vivo and in vitro by comparing to those of coculture using bone marrow mesenchymal stem cells with HUVEC. For the in vivo experiment, cells (HUVEC-monoculture, HUVEC-hAMSC coculture, and HUVEC-BMMSC coculture) were seeded in fibrin gels and injected subcutaneously in nude mice. The samples were collected on days 7 and 14 and histologically analyzed by H&E and CD31 staining. CD31-positive staining percentage and vessel-like structure (VLS) density were evaluated as quantitative parameters for angiogenesis. The increases of CD31-positive staining area and VLS density in both HUVEC-hAMSC group and HUVEC-BMMSC group were found between two time points, while obvious decline of those was observed in HUVEC-only group. For the in vitro experiment, we utilized the same 3D culture model to investigate the proteolytic mechanism related to capillary formation. Intensive vascular networks formed by HUVECs were associated with hAMSCs or BMMSCs and related to MMP2 and MMP9. In conclusion, hAMSCs shared similar capacity and proteolytic mechanism with BMMSCs on neovascularization.
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König J, Weiss G, Rossi D, Wankhammer K, Reinisch A, Kinzer M, Huppertz B, Pfeiffer D, Parolini O, Lang I. Placental mesenchymal stromal cells derived from blood vessels or avascular tissues: what is the better choice to support endothelial cell function? Stem Cells Dev 2015; 24:115-31. [PMID: 25244528 DOI: 10.1089/scd.2014.0115] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are promising tools for therapeutic revascularization of ischemic tissues and for support of vessel formation in engineered tissue constructs. Recently, we could show that avascular-derived MSCs from placental amnion release soluble factors that exhibit survival-enhancing effects on endothelial cells (ECs). We hypothesize that MSCs derived from placental blood vessels might have even more potent angiogenic effects. Therefore, we isolated and characterized MSCs from placental chorionic blood vessels (bv-MSCs) and tested their angiogenic potential in comparison to amnion-derived avascular MSCs (av-MSCs). bv-MSCs express a very similar surface marker profile compared with av-MSCs and could be differentiated toward the adipogenic and osteogenic lineages. bv-MSCs exert immunosuppressive properties on peripheral blood mononuclear cells, suggesting that they are suitable for cell transplantation settings. Conditioned medium (Cdm) from av-MSCs and bv-MSCs significantly enhanced EC viability, whereas only Cdm from bv-MSCs significantly increased EC migration and network formation (Matrigel assay). Angiogenesis array analysis of av- and bv-MSC-Cdm revealed a similar secretion pattern of angiogenic factors, including angiogenin, interleukins-6 and -8, and tissue inhibitors of matrix metalloproteinase-1 and 2. Enzyme-linked immunosorbent assay analysis showed that, in contrast to av-MSCs, bv-MSCs secreted vascular endothelial growth factor. In direct coculture with bv-MSCs, ECs showed a significantly increased formation of vessel-like structures compared with av-MSCs. With regard to therapeutic treatment, bv-MSCs and particularly their Cdm might be valuable to stimulate angiogenesis especially in ischemic tissues. av-MSCs and their Cdm could be beneficial in conditions when it is required to promote the survival and stabilization of blood vessels without the risk of unmeant angiogenesis.
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Affiliation(s)
- Julia König
- 1 Institute of Cell Biology, Histology and Embryology, Medical University of Graz , Graz, Austria
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Sawada K, Caballé-Serrano J, Schuldt Filho G, Bosshardt DD, Schaller B, Buser D, Gruber R. Thermal processing of bone: in vitro response of mesenchymal cells to bone-conditioned medium. Int J Oral Maxillofac Surg 2015; 44:1060-6. [PMID: 25868709 DOI: 10.1016/j.ijom.2015.03.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 12/20/2014] [Accepted: 03/17/2015] [Indexed: 11/25/2022]
Abstract
The autoclaving, pasteurization, and freezing of bone grafts to remove bacteria and viruses, and for preservation, respectively, is considered to alter biological properties during graft consolidation. Fresh bone grafts release paracrine-like signals that are considered to support tissue regeneration. However, the impact of the autoclaving, pasteurization, and freezing of bone grafts on paracrine signals remains unknown. Therefore, conditioned medium was prepared from porcine cortical bone chips that had undergone thermal processing. The biological properties of the bone-conditioned medium were assessed by examining the changes in expression of target genes in oral fibroblasts. The data showed that conditioned medium obtained from bone chips that had undergone pasteurization and freezing changed the expression of adrenomedullin, pentraxin 3, BTB/POZ domain-containing protein 11, interleukin 11, NADPH oxidase 4, and proteoglycan 4 by at least five-fold in oral fibroblasts. Bone-conditioned medium obtained from autoclaved bone chips, however, failed to change the expression of the respective genes. Also, when bone-conditioned medium was prepared from fresh bone chips, autoclaving blocked the capacity of bone-conditioned medium to modulate gene expression. These in vitro results suggest that pasteurization and freezing of bone grafts preserve the release of biologically active paracrine signals, but autoclaving does not.
