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Xiang JY, Kang L, Li ZM, Tseng SL, Wang LQ, Li TH, Li ZJ, Huang JZ, Yu NZ, Long X. Biological scaffold as potential platforms for stem cells: Current development and applications in wound healing. World J Stem Cells 2024; 16:334-352. [PMID: 38690516 PMCID: PMC11056631 DOI: 10.4252/wjsc.v16.i4.334] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/20/2024] [Accepted: 03/12/2024] [Indexed: 04/25/2024] Open
Abstract
Wound repair is a complex challenge for both clinical practitioners and researchers. Conventional approaches for wound repair have several limitations. Stem cell-based therapy has emerged as a novel strategy to address this issue, exhibiting significant potential for enhancing wound healing rates, improving wound quality, and promoting skin regeneration. However, the use of stem cells in skin regeneration presents several challenges. Recently, stem cells and biomaterials have been identified as crucial components of the wound-healing process. Combination therapy involving the development of biocompatible scaffolds, accompanying cells, multiple biological factors, and structures resembling the natural extracellular matrix (ECM) has gained considerable attention. Biological scaffolds encompass a range of biomaterials that serve as platforms for seeding stem cells, providing them with an environment conducive to growth, similar to that of the ECM. These scaffolds facilitate the delivery and application of stem cells for tissue regeneration and wound healing. This article provides a comprehensive review of the current developments and applications of biological scaffolds for stem cells in wound healing, emphasizing their capacity to facilitate stem cell adhesion, proliferation, differentiation, and paracrine functions. Additionally, we identify the pivotal characteristics of the scaffolds that contribute to enhanced cellular activity.
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Affiliation(s)
- Jie-Yu Xiang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lin Kang
- Biomedical Engineering Facility, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Zi-Ming Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Song-Lu Tseng
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Li-Quan Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Tian-Hao Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhu-Jun Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jiu-Zuo Huang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Nan-Ze Yu
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
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Feng X, Qi F, Wang H, Li W, Gan Y, Qi C, Lin Z, Chen L, Wang P, Hu Z, Miao Y. Sorting Technology for Mesenchymal Stem Cells from a Single Tissue Source. Stem Cell Rev Rep 2024; 20:524-537. [PMID: 38112926 DOI: 10.1007/s12015-023-10635-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2023] [Indexed: 12/21/2023]
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that can be obtained, enriched and proliferated in vitro. They owned enormous potential in fields like regenerative medicine, tissue engineering and immunomodulation. However, though isolated from the same origin, MSCs are still essentially heterogeneous cell populations with different phenotypes and functions. This heterogeneity of MSCs significantly affects their therapeutic efficacy and brings obstacles to scientific research. Thus, reliable sorting technology which can isolate or purify MSC subpopulations with various potential and differentiation pathways is urgently needed. This review summarized principles, application status and clinical implications for these sorting methods, aiming at improving the understanding of MSC heterogeneity as well as providing fresh perspectives for subsequent clinical applications.
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Affiliation(s)
- Xinyi Feng
- The First Clinical School of Southern Medical University, Guangzhou, China
| | - Fangfang Qi
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Hailin Wang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Wenzhen Li
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Yuyang Gan
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Caiyu Qi
- The First Clinical School of Southern Medical University, Guangzhou, China
| | - Zhen Lin
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Lu Chen
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Piao Wang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
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Jahangirnezhad M, Mahmoudinezhad SS, Moradi M, Moradi K, Rohani A, Tayebi L. Bone Scaffold Materials in Periodontal and Tooth-supporting Tissue Regeneration: A Review. Curr Stem Cell Res Ther 2024; 19:449-460. [PMID: 36578254 DOI: 10.2174/1574888x18666221227142055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/23/2022] [Accepted: 09/28/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND OBJECTIVES Periodontium is an important tooth-supporting tissue composed of both hard (alveolar bone and cementum) and soft (gingival and periodontal ligament) sections. Due to the multi-tissue architecture of periodontium, reconstruction of each part can be influenced by others. This review focuses on the bone section of the periodontium and presents the materials used in tissue engineering scaffolds for its reconstruction. MATERIALS AND METHODS The following databases (2015 to 2021) were electronically searched: ProQuest, EMBASE, SciFinder, MRS Online Proceedings Library, Medline, and Compendex. The search was limited to English-language publications and in vivo studies. RESULTS Eighty-three articles were found in primary searching. After applying the inclusion criteria, seventeen articles were incorporated into this study. CONCLUSION In complex periodontal defects, various types of scaffolds, including multilayered ones, have been used for the functional reconstruction of different parts of periodontium. While there are some multilayered scaffolds designed to regenerate alveolar bone/periodontal ligament/cementum tissues of periodontium in a hierarchically organized construct, no scaffold could so far consider all four tissues involved in a complete periodontal defect. The progress and material considerations in the regeneration of the bony part of periodontium are presented in this work to help investigators develop tissue engineering scaffolds suitable for complete periodontal regeneration.
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Affiliation(s)
- Mahmood Jahangirnezhad
- Department of Periodontics, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sadaf Sadat Mahmoudinezhad
- Department of Periodontics, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Melika Moradi
- Department of Periodontics, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kooshan Moradi
- Department of Periodontics, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Rohani
- Department of Periodontics, School of Dentistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Lobat Tayebi
- School of Dentistry, Marquette University, Milwaukee, WI, 53233, USA
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Yoshida Y, Takeda Y, Yamahara K, Yamamoto H, Takagi T, Kuramoto Y, Nakano-Doi A, Nakagomi T, Soma T, Matsuyama T, Doe N, Yoshimura S. Enhanced angiogenic properties of umbilical cord blood primed by OP9 stromal cells ameliorates neurological deficits in cerebral infarction mouse model. Sci Rep 2023; 13:262. [PMID: 36609640 PMCID: PMC9822952 DOI: 10.1038/s41598-023-27424-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/29/2022] [Indexed: 01/09/2023] Open
Abstract
Umbilical cord blood (UCB) transplantation shows proangiogenic effects and contributes to symptom amelioration in animal models of cerebral infarction. However, the effect of specific cell types within a heterogeneous UCB population are still controversial. OP9 is a stromal cell line used as feeder cells to promote the hematoendothelial differentiation of embryonic stem cells. Hence, we investigated the changes in angiogenic properties, underlying mechanisms, and impact on behavioral deficiencies caused by cerebral infarction in UCB co-cultured with OP9 for up to 24 h. In the network formation assay, only OP9 pre-conditioned UCB formed network structures. Single-cell RNA sequencing and flow cytometry analysis showed a prominent phenotypic shift toward M2 in the monocytic fraction of OP9 pre-conditioned UCB. Further, OP9 pre-conditioned UCB transplantation in mice models of cerebral infarction facilitated angiogenesis in the peri-infarct lesions and ameliorated the associated symptoms. In this study, we developed a strong, fast, and feasible method to augment the M2, tissue-protecting, pro-angiogenic features of UCB using OP9. The ameliorative effect of OP9-pre-conditioned UCB in vivo could be partly due to promotion of innate angiogenesis in peri-infarct lesions.
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Affiliation(s)
- Yasunori Yoshida
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yuki Takeda
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Kenichi Yamahara
- Laboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Hanae Yamamoto
- grid.272264.70000 0000 9142 153XLaboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshinori Takagi
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yoji Kuramoto
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Akiko Nakano-Doi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Takayuki Nakagomi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshihiro Soma
- grid.272264.70000 0000 9142 153XDepartment of Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Tomohiro Matsuyama
- grid.272264.70000 0000 9142 153XDepartment of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Nobutaka Doe
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan ,grid.272264.70000 0000 9142 153XDepartment of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, 1-3-6 Minatojima, Chuo-Ku, Kobe, Hyogo 650-8530 Japan
| | - Shinichi Yoshimura
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
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Maji K, Pramanik K. Future of encapsulation in regenerative medicine. PRINCIPLES OF BIOMATERIALS ENCAPSULATION : VOLUME TWO 2023:749-772. [DOI: 10.1016/b978-0-12-824345-9.00003-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Nadine S, Fernandes I, Patrício SG, Correia CR, Mano JF. Liquefied Microcapsules Compartmentalizing Macrophages and Umbilical Cord-Derived Cells for Bone Tissue Engineering. Adv Healthc Mater 2022; 11:e2200651. [PMID: 35904030 DOI: 10.1002/adhm.202200651] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 07/22/2022] [Indexed: 01/28/2023]
Abstract
Extraordinary capabilities underlie the potential use of immune cells, particularly macrophages, in bone tissue engineering. Indeed, the depletion of macrophages during bone repair often culminates in disease scenarios. Inspired by the native dynamics between immune and skeletal systems, this work proposes a straightforward in vitro method to bioengineer biomimetic bone niches using biological waste. For that, liquefied and semipermeable reservoirs generated by electrohydrodynamic atomization and layer-by-layer techniques are developed to coculture umbilical cord-derived human cells, namely monocyte-derived macrophages, mesenchymal-derived stromal cells (MSCs), and human umbilical vein endothelial cells (HUVECs). Poly(ε-caprolactone) microparticles are also added to the liquefied core to act as cell carriers. The fabricated microcapsules grant the successful development of viable microtissues, ensuring the high diffusion of bioactive factors. Interestingly, macrophages within the bioengineered microcapsules increase the release of osteocalcin, osteoprotegerin, and vascular endothelial growth factor. The cytokines profile variation indicates macrophages' polarization into a prohealing phenotype. Altogether, the incorporation of macrophages within the fabricated microcapsules allows to recreate an appropriate bone microenvironment for developing new bone mineralized microtissues. The proposed bioencapsulation protocol is a powerful self-regulated system, which might find great applicability in bone tissue engineering based on bottom-up approaches or disease modeling.
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Affiliation(s)
- Sara Nadine
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Inês Fernandes
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Sónia G Patrício
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - Clara R Correia
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
| | - João F Mano
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
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Nadine S, Correia CR, Mano JF. Engineering immunomodulatory hydrogels and cell-laden systems towards bone regeneration. BIOMATERIALS ADVANCES 2022; 140:213058. [PMID: 35933955 DOI: 10.1016/j.bioadv.2022.213058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/27/2022] [Accepted: 07/31/2022] [Indexed: 06/15/2023]
Abstract
The well-known synergetic interplay between the skeletal and immune systems has changed the design of advanced bone tissue engineering strategies. The immune system is essential during the bone lifetime, with macrophages playing multiple roles in bone healing and biomaterial integration. If in the past, the most valuable aspect of implants was to avoid immune responses of the host, nowadays, it is well-established how important are the crosstalks between immune cells and bone-engineered niches for an efficient regenerative process to occur. For that, it is essential to recapitulate the multiphenotypic cellular environment of bone tissue when designing new approaches. Indeed, the lack of osteoimmunomodulatory knowledge may be the explanation for the poor translation of biomaterials into clinical practice. Thus, smarter hydrogels incorporating immunomodulatory bioactive factors, stem cells, and immune cells are being proposed to develop a new generation of bone tissue engineering strategies. This review highlights the power of immune cells to upgrade the development of innovative engineered strategies, mainly focusing on orthopaedic and dental applications.
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Affiliation(s)
- Sara Nadine
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
| | - Clara R Correia
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - João F Mano
- CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
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Garzón H, Suárez LJ, Muñoz S, Cardona J, Fontalvo M, Alfonso-Rodríguez CA. Biomaterials Used for Periodontal Disease Treatment: Focusing on Immunomodulatory Properties. Int J Biomater 2022; 2022:7693793. [PMID: 35528847 PMCID: PMC9072036 DOI: 10.1155/2022/7693793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/23/2022] [Accepted: 03/05/2022] [Indexed: 12/25/2022] Open
Abstract
The growing use of biomaterials with different therapeutic purposes increases the need for their physiological understanding as well as to seek its integration with the human body. Chronic inflammatory local pathologies, generally associated with infectious or autoimmunity processes, have been a current therapeutic target due to the difficulty in their treatment. The recent development of biomaterials with immunomodulatory capacity would then become one of the possible strategies for their management in local pathologies, by intervening in situ, without generating alterations in the systemic immune response. The treatment of periodontal disease as an inflammatory entity has involved the use of different approaches and biomaterials. There is no conclusive, high evidence about the use of these biomaterials in the regeneration of periodontitis sequelae, so the profession keeps looking for other different strategies. The use of biomaterials with immunomodulatory properties could be one, with a promising future. This review of the literature summarizes the scientific evidence about biomaterials used in the treatment of periodontal disease.
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Affiliation(s)
- H. Garzón
- Grupo de Investigación en Salud Oral, Departamento de Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia
| | - L. J. Suárez
- Departamento de Ciencias Básicas y Medicina Oral, Universidad Nacional de Colombia, Bogotá, Colombia
| | - S. Muñoz
- Grupo de Investigación en Salud Oral, Departamento de Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia
| | - J. Cardona
- Grupo de Investigación en Salud Oral, Departamento de Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia
| | - M. Fontalvo
- Grupo de Investigación en Salud Oral, Departamento de Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia
| | - C. A. Alfonso-Rodríguez
- Grupo de Investigación en Salud Oral, Departamento de Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia
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Zhao X, Li Q, Guo Z, Li Z. Constructing a cell microenvironment with biomaterial scaffolds for stem cell therapy. Stem Cell Res Ther 2021; 12:583. [PMID: 34809719 PMCID: PMC8607654 DOI: 10.1186/s13287-021-02650-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/03/2021] [Indexed: 01/08/2023] Open
Abstract
Stem cell therapy is widely recognized as a promising strategy for exerting therapeutic effects after injury in degenerative diseases. However, limitations such as low cell retention and survival rates after transplantation exist in clinical applications. In recent years, emerging biomaterials that provide a supportable cellular microenvironment for transplanted cells have optimized the therapeutic efficacy of stem cells in injured tissues or organs. Advances in the engineered microenvironment are revolutionizing our understanding of stem cell-based therapies by co-transplanting with synthetic and tissue-derived biomaterials, which offer a scaffold for stem cells and propose an unprecedented opportunity to further employ significant influences in tissue repair and regeneration.