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Affiliation(s)
- K Sawada
- Department of Cranio-maxillofacial Surgery, Inselspital, University of Bern, Bern, Switzerland; Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - J Caballé-Serrano
- Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Oral and Maxillofacial Surgery, College of Dentistry, Universitat Internacional de Catalunya, Barcelona, Spain
| | - G Schuldt Filho
- Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Implant Dentistry, Federal University of Santa Catarina, Florianopolis, Brazil
| | - D D Bosshardt
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland; Robert K. Schenk Laboratory of Oral Histology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - B Schaller
- Department of Cranio-maxillofacial Surgery, Inselspital, University of Bern, Bern, Switzerland
| | - D Buser
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - R Gruber
- Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland; Department of Oral Biology, Medical University of Vienna, Vienna, Austria.
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Shin EH, Caterson EJ, Jackson WM, Nesti LJ. Quality of healing: defining, quantifying, and enhancing skeletal muscle healing. Wound Repair Regen 2015; 22 Suppl 1:18-24. [PMID: 24813360 DOI: 10.1111/wrr.12163] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 01/24/2014] [Indexed: 12/12/2022]
Abstract
Skeletal muscle injury is common in everyday physical activity and athletics, as well as in orthopedic trauma and disease. The overall functional disability resulting from muscle injury is directly related to the intrinsic healing properties of muscle and extrinsic treatment options designed to maximize repair and/or regeneration of muscle tissue all while minimizing pathologic healing pathways. It is important to understand the injury and repair pathways in order to improve the speed and quality of recovery. Recent military conflicts in Iraq and Afghanistan have highlighted the importance of successfully addressing muscular injury and showed the need for novel treatment options that will maximize functional regeneration of the damaged tissue. These severe, wartime injuries, when juxtaposed to peacetime, sports-related injuries, provide us with interesting case examples of the two extreme forms of muscular damage. Comparing and contrasting the differences in these healing pathways will likely provide helpful cues that will help physicians recapitulate the near complete repair and regeneration in less traumatic injuries in addition to more severe cases.
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Affiliation(s)
- Emily H Shin
- Department of Orthopaedic Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland; Clinical and Experimental Orthopaedics group, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
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Guerra AD, Cantu DA, Vecchi JT, Rose WE, Hematti P, Kao WJ. Mesenchymal Stromal/Stem Cell and Minocycline-Loaded Hydrogels Inhibit the Growth of Staphylococcus aureus that Evades Immunomodulation of Blood-Derived Leukocytes. AAPS JOURNAL 2015; 17:620-30. [PMID: 25716147 DOI: 10.1208/s12248-015-9728-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/28/2015] [Indexed: 01/03/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) have demonstrated favorable wound healing properties in addition to their differentiation capacity. MSCs encapsulated in biomaterials such as gelatin and polyethylene glycol (PEG) composite hydrogels have displayed an immunophenotype change that leads to the release of cytokines and growth factors to accelerate wound healing. However, therapeutic potential of implanted MSC-loaded hydrogels may be limited by non-specific protein adsorption that facilitates adhesion of bacterial pathogens such as planktonic Staphylococcus aureus (SA) to the surface with subsequent biofilm formation resistant to immune cell recognition and antibiotic activity. In this study, we demonstrate that blood-derived primary leukocytes and bone marrow-derived MSCs cannot inhibit colony-forming abilities of planktonic or biofilm-associated SA. However, we show that hydrogels loaded with MSCs and minocycline significantly inhibit colony-forming abilities of planktonic SA while maintaining MSC viability and multipotency. Our results suggest that minocycline and MSC-loaded hydrogels may decrease the bioburden of SA at implant sites in wounds, and may improve the wound healing capabilities of MSC-loaded hydrogels.