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Affiliation(s)
- Xiaotong Zhao
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China.,Department of Cardiology, Zhengzhou Seventh People's Hospital, Zhengzhou, China
| | - Qiong Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China. .,Department of Cardiology, Zhengzhou Seventh People's Hospital, Zhengzhou, China.
| | - Zongjin Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China. .,Nankai University School of Medicine, 94 Weijin Road, Tianjin, 300071, China.
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Nadine S, Correia CR, Mano JF. An Immunomodulatory Miniaturized 3D Screening Platform Using Liquefied Capsules. Adv Healthc Mater 2021; 10:e2001993. [PMID: 33506631 DOI: 10.1002/adhm.202001993] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/12/2021] [Indexed: 12/11/2022]
Abstract
A critical determinant of successful clinical outcomes is the host's response to the biomaterial. Therefore, the prediction of the immunomodulatory bioperformance of biomedical devices following implantation is of utmost importance. Herein, liquefied capsules are proposed as immunomodulatory miniaturized 3D platforms for the high-content combinatorial screening of different polymers that could be used generically in scaffolds. Additionally, the confined and liquefied core of capsules affords a cell-mediated 3D assembly with bioinstructive microplatforms, allowing to study the potential synergistic effect that cells in tissue engineering therapies have on the immunological environment before implantation. As a proof-of-concept, three different polyelectrolytes, ranging in charge density and source, are used. Poly(L-lysine)-, alginate-, and chitosan-ending capsules with or without encapsulated mesenchymal stem/stromal cells (MSCs) are placed on top of a 2D culture of macrophages. Results show that chitosan-ending capsules, as well as the presence of MSCs, favor the balance of macrophage polarization toward a more regenerative profile, through the up-regulation of anti-inflammatory markers, and the release of pro-regenerative cytokines. Overall, the developed system enables the study of the immunomodulatory bioperformance of several polymers in a cost-effective and scalable fashion, while the paracrine signaling between encapsulated cells and the immunological environment can be simultaneously evaluated.
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Affiliation(s)
- Sara Nadine
- CICECO – Aveiro Institute of Materials Department of Chemistry University of Aveiro Campus Universitário de Santiago Aveiro 3810‐193 Portugal
| | - Clara R. Correia
- CICECO – Aveiro Institute of Materials Department of Chemistry University of Aveiro Campus Universitário de Santiago Aveiro 3810‐193 Portugal
| | - João F. Mano
- CICECO – Aveiro Institute of Materials Department of Chemistry University of Aveiro Campus Universitário de Santiago Aveiro 3810‐193 Portugal
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Jin M, Kim BS, Seo SH, Kim M, Kang YG, Shin JW, Cho KH, Shin MC, Yoon C, Min KA. Synergistic Effect of Growth Factor Releasing Polymeric Nanoparticles and Ultrasound Stimulation on Osteogenic Differentiation. Pharmaceutics 2021; 13:pharmaceutics13040457. [PMID: 33801692 PMCID: PMC8066944 DOI: 10.3390/pharmaceutics13040457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 01/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been extensively used in the tissue regeneration therapy. Ex vivo therapy with well-differentiated osteogenic cells is known as an efficient treatment for musculoskeletal diseases, including rheumatoid diseases. However, along with its high cost, the current therapy has limitations in terms of restoring bone regeneration procedures. An efficient process for the cell differentiation to obtain a large number of functionalized osteogenic cells is necessary. Therefore, it is strongly recommended to develop strategies to produce sufficient numbers of well-differentiated osteogenic cells from the MSCs. In general, differentiation media with growth factors have been used to facilitate cell differentiation. In the present study, the poly (lactic-co-glycolic acid) (PLGA) nanoparticles incorporating the growth factors were included in the media, resulting in releasing growth factors (dexamethasone and β-glycerophosphate) in the media in the controlled manner. Stable growth and early differentiation of osteogenic cells were achieved by the PLGA-based growth factor releasing system. Moreover, low intensity pulsed ultrasound was applied to this system to induce cell differentiation process. The results revealed that, as a biomarker at early stage of osteogenic cell differentiation, Lamin A/C nuclear protein was efficiently expressed in the cells growing in the presence of PLGA-based growth factor reservoirs and ultrasound. In conclusion, our results showed that the ultrasound stimulation combined with polymeric nanoparticles releasing growth factors could potentially induce osteogenic cell differentiation.
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Affiliation(s)
- Minki Jin
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.J.); (K.H.C.)
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea
| | - Bo Seok Kim
- Department of Nanoscience and Engineering, School of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (B.S.K.); (S.H.S.)
| | - Sung Ho Seo
- Department of Nanoscience and Engineering, School of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (B.S.K.); (S.H.S.)
| | - Minjeong Kim
- Department of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.K.); (Y.G.K.); (J.-W.S.)
| | - Yun Gyeong Kang
- Department of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.K.); (Y.G.K.); (J.-W.S.)
| | - Jung-Woog Shin
- Department of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.K.); (Y.G.K.); (J.-W.S.)
| | - Kwan Hyung Cho
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.J.); (K.H.C.)
| | - Meong Cheol Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Gyeongnam, Korea;
| | - Changhan Yoon
- Department of Nanoscience and Engineering, School of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (B.S.K.); (S.H.S.)
- Department of Biomedical Engineering, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.K.); (Y.G.K.); (J.-W.S.)
- Correspondence: (C.Y.); (K.A.M.); Tel.: +82-55-320-3301 (C.Y.); +82-55-320-3459 (K.A.M.)
| | - Kyoung Ah Min
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Korea; (M.J.); (K.H.C.)
- Correspondence: (C.Y.); (K.A.M.); Tel.: +82-55-320-3301 (C.Y.); +82-55-320-3459 (K.A.M.)
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12
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Zonderland J, Gomes DB, Pallada Y, Moldero IL, Camarero‐Espinosa S, Moroni L. Mechanosensitive regulation of stanniocalcin-1 by zyxin and actin-myosin in human mesenchymal stromal cells. Stem Cells 2020; 38:948-959. [PMID: 32379914 PMCID: PMC7497098 DOI: 10.1002/stem.3198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/29/2020] [Accepted: 04/16/2020] [Indexed: 12/16/2022]
Abstract
Stanniocalcin-1 (STC1) secreted by mesenchymal stromal cells (MSCs) has anti-inflammatory functions, reduces apoptosis, and aids in angiogenesis, both in vitro and in vivo. However, little is known about the molecular mechanisms of its regulation. Here, we show that STC1 secretion is increased only under specific cell-stress conditions. We find that this is due to a change in actin stress fibers and actin-myosin tension. Abolishment of stress fibers by blebbistatin and knockdown of the focal adhesion protein zyxin leads to an increase in STC1 secretion. To also study this connection in 3D, where few focal adhesions and actin stress fibers are present, STC1 expression was analyzed in 3D alginate hydrogels and 3D electrospun scaffolds. Indeed, STC1 secretion was increased in these low cellular tension 3D environments. Together, our data show that STC1 does not directly respond to cell stress, but that it is regulated through mechanotransduction. This research takes a step forward in the fundamental understanding of STC1 regulation and can have implications for cell-based regenerative medicine, where cell survival, anti-inflammatory factors, and angiogenesis are critical.
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Affiliation(s)
- Jip Zonderland
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - David B. Gomes
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Yves Pallada
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Ivan L. Moldero
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Sandra Camarero‐Espinosa
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Lorenzo Moroni
- Complex Tissue Regeneration Department, MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastrichtThe Netherlands
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13
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Chisari E, Rehak L, Khan WS, Maffulli N. The role of the immune system in tendon healing: a systematic review. Br Med Bull 2020; 133:49-64. [PMID: 32163543 DOI: 10.1093/bmb/ldz040] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The role of the immune system in tendon healing relies on polymorphonucleocytes, mast cells, macrophages and lymphocytes, the 'immune cells' and their cytokine production. This systematic review reports how the immune system affects tendon healing. SOURCES OF DATA We registered our protocol (registration number: CRD42019141838). After searching PubMed, Embase and Cochrane Library databases, we included studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. The PRISMA guidelines were applied, and risk of bias and the methodological quality of the included studies were assessed. We excluded all the articles with high risk of bias and/or low quality after the assessment. We included 62 articles assessed as medium or high quality. AREAS OF AGREEMENT Macrophages are major actors in the promotion of proper wound healing as well as the resolution of inflammation in response to pathogenic challenge or tissue damage. The immune cells secrete cytokines involving both pro-inflammatory and anti-inflammatory factors which could affect both healing and macrophage polarization. AREAS OF CONTROVERSY The role of lymphocytes, mast cells and polymorphonucleocytes is still inconclusive. GROWING POINTS The immune system is a major actor in the complex mechanism behind the healing response occurring in tendons after an injury. A dysregulation of the immune response can ultimately lead to a failed healing response. AREAS TIMELY FOR DEVELOPING RESEARCH Further studies are needed to shed light on therapeutic targets to improve tendon healing and in managing new way to balance immune response.
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Affiliation(s)
- Emanuele Chisari
- University of Catania, Department of General Surgery and Medical Specialities, Via Santa Sofia 78, Catania 95123, Italy
| | - Laura Rehak
- Athena Biomedical innovations, Viale Europa 139, Florence, 50126, Italy
| | - Wasim S Khan
- Division of Trauma & Orthopaedics, Addenbrooke's Hospital, University of Cambridge, Hills Rd, Cambridge CB2 0QQ, UK
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Via Salvator Allende 23, Baronissi, 89100 Salerno, Italy.,Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D'Aragona, Largo Città di Ippocrate, Salerno, 84131 Italy.,Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, 275 Bancroft Road, London E1 4DG, UK.,School of Pharmacy and Bioengineering, Keele University of School of Medicine, Guy Hilton Research Centre, Thornburrow Drive, Hartshill, Stoke-on-Trent, ST4 7QB, UK
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14
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Pan J, Deng J, Yu L, Wang Y, Zhang W, Han X, Camargo PHC, Wang J, Liu Y. Investigating the repair of alveolar bone defects by gelatin methacrylate hydrogels-encapsulated human periodontal ligament stem cells. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2019; 31:3. [PMID: 31811403 DOI: 10.1007/s10856-019-6333-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 11/16/2019] [Indexed: 06/10/2023]
Abstract
Although various efforts have been made to develop effective treatments for alveolar bone defect, alveolar regeneration has been emerging as the one with the most potential Herein, we investigated the potential of gelatin methacrylate (GelMA) hydrogels-encapsulated human periodontal ligament stem cells (hPDLSCs) to regenerate alveolar bone. The easy, rapid, and cost-effective nature of GelMA hydrogels makes them a promising mode of stem cell-delivery for clinically relevant alveolar bone regeneration. More importantly, GelMA hydrogels provide an optimal niche for hPDLSCs proliferation, migration and osteogenic differentiation, which are critical for alveolar bone regeneration. In this study, we examined the microstructure of GelMA hydrogels, and identified a highly porous and interconnected network. Compressive test of GelMA hydrogels showed that the stress reached a maximum value of 13.67 ± 0.03 kPa when the strain reached 55%. The maximum values of swelling ratio were 700 ± 47% at the fifth hour. The proliferation rate of hPDLSCs in the GelMA hydrogels resembled that in 2D culture and gradually increased. We established a critical-sized rat model of alveolar bone defects, and applied Micro-CT to assess new bone formation. Compared to the control group, there was substantial bone regeneration in the GelMA + hPDLSCs group at both 4 and 8 weeks after the operation. Histological analysis results were consistent with Micro-CT results. Our study demonstrates that the GelMA hydrogels-encapsulated hPDLSCs have a significant alveolar regenerative potential, and may represent a new strategy for the therapy of alveolar bone defects.
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Affiliation(s)
- Jie Pan
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Jiajia Deng
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Liming Yu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Yuhui Wang
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Weihua Zhang
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Xinxin Han
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China
| | - Pedro H C Camargo
- Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, FI, 00014, Helsinki, Finland
- Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP, 05508-000, Brazil
| | - Jiale Wang
- College of Science, Donghua University, Shanghai, 201620, China.
- Shanghai Institute of Intelligent Electronics and Systems, Donghua University, Shanghai, 201620, China.
| | - Yuehua Liu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China.
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, PR China.