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Affiliation(s)
- Alberto Daniel Guerra
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA
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Kuchroo P, Dave V, Vijayan A, Viswanathan C, Ghosh D. Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway. Stem Cells Dev 2015; 24:437-50. [PMID: 25229480 PMCID: PMC4313407 DOI: 10.1089/scd.2014.0184] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 09/16/2014] [Indexed: 12/13/2022] Open
Abstract
Improvement in angiogenesis using mesenchymal stem cells (MSCs) is evolving as an option in patients with vascular insufficiencies. The paracrine factors secreted by MSCs have been attributed to the angiogenic response. This study was conducted to identify the factors secreted by umbilical cord-derived MSCs (UCMSCs) that might play a role in angiogenesis. To this aim, we evaluated the presence of well known proangiogenic factors in the conditioned media (CM) derived from UCMSCs by ELISA. While vascular endothelial growth factor (VEGF), a well known angiogenic factor, was not detected in the CM, gene expression was nevertheless detected in these cells. Further investigations revealed the presence of soluble VEGF receptors (sVEGF-R1 and R2) that were capable of neutralizing exogenous VEGF. Human umbilical cord vein-derived endothelial cells exposed in vitro to CM, in comparison to control media, showed improved migration (P<0.007) and capillary-like network formation (P<0.001) with no significant change in endothelial cell proliferation. The angiogenic response observed with the paracrine factors secreted by UCMSC could be due to the presence of significant levels of a metalloprotease and matrix metalloproteases-2 (237.4±47.1 ng/10(6) cells). Data suggest that a VEGF-independent pathway is involved in the angiogenic response observed with endothelial cells in the presence of UCMSC-CM.
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Affiliation(s)
- Pushpa Kuchroo
- Tissue Engineering Group, Regenerative Medicine, Reliance Life Sciences Pvt. Ltd. , Navi-Mumbai, Maharashtra, India
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40
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Li J, Fan L, Yu Z, Dang X, Wang K. The effect of deferoxamine on angiogenesis and bone repair in steroid-induced osteonecrosis of rabbit femoral heads. Exp Biol Med (Maywood) 2014; 240:273-80. [PMID: 25294892 DOI: 10.1177/1535370214553906] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In this study, we examined whether local deferoxamine (DFO) administration can promote angiogenesis and bone repair in steroid-induced osteonecrosis of the femoral head (ONFH). Steroid-induced ONFH was induced in 65 mature male New Zealand white rabbits by methylprednisolone in combination with lipopolysaccharide. Six weeks later, the rabbits received no treatment (model group, N = 15), bilateral core decompression (CD group, N = 20) or CD in combination with local DFO administration (DFO group, N = 20). Six weeks after the surgery, vascularization in the femoral head was evaluated by ink artery infusion angiography and immunohistochemical staining for von Willebrand Factor (vWF). Bone repair was assessed by histologic analysis and micro-computed tomography (micro-CT). Immunohistochemical staining was performed to analyze the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), bone morphogenetic protein-2 (BMP-2), and osteocalcin (OCN). Ink artery infusion angiography and microvessel analysis by immuohistochemical staining for vWF showed more blood vessels in the DFO group than other groups. The expression of HIF-1α, VEGF, BMP-2, and OCN, indicated by immunohistochemical staining, was higher in the DFO group compared with other groups. Micro-CT scanning results indicated that the DFO group had larger volume of newly formed bone than the CD group. This work indicated that local DFO administration improved angiogenesis and bone repair of early stage ONFH in rabbit model, and it may offer an efficient, economic, and simple therapy for early stage ONFH.