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15
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Chamberlain CS, Clements AEB, Kink JA, Choi U, Baer GS, Halanski MA, Hematti P, Vanderby R. Extracellular Vesicle-Educated Macrophages Promote Early Achilles Tendon Healing. Stem Cells 2019; 37:652-662. [PMID: 30720911 PMCID: PMC6850358 DOI: 10.1002/stem.2988] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 12/14/2018] [Accepted: 01/21/2019] [Indexed: 12/20/2022]
Abstract
Tendon healing follows a complex series of coordinated events, which ultimately produces a mechanically inferior tissue more scar‐like than native tendon. More regenerative healing occurs when anti‐inflammatory M2 macrophages play a more dominant role. Mesenchymal stromal/stem cells (MSCs) are able to polarize macrophages to an M2 immunophenotype via paracrine mechanisms. We previously reported that coculture of CD14+ macrophages (MQs) with MSCs resulted in a unique M2‐like macrophage. More recently, we generated M2‐like macrophages using only extracellular vesicles (EVs) isolated from MSCs creating “EV‐educated macrophages” (also called exosome‐educated macrophages [EEMs]), thereby foregoing direct use of MSCs. For the current study, we hypothesized that cell therapy with EEMs would improve in vivo tendon healing by modulating tissue inflammation and endogenous macrophage immunophenotypes. We evaluated effects of EEMs using a mouse Achilles tendon rupture model and compared results to normal tendon healing (without any biologic intervention), MSCs, MQs, or EVs. We found that exogenous administration of EEMs directly into the wound promoted a healing response that was significantly more functional and more regenerative. Injured tendons treated with exogenous EEMs exhibited (a) improved mechanical properties, (b) reduced inflammation, and (c) earlier angiogenesis. Treatment with MSC‐derived EVs alone were less effective functionally but stimulated a biological response as evidenced by an increased number of endothelial cells and decreased M1/M2 ratio. Because of their regenerative and immunomodulatory effects, EEM treament could provide a novel strategy to promote wound healing in this and various other musculoskeletal injuries or pathologies where inflammation and inadequate healing is problematic. Stem Cells2019;37:652–662
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Affiliation(s)
- Connie S Chamberlain
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Anna E B Clements
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - John A Kink
- Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA
| | - Ugeun Choi
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA
| | - Geoffrey S Baer
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Matthew A Halanski
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA
| | - Ray Vanderby
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA
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16
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He XT, Wu RX, Xu XY, Wang J, Yin Y, Chen FM. Macrophage involvement affects matrix stiffness-related influences on cell osteogenesis under three-dimensional culture conditions. Acta Biomater 2018; 71:132-147. [PMID: 29462712 DOI: 10.1016/j.actbio.2018.02.015] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/29/2018] [Accepted: 02/12/2018] [Indexed: 12/16/2022]
Abstract
Accumulating evidence indicates that the physicochemical properties of biomaterials exert profound influences on stem cell fate decisions. However, matrix-based regulation selected through in vitro analyses based on a given cell population do not genuinely reflect the in vivo conditions, in which multiple cell types are involved and interact dynamically. This study constitutes the first investigation of how macrophages (Mφs) in stiffness-tunable transglutaminase cross-linked gelatin (TG-gel) affect the osteogenesis of bone marrow-derived mesenchymal stem cells (BMMSCs). When a single cell type was cultured, low-stiffness TG-gels promoted BMMSC proliferation, whereas high-stiffness TG-gels supported cell osteogenic differentiation. However, Mφs in high-stiffness TG-gels were more likely to polarize toward the pro-inflammatory M1 phenotype. Using either conditioned medium (CM)-based incubation or Transwell-based co-culture, we found that Mφs encapsulated in the low-stiffness matrix exerted a positive effect on the osteogenesis of co-cultured BMMSCs. Conversely, Mφs in high-stiffness TG-gels negatively affected cell osteogenic differentiation. When both cell types were cultured in the same TG-gel type and placed into the Transwell system, the stiffness-related influences of Mφs on BMMSCs were significantly altered; both the low- and high-stiffness matrix induced similar levels of BMMSC osteogenesis. Although the best material parameter for synergistically affecting Mφs and BMMSCs remains unknown, our data suggest that Mφ involvement in the co-culture system alters previously identified material-related influences on BMMSCs, such as matrix stiffness-related effects, which were identified based on a culture system involving a single cell type. Such Mφ-stem cell interactions should be considered when establishing proper matrix parameter-associated cell regulation in the development of biomimetic biomaterials for regenerative applications. STATEMENT OF SIGNIFICANCE The substrate stiffness of a scaffold plays critical roles in modulating both reparative cells, such as mesenchymal stem cells (MSCs), and immune cells, such as macrophages (Mφs). Although the influences of material stiffness on either Mφs or MSCs, have been extensively described, how the two cell types respond to matrix cues to dynamically affect each other in a three-dimensional (3D) biosystem remains largely unknown. Here, we report our findings that, in a platform wherein Mφs and bone marrow-derived MSCs coexist, matrix stiffness can influence stem cell fate through both direct matrix-associated regulation and indirect Mφ-based modulation. Our data support future studies of the MSC-Mφ-matrix interplay in the 3D context to optimize matrix parameters for the development of the next biomaterial.
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17
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Oh B, Levinson A, Lam V, Song S, George P. Electrically Conductive Scaffold to Modulate and Deliver Stem Cells. J Vis Exp 2018. [PMID: 29708538 DOI: 10.3791/57367] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Stem cell therapy has emerged as an exciting stroke therapeutic, but the optimal delivery method remains unclear. While the technique of microinjection has been used for decades to deliver stem cells in stroke models, this technique is limited by the lack of ability to manipulate the stem cells prior to injection. This paper details a method of using an electrically conductive polymer scaffold for stem cell delivery. Electrical stimulation of stem cells using a conductive polymer scaffold alters the stem cell's genes involved in cell survival, inflammatory response, and synaptic remodeling. After electrical preconditioning, the stem cells on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. This protocol describes a powerful technique to manipulate stem cells via a conductive polymer scaffold and creates a new tool to further develop stem cell-based therapy.
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Affiliation(s)
- Byeongtaek Oh
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine
| | - Alexa Levinson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine
| | - Vivek Lam
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine
| | - Shang Song
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine
| | - Paul George
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Stanford Stroke Center and Stanford University School of Medicine;
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18
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Ansari S, Diniz IM, Chen C, Sarrion P, Tamayol A, Wu BM, Moshaverinia A. Human Periodontal Ligament- and Gingiva-derived Mesenchymal Stem Cells Promote Nerve Regeneration When Encapsulated in Alginate/Hyaluronic Acid 3D Scaffold. Adv Healthc Mater 2017; 6:10.1002/adhm.201700670. [PMID: 29076281 PMCID: PMC5813692 DOI: 10.1002/adhm.201700670] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 08/29/2017] [Indexed: 12/25/2022]
Abstract
Repair or regeneration of damaged nerves is still a challenging clinical task in reconstructive surgeries and regenerative medicine. Here, it is demonstrated that periodontal ligament stem cells (PDLSCs) and gingival mesenchymal stem cells (GMSCs) isolated from adult human periodontal and gingival tissues assume neuronal phenotype in vitro and in vivo via a subcutaneous transplantation model in nude mice. PDLSCs and GMSCs are encapsulated in a 3D scaffold based on alginate and hyaluronic acid hydrogels capable of sustained release of human nerve growth factor (NGF). The elasticity of the hydrogels affects the proliferation and differentiation of encapsulated MSCs within scaffolds. Moreover, it is observed that PDLSCs and GMSCs are stained positive for βIII-tubulin, while exhibiting high levels of gene expression related to neurogenic differentiation (βIII-tubulin and glial fibrillary acidic protein) via quantitative polymerase chain reaction (qPCR). Western blot analysis shows the importance of elasticity of the matrix and the presence of NGF in the neurogenic differentiation of encapsulated MSCs. In vivo, immunofluorescence staining for neurogenic specific protein markers confirms islands of dense positively stained structures inside transplanted hydrogels. As far as it is known, this study is the first demonstration of the application of PDLSCs and GMSCs as promising cell therapy candidates for nerve regeneration.