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Affiliation(s)
- Jia Li
- The First Department of Orthopedics, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xiwu Road, Xi'an, Shaanxi Province 710004, China
| | - Lihong Fan
- The First Department of Orthopedics, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xiwu Road, Xi'an, Shaanxi Province 710004, China
| | - Zefeng Yu
- The First Department of Orthopedics, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xiwu Road, Xi'an, Shaanxi Province 710004, China
| | - Xiaoqian Dang
- The First Department of Orthopedics, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xiwu Road, Xi'an, Shaanxi Province 710004, China
| | - Kunzheng Wang
- The First Department of Orthopedics, The Second Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xiwu Road, Xi'an, Shaanxi Province 710004, China
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Lozito TP, Tuan RS. Endothelial and cancer cells interact with mesenchymal stem cells via both microparticles and secreted factors. J Cell Mol Med 2014; 18:2372-84. [PMID: 25250510 PMCID: PMC4302643 DOI: 10.1111/jcmm.12391] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/27/2014] [Indexed: 12/13/2022] Open
Abstract
Tightly associated with blood vessels in their perivascular niche, human mesenchymal stem cells (MSCs) closely interact with endothelial cells (ECs). MSCs also home to tumours and interact with cancer cells (CCs). Microparticles (MPs) are cell-derived vesicles released into the extracellular environment along with secreted factors. MPs are capable of intercellular signalling and, as biomolecular shuttles, transfer proteins and RNA from one cell to another. Here, we characterize interactions among ECs, CCs and MSCs via MPs and secreted factors in vitro. MPs and non-MP secreted factors (Sup) were isolated from serum-free medium conditioned by human microvascular ECs (HMEC-1) or by the CC line HT1080. Fluorescently labelled MPs were prepared from cells treated with membrane dyes, and cytosolic GFP-containing MPs were isolated from cells transduced with CMV-GFP lentivirus. MSCs were treated with MPs, Sup, or vehicle controls, and analysed for MP uptake, proliferation, migration, activation of intracellular signalling pathways and cytokine release. Fluorescently labelled MPs fused with MSCs, transferring the fluorescent dyes to the MSC surface. GFP was transferred to and retained in MSCs incubated with GFP-MPs, but not free GFP. Thus, only MP-associated cellular proteins were taken up and retained by MSCs, suggesting that MP biomolecules, but not secreted factors, are shuttled to MSCs. MP and Sup treatment significantly increased MSC proliferation, migration, and MMP-1, MMP-3, CCL-2/MCP-1 and IL-6 secretion compared with vehicle controls. MSCs treated with Sup and MPs also exhibited activated NF-κB signalling. Taken together, these results suggest that MPs act to regulate MSC functions through several mechanisms.
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Affiliation(s)
- Thomas P Lozito
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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42
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The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. BIOMED RESEARCH INTERNATIONAL 2014; 2014:239356. [PMID: 24895555 PMCID: PMC4034436 DOI: 10.1155/2014/239356] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/23/2014] [Accepted: 02/16/2014] [Indexed: 02/06/2023]
Abstract
Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-α via inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.
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Hilkens P, Fanton Y, Martens W, Gervois P, Struys T, Politis C, Lambrichts I, Bronckaers A. Pro-angiogenic impact of dental stem cells in vitro and in vivo. Stem Cell Res 2014; 12:778-90. [DOI: 10.1016/j.scr.2014.03.008] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 03/20/2014] [Accepted: 03/23/2014] [Indexed: 01/09/2023] Open
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44
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Yoo SM, Jang J, Yoo C, Lee MS. Kaposi’s sarcoma-associated herpesvirus infection of human bone-marrow-derived mesenchymal stem cells and their angiogenic potential. Arch Virol 2014; 159:2377-86. [DOI: 10.1007/s00705-014-2094-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Accepted: 04/16/2014] [Indexed: 12/14/2022]
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45
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Mesenchymal stem cells for chronic wounds therapy. Cell Tissue Bank 2014; 16:19-26. [PMID: 24651970 DOI: 10.1007/s10561-014-9440-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Accepted: 03/14/2014] [Indexed: 12/13/2022]
Abstract
Wound healing is a complex process that involves interaction of soluble mediators, extracellular matrix and infiltrating blood cells. Chronic and non-healing skin defects contribute significantly to morbidity and mortality of many patients. Recently, despite the current medical progress, the chronic and non-healing wounds still represent a serious medical problem. In many cases, conventional therapeutic approaches, such as dermal substitutes and growth factor therapy failed and do not produce the expected results, patients are exposed to a high risk of infection, sepsis or amputation. For that reason clinicians and researchers are forced to searching for alternative methods to induce healing process which may result into complete wound closure. Mesenchymal stem cells (MSCs) represent a unique tool of tissue engineering and regenerative medicine and a promising therapeutic strategy. Due to their unique biological properties, MSCs seem to be the perspective modality method for these patients. Many preclinical and clinical studies suggest the possibility of using these cells in tissue regeneration, healing acute and chronic wounds and scar remodelling. The objective of the present review is to summarize the current information and preclinical data about MSCs, their biological characteristics and mode of action during regenerative and healing processes, as well as their clinical application in chronic wounds treatment.
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Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, Lambrichts I. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther 2014; 143:181-96. [PMID: 24594234 DOI: 10.1016/j.pharmthera.2014.02.013] [Citation(s) in RCA: 261] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 12/30/2013] [Indexed: 12/16/2022]
Abstract
Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically.
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Affiliation(s)
- Annelies Bronckaers
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
| | - Petra Hilkens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Wendy Martens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Jessica Ratajczak
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Tom Struys
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
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47
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Nassiri SM, Rahbarghazi R. Interactions of Mesenchymal Stem Cells with Endothelial Cells. Stem Cells Dev 2014; 23:319-32. [DOI: 10.1089/scd.2013.0419] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Seyed Mahdi Nassiri
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Reza Rahbarghazi
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
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Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol 2014; 34:132-43. [PMID: 24140982 DOI: 10.1016/j.matbio.2013.10.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 10/08/2013] [Accepted: 10/09/2013] [Indexed: 12/23/2022]
Abstract
Mesenchymal stem cells (MSCs) are attractive candidates for inclusion in cell-based therapies by virtue of their abilities to home to wound sites. However, in-depth characterization of the specific effects of MSCs on their microenvironments is needed to realize their full therapeutic potentials. Furthermore, since MSCs of varying properties can be isolated from a diverse spectrum of tissues, a strategic and rational approach in MSC sourcing for a particular application has yet to be achieved. For example, MSCs that activate their proteolytic environments may promote tissue remodeling, while those from different tissue sources may inhibit proteases and promote tissue stabilization. This study attempts to address these issues by analyzing MSCs isolated from three adult tissue sources in terms of their effects on their proteolytic microenvironments. Human bone marrow, adipose, and traumatized muscle derived MSCs were compared in their soluble and cellular-associated MMP components and activity. For all types of MSCs, MMP activity associated with the cell surface, but activity levels and MMP profiles differed with tissue source. All MSC types bound exogenous active MMPs at their surfaces. MSCs were also able to activate exogenous proMMP-2 and proMMP-13. This is in marked contrast to the MSC soluble compartment, which strongly inhibited MMPs via endogenous TIMPs. The exact TIMP used to inhibit the exogenous MMP differed with MSC type. Thus, MSCs saturate their environment with both MMPs and TIMPs. Since they bind and activate MMPs at their surfaces, the net result is a very controlled pericellular localization of MMP activities by MSCs.