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Affiliation(s)
- Sahar Ansari
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, 90095, USA
| | - Ivana M Diniz
- Faculdade de Odontologia da UFMG, Departamento de Odontologia Restauradora, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-910, Brazil
| | - Chider Chen
- School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA, 19104, USA
| | - Patricia Sarrion
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, 90095, USA
| | - Ali Tamayol
- Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, NE 68508, Lincoln
| | - Benjamin M Wu
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, 90095, USA
| | - Alireza Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, 90095, USA
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19
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Ansari S, Sarrion P, Hasani-Sadrabdi MM, Aghaloo T, Wu BM, Moshaverinia A. Regulation of the fate of dental-derived mesenchymal stem cells using engineered alginate-GelMA hydrogels. J Biomed Mater Res A 2017; 105:2957-2967. [PMID: 28639378 PMCID: PMC5623163 DOI: 10.1002/jbm.a.36148] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 06/14/2017] [Accepted: 06/20/2017] [Indexed: 11/11/2022]
Abstract
Mesenchymal stem cells (MSCs) derived from dental and orofacial tissues provide an alternative therapeutic option for craniofacial bone tissue regeneration. However, there is still a need to improve stem cell delivery vehicles to regulate the fate of the encapsulated MSCs for high quality tissue regeneration. Matrix elasticity plays a vital role in MSC fate determination. Here, we have prepared various hydrogel formulations based on alginate and gelatin methacryloyl (GelMA) and have encapsulated gingival mesenchymal stem cells (GMSCs) and human bone marrow MSCs (hBMMSCs) within these fabricated hydrogels. We demonstrate that addition of the GelMA to alginate hydrogel reduces the elasticity of the hydrogel mixture. While presence of GelMA in an alginate-based scaffold significantly increased the viability of encapsulated MSCs, increasing the concentration of GelMA downregulated the osteogenic differentiation of encapsulated MSCs in vitro due to decrease in the stiffness of the hydrogel matrix. The osteogenic suppression was rescued by addition of a potent osteogenic growth factor such as rh-BMP-2. In contrast, MSCs encapsulated in alginate hydrogel without GelMA were successfully osteo-differentiated without the aid of additional growth factors, as confirmed by expression of osteogenic markers (Runx2 and OCN), as well as positive staining using Xylenol orange. Interestingly, after two weeks of osteo-differentiation, hBMMSCs and GMSCs encapsulated in alginate/GelMA hydrogels still expressed CD146, an MSC surface marker, while MSCs encapsulated in alginate hydrogel failed to express any positive staining. Altogether, our findings suggest that it is possible to control the fate of encapsulated MSCs within hydrogels by tuning the mechanical properties of the matrix. We also reconfirmed the important role of the presence of inductive signals in guiding MSC differentiation. These findings may enable the design of new multifunctional scaffolds for spatial and temporal control over the fate and function of stem cells even post-transplantation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2957-2967, 2017.
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Affiliation(s)
- Sahar Ansari
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA
| | - Patricia Sarrion
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA
| | - Mohammad Mahdi Hasani-Sadrabdi
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA
- Parker H. Petit Institute for Bioengineering and Bioscience, G. W. Woodruff School of Mechanical Engineering and School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Tara Aghaloo
- Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA
| | - Benjamin M Wu
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA
| | - Alireza Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA
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20
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Ansari S, Diniz IM, Chen C, Aghaloo T, Wu BM, Shi S, Moshaverinia A. Alginate/hyaluronic acid hydrogel delivery system characteristics regulate the differentiation of periodontal ligament stem cells toward chondrogenic lineage. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2017; 28:162. [PMID: 28914392 DOI: 10.1007/s10856-017-5974-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/01/2017] [Indexed: 06/07/2023]
Abstract
Cartilage tissue regeneration often presents a challenging clinical situation. Recently, it has been shown that Periodontal Ligament Stem Cells (PDLSCs) possess high chondrogenic differentiation capacity. In this study, we developed a stem cell delivery system based on alginate/hyaluronic acid (HA) loaded with TGF-β1 ligand, encapsulating PDLSCs; and investigated the chondrogenic differentiation of encapsulated cells in alginate/HA hydrogel microspheres in vitro and in vivo. The results showed that PDLSCs, as well as human bone marrow mesenchymal stem cells (hBMMSCs), as the positive control, were stained positive for both toluidine blue and alcian blue staining, while exhibiting high levels of gene expression related to chondrogenesis (Col II, Aggrecan and Sox-9), as assessed via qPCR. The quantitative PCR analyses exhibited that the chondrogenic differentiation of encapsulated MSCs can be regulated by the modulus of elasticity of hydrogel delivery system, confirming the vital role of the microenvironment, and the presence of inductive signals for viability and differentiation of MSCs. In vivo, histological and immunofluorescence staining for chondrogenic specific protein markers confirmed ectopic cartilage-like tissue regeneration inside transplanted hydrogels. PDLSCs presented significantly greater capability for chondrogenic differentiation than hBMMSCs (P < 0.05). Altogether, our findings confirmed that alginate/HA hydrogels encapsulating PDLSCs are a promising candidate for cartilage regeneration.
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Affiliation(s)
- Sahar Ansari
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Ivana M Diniz
- Departamento de Odontologia Restauradora, Faculdade de Odontologia da UFMG, Belo Horizonte, Brazil
| | - Chider Chen
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Tara Aghaloo
- Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Benjamin M Wu
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Songtao Shi
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alireza Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, USA.
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21
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Guerra AD, Yeung OW, Qi X, Kao WJ, Man K. The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma. Am J Cancer Res 2017; 7:3732-3744. [PMID: 29109772 PMCID: PMC5667344 DOI: 10.7150/thno.20251] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/03/2017] [Indexed: 12/26/2022] Open
Abstract
Background and Aims: Recently we reported that direct injection of M1 macrophages significantly caused tumor regression in vivo. Despite the promising result, a major limitation in translating this approach is the induction of acute inflammatory response. To improve the strategy, a biocompatible scaffold for cell presentation and support is essential to control cell fate. Here, we aimed to elucidate the anti-tumor effects of a poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) cross-linked hydrogels capsulated with M1 macrophages in both in vitro and in vivo disease models. Methods: Hydrogels were made at 0.5% (w/v) Iragcure 2959 photoinitiator, 10% (w/v) PEGdA, and 10% (w/v) Gel-PEG-Cys. Monocytic THP-1 cells were loaded into hydrogels and differentiated into M1 macrophages with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). The M1 hydrogels were then cocultivated with HCC cell-lines Hep3B and MHCC97L to investigate the anti-tumor capacities and the associated molecular profiles in vitro. A nude mice ectopic liver cancer model with dorsal window chamber (DWC) and a subcutaneous tumor model were both performed to validate the in vivo application of M1 hydrogels. Results: M1 hydrogels significantly decreased the viability of HCC cells (MHCC97L: -46%; Hep3B: -56.9%; P<0.05) compared to the control in vitro. In response to HCC cells, the hydrogel embedded M1 macrophages up-regulated nitrite and tumor necrosis factor alpha (TNF-α) activating caspase-3 induced apoptosis in the tumor cells. Increased tumor necrosis was observed in DWC filled with M1 hydrogels. In addition, mice treated with M1 hydrogels exhibited a significant 2.4-fold decrease in signal intensity of subcutaneous HCC tumor compared to control (P=0.036). Conclusion: M1 hydrogels induced apoptosis in HCC cells and tumor regression in vivo. Continuous development of the scaffold-based cancer immunotherapy may provide an alternative and innovative strategy against HCC.
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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: 14] [Impact Index Per Article: 1.8] [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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Goonoo N. Modulating Immunological Responses of Electrospun Fibers for Tissue Engineering. ACTA ACUST UNITED AC 2017; 1:e1700093. [PMID: 32646177 DOI: 10.1002/adbi.201700093] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Indexed: 12/28/2022]
Abstract
The promise of tissue engineering is to improve or restore functions of impaired tissues or organs. However, one of the biggest challenges to its translation to clinical applications is the lack of tissue integration and functionality. The plethora of cellular and molecular events occurring following scaffold implantation is a major bottleneck. Recent studies confirmed that inflammation is a crucial component influencing tissue regeneration. Immuno-modulation or immune-engineering has been proposed as a potential solution to overcome this key challenge in regenerative medicine. In this review, strategies to modify scaffold physicochemical properties through the use of the electrospinning technique to modulate host response and improve scaffold integration will be discussed. Electrospinning, being highly versatile allows the fabrication of ECM-mimicking scaffolds and also offers the possibility to control scaffold properties for instance, tailoring of fiber properties, chemical conjugation or physical adsorption of non-immunogenic materials on the scaffold surface, encapsulating cells or anti-inflammatory molecules within the scaffold. Such electrospun scaffold-based immune-engineering strategies can significantly improve the resulting outcomes of tissue engineering scaffolds.
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Affiliation(s)
- Nowsheen Goonoo
- Physical Chemistry I, Department of Chemistry and Biology & Research Center of Micro and Nanochemistry and Engineering (Cµ), University of Siegen, 57076, Siegen, Germany.,Biomaterials, Drug Delivery & Nanotechnology Unit, Centre for Biomedical and Biomaterials Research, MSIRI Building, University of Mauritius, Réduit, Mauritius
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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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25
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Extracellular Superoxide Dismutase Expression in Papillary Thyroid Cancer Mesenchymal Stem/Stromal Cells Modulates Cancer Cell Growth and Migration. Sci Rep 2017; 7:41416. [PMID: 28216675 PMCID: PMC5316948 DOI: 10.1038/srep41416] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 12/19/2016] [Indexed: 12/14/2022] Open
Abstract
Tumor stroma-secreted growth factors, cytokines, and reactive oxygen species (ROS) influence tumor development from early stages to the metastasis phase. Previous studies have demonstrated downregulation of ROS-producing extracellular superoxide dismutase (SOD3) in thyroid cancer cell lines although according to recent data, the expression of SOD3 at physiological levels stimulates normal and cancer cell proliferation. Therefore, to analyze the expression of SOD3 in tumor stroma, we characterized stromal cells from the thyroid. We report mutually exclusive desmoplasia and inflammation in papillary and follicular thyroid cancers and the presence of multipotent mesenchymal stem/stromal cells (MSCs) in non-carcinogenic thyroids and papillary thyroid cancer (PTC). The phenotypic and differentiation characteristics of Thyroid MSCs and PTC MSCs were comparable with bone marrow MSCs. A molecular level analysis showed increased FIBROBLAST ACTIVATING PROTEIN, COLLAGEN 1 TYPE A1, TENASCIN, and SOD3 expression in PTC MSCs compared to Thyroid MSCs, suggesting the presence of MSCs with a fibrotic fingerprint in papillary thyroid cancer tumors and the autocrine-paracrine conversion of SOD3 expression, which was enhanced by cancer cells. Stromal SOD3 had a stimulatory effect on cancer cell growth and an inhibitory effect on cancer cell migration, thus indicating that SOD3 might be a novel player in thyroid tumor stroma.
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Vishwakarma A, Bhise NS, Evangelista MB, Rouwkema J, Dokmeci MR, Ghaemmaghami AM, Vrana NE, Khademhosseini A. Engineering Immunomodulatory Biomaterials To Tune the Inflammatory Response. Trends Biotechnol 2016; 34:470-482. [DOI: 10.1016/j.tibtech.2016.03.009] [Citation(s) in RCA: 301] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 03/27/2016] [Accepted: 03/29/2016] [Indexed: 11/24/2022]
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Ansari S, Chen C, Xu X, Annabi N, Zadeh HH, Wu BM, Khademhosseini A, Shi S, Moshaverinia A. Muscle Tissue Engineering Using Gingival Mesenchymal Stem Cells Encapsulated in Alginate Hydrogels Containing Multiple Growth Factors. Ann Biomed Eng 2016; 44:1908-20. [PMID: 27009085 DOI: 10.1007/s10439-016-1594-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 03/14/2016] [Indexed: 12/15/2022]
Abstract
Repair and regeneration of muscle tissue following traumatic injuries or muscle diseases often presents a challenging clinical situation. If a significant amount of tissue is lost the native regenerative potential of skeletal muscle will not be able to grow to fill the defect site completely. Dental-derived mesenchymal stem cells (MSCs) in combination with appropriate scaffold material, present an advantageous alternative therapeutic option for muscle tissue engineering in comparison to current treatment modalities available. To date, there has been no report on application of gingival mesenchymal stem cells (GMSCs) in three-dimensional scaffolds for muscle tissue engineering. The objectives of the current study were to develop an injectable 3D RGD-coupled alginate scaffold with multiple growth factor delivery capacity for encapsulating GMSCs, and to evaluate the capacity of encapsulated GMSCs to differentiate into myogenic tissue in vitro and in vivo where encapsulated GMSCs were transplanted subcutaneously into immunocompromised mice. The results demonstrate that after 4 weeks of differentiation in vitro, GMSCs as well as the positive control human bone marrow mesenchymal stem cells (hBMMSCs) exhibited muscle cell-like morphology with high levels of mRNA expression for gene markers related to muscle regeneration (MyoD, Myf5, and MyoG) via qPCR measurement. Our quantitative PCR analyzes revealed that the stiffness of the RGD-coupled alginate regulates the myogenic differentiation of encapsulated GMSCs. Histological and immunohistochemical/fluorescence staining for protein markers specific for myogenic tissue confirmed muscle regeneration in subcutaneous transplantation in our in vivo animal model. GMSCs showed significantly greater capacity for myogenic regeneration in comparison to hBMMSCs (p < 0.05). Altogether, our findings confirmed that GMSCs encapsulated in RGD-modified alginate hydrogel with multiple growth factor delivery capacity is a promising candidate for muscle tissue engineering.
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Affiliation(s)
- Sahar Ansari
- Division of Growth and Development, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Chider Chen
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xingtian Xu
- Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
| | - Nasim Annabi
- Department of Chemical Engineering, Northeastern University, Boston, MA, USA.,Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Homayoun H Zadeh
- Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
| | - Benjamin M Wu
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prothodontics, School of Dentistry, University of California, Los Angeles, CA, USA
| | - Ali Khademhosseini
- Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Songtao Shi
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alireza Moshaverinia
- Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prothodontics, School of Dentistry, University of California, Los Angeles, CA, USA.