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Affiliation(s)
- Thomas P Lozito
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Wesley M Jackson
- Orthopaedic Research Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States
| | - Leon J Nesti
- Orthopaedic Research Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States; Department of Orthopaedics and Rehabilitation, Walter Reed Army Medical Center, Washington, DC, United States; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
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Peng J, Nemec M, Brolese E, Bosshardt DD, Schaller B, Buser D, Gruber R. Bone-Conditioned Medium Inhibits Osteogenic and Adipogenic Differentiation of Mesenchymal Cells In Vitro. Clin Implant Dent Relat Res 2014; 17:938-49. [PMID: 24461197 DOI: 10.1111/cid.12200] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND PURPOSE Autografts are used for bone reconstruction in regenerative medicine including oral and maxillofacial surgery. Bone grafts release paracrine signals that can reach mesenchymal cells at defect sites. The impact of the paracrine signals on osteogenic, adipogenic, and chondrogenic differentiation of mesenchymal cells has remained unclear. MATERIAL AND METHODS Osteogenesis, adipogenesis, and chondrogenesis were studied with murine ST2 osteoblast progenitors, 3T3-L1 preadipocytes, and ATDC5 prechondrogenic cells, respectively. Primary periodontal fibroblasts from the gingiva, from the periodontal ligament, and from bone were also included in the analysis. Cells were exposed to bone-conditioned medium (BCM) that was prepared from porcine cortical bone chips. RESULTS BCM inhibited osteogenic and adipogenic differentiation of ST2 and 3T3-L1 cells, respectively, as shown by histological staining and gene expression. No substantial changes in the expression of chondrogenic genes were observed in ATDC5 cells. Primary periodontal fibroblasts also showed a robust decrease in alkaline phosphatase and peroxisome proliferator-activated receptor gamma (PPARγ) expression when exposed to BCM. BCM also increased collagen type 10 expression. Pharmacologic blocking of transforming growth factor (TGF)-β receptor type I kinase with SB431542 and the smad-3 inhibitor SIS3 at least partially reversed the effect of BCM on PPARγ and collagen type 10 expression. In support of BCM having TGF-β activity, the respective target genes were increasingly expressed in periodontal fibroblasts. CONCLUSIONS The present work is a pioneer study on the paracrine activity of bone grafts. The findings suggest that cortical bone chips release soluble signals that can modulate differentiation of mesenchymal cells in vitro at least partially involving TGF-β signaling.
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Affiliation(s)
- Jianbo Peng
- Department of Cranio-Maxillofacial Surgery, Inselspital, University of Bern, Bern, Switzerland.,Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland.,College of Stomatology, GuangXi Medical University, GuangXi, China
| | - Michael Nemec
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.,Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Eliane Brolese
- Department of Cranio-Maxillofacial Surgery, Inselspital, University of Bern, Bern, Switzerland.,Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Dieter D Bosshardt
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.,Robert K. Schenk Laboratory of Oral Histology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Benoit Schaller
- Department of Cranio-Maxillofacial Surgery, Inselspital, University of Bern, Bern, Switzerland
| | - Daniel Buser
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Reinhard Gruber
- Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.,Laboratory of Oral Cell Biology, School of Dental Medicine, University of Bern, Bern, Switzerland
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Aziz Aly LA, Menoufy HE, Ragae A, Rashed LA, Sabry D. Adipose stem cells as alternatives for bone marrow mesenchymal stem cells in oral ulcer healing. Int J Stem Cells 2013; 5:104-14. [PMID: 24298363 DOI: 10.15283/ijsc.2012.5.2.104] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2012] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Adipose tissue is now recognized as an accessible, abundant, and reliable site for the isolation of adult stem cells suitable for tissue engineering and regenerative medicine applications. METHODS AND RESULTS Oral ulcers were induced by topical application of formocresol in the oral cavity of dogs. Transplantation of undifferentiated GFP-labeled Autologous Bone Marrow Stem Cell (BMSCs), Adipose Derived Stem Cell (ADSCs) or vehicle (saline) was injected around the ulcer in each group. The healing process of the ulcer was monitored clinically and histopathologically. Gene expression of vascular endothelial growth factor (VEGF) was detected in MSCs by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Expression of VEGF and collagen genes was detected in biopsies from all ulcers. RESULTS MSCs expressed mRNA for VEGF MSCs transplantation significantly accelerated oral ulcer healing compared with controls. There was increased expression of both collagen and VEGF genes in MSCs-treated ulcers compared to controls. CONCLUSIONS MSCs transplantation may help to accelerate oral ulcer healing, possibly through the induction of angiogenesis by VEGF together with increased intracellular matrix formation as detected by increased collagen gene expression. This body of work has provided evidence supporting clinical applications of adipose-derived cells in safety and efficacy trials as an alternative for bone marrow mesenchymal stem cells in oral ulcer healing.
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Affiliation(s)
- Lobna Abdel Aziz Aly
- Assistant Professor of Oral and Maxillofacial Surgery, Faculty of Dentistry, Future University
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