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Crupi A, Costa A, Tarnok A, Melzer S, Teodori L. Inflammation in tissue engineering: The Janus between engraftment and rejection. Eur J Immunol 2015; 45:3222-36. [DOI: 10.1002/eji.201545818] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 10/07/2015] [Accepted: 11/05/2015] [Indexed: 01/10/2023]
Affiliation(s)
- Annunziata Crupi
- Department of Fusion and Technologies for Nuclear Safety and Security; Diagnostic and Metrology (FSN-TECFIS-DIM), ENEA; Frascati-Rome Italy
- Fondazione San Raffaele; Ceglie Messapica Italy
| | - Alessandra Costa
- Department of Surgery; McGowan Institute; University of Pittsburgh Medical Center; Pittsburgh PA USA
| | - Attila Tarnok
- Department of Pediatric Cardiology; Heart Center GmbH Leipzig; and Translational Center for Regenerative Medicine; University Leipzig; Leipzig Germany
| | - Susanne Melzer
- Department of Pediatric Cardiology; Heart Center GmbH Leipzig; and Translational Center for Regenerative Medicine; University Leipzig; Leipzig Germany
| | - Laura Teodori
- Department of Fusion and Technologies for Nuclear Safety and Security; Diagnostic and Metrology (FSN-TECFIS-DIM), ENEA; Frascati-Rome Italy
- Fondazione San Raffaele; Ceglie Messapica Italy
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29
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Hashemi M, Kalalinia F. Application of encapsulation technology in stem cell therapy. Life Sci 2015; 143:139-46. [DOI: 10.1016/j.lfs.2015.11.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 10/15/2015] [Accepted: 11/06/2015] [Indexed: 11/26/2022]
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30
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Molina ER, Smith BT, Shah SR, Shin H, Mikos AG. Immunomodulatory properties of stem cells and bioactive molecules for tissue engineering. J Control Release 2015; 219:107-118. [PMID: 26307349 DOI: 10.1016/j.jconrel.2015.08.038] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/13/2015] [Accepted: 08/19/2015] [Indexed: 02/06/2023]
Abstract
The immune system plays a crucial role in the success of tissue engineering strategies. Failure to consider the interactions between implantable scaffolds, usually containing cells and/or bioactive molecules, and the immune system can result in rejection of the implant and devastating clinical consequences. However, recent research into mesenchymal stem cells, which are commonly used in many tissue engineering applications, indicates that they may play a beneficial role modulating the immune system. Likewise, direct delivery of bioactive molecules involved in the inflammatory process can promote the success of tissue engineering constructs. In this article, we will review the various mechanisms in which modulation of the immune system is achieved through delivered bioactive molecules and cells and contextualize this information for future strategies in tissue engineering.
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Affiliation(s)
- Eric R Molina
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Brandon T Smith
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Sarita R Shah
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Heungsoo Shin
- Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Bioengineering, Hanyang University, Seoul 133-791, South Korea; BK21 Plus Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University, Seoul 133-791, South Korea.
| | - Antonios G Mikos
- Department of Bioengineering, Rice University, Houston, TX 77030, USA.
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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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Javid A, Kumar M, Han JG. Nanoscale surface conductivity analysis of plasma sputtered carbon thin films. RSC Adv 2015. [DOI: 10.1039/c5ra17068k] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The present work demonstrates the phenomenon of nanoscale surface conductivity variation in various plasma conditions of sputtering induced carbon thin films.
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Affiliation(s)
- Amjed Javid
- Center for Advanced Plasma Surface Technology (CAPST)
- NU-SKKU Joint Institute for Plasma Nano-Materials (IPNM)
- Advanced Materials Science and Engineering
- Sungkyunkwan University
- Suwon
| | - Manish Kumar
- Center for Advanced Plasma Surface Technology (CAPST)
- NU-SKKU Joint Institute for Plasma Nano-Materials (IPNM)
- Advanced Materials Science and Engineering
- Sungkyunkwan University
- Suwon
| | - Jeon Geon Han
- Center for Advanced Plasma Surface Technology (CAPST)
- NU-SKKU Joint Institute for Plasma Nano-Materials (IPNM)
- Advanced Materials Science and Engineering
- Sungkyunkwan University
- Suwon
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Battiston KG, Cheung JWC, Jain D, Santerre JP. Biomaterials in co-culture systems: towards optimizing tissue integration and cell signaling within scaffolds. Biomaterials 2014; 35:4465-76. [PMID: 24602569 DOI: 10.1016/j.biomaterials.2014.02.023] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 02/12/2014] [Indexed: 02/07/2023]
Abstract
Most natural tissues consist of multi-cellular systems made up of two or more cell types. However, some of these tissues may not regenerate themselves following tissue injury or disease without some form of intervention, such as from the use of tissue engineered constructs. Recent studies have increasingly used co-cultures in tissue engineering applications as these systems better model the natural tissues, both physically and biologically. This review aims to identify the challenges of using co-culture systems and to highlight different approaches with respect to the use of biomaterials in the use of such systems. The application of co-culture systems to stimulate a desired biological response and examples of studies within particular tissue engineering disciplines are summarized. A description of different analytical co-culture systems is also discussed and the role of biomaterials in the future of co-culture research are elaborated on. Understanding the complex cell-cell and cell-biomaterial interactions involved in co-culture systems will ultimately lead the field towards biomaterial concepts and designs with specific biochemical, electrical, and mechanical characteristics that are tailored towards the needs of distinct co-culture systems.
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Affiliation(s)
- Kyle G Battiston
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 124 Edward Street, Room 461, Toronto, Ontario, Canada M5G 1G6
| | - Jane W C Cheung
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 124 Edward Street, Room 461, Toronto, Ontario, Canada M5G 1G6
| | - Devika Jain
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 124 Edward Street, Room 461, Toronto, Ontario, Canada M5G 1G6
| | - J Paul Santerre
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, 124 Edward Street, Room 461, Toronto, Ontario, Canada M5G 1G6; Department of Biomaterials, Faculty of Dentistry, University of Toronto, 124 Edward Street, Room 464D, Toronto, Ontario, Canada M5G 1G6.
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Moshaverinia A, Xu X, Chen C, Ansari S, Zadeh HH, Snead ML, Shi S. Application of stem cells derived from the periodontal ligament or gingival tissue sources for tendon tissue regeneration. Biomaterials 2014; 35:2642-50. [PMID: 24397989 DOI: 10.1016/j.biomaterials.2013.12.053] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 12/19/2013] [Indexed: 12/24/2022]
Abstract
Tendon injuries are often associated with significant dysfunction and disability due to tendinous tissue's very limited self-repair capacity and propensity for scar formation. Dental-derived mesenchymal stem cells (MSCs) in combination with appropriate scaffold material present an alternative therapeutic option for tendon repair/regeneration that may be advantageous compared to other current treatment modalities. The MSC delivery vehicle is the principal determinant for successful implementation of MSC-mediated regenerative therapies. In the current study, a co-delivery system based on TGF-β3-loaded RGD-coupled alginate microspheres was developed for encapsulating periodontal ligament stem cells (PDLSCs) or gingival mesenchymal stem cells (GMSCs). The capacity of encapsulated dental MSCs to differentiate into tendon tissue was investigated in vitro and in vivo. Encapsulated dental-derived MSCs were transplanted subcutaneously into immunocompromised mice. Our results revealed that after 4 weeks of differentiation in vitro, PDLSCs and GMSCs as well as the positive control human bone marrow mesenchymal stem cells (hBMMSCs) exhibited high levels of mRNA expression for gene markers related to tendon regeneration (Scx, DCn, Tnmd, and Bgy) via qPCR measurement. In a corresponding in vivo animal model, ectopic neo-tendon regeneration was observed in subcutaneous transplanted MSC-alginate constructs, as confirmed by histological and immunohistochemical staining for protein markers specific for tendons. Interestingly, in our quantitative PCR and in vivo histomorphometric analyses, PDLSCs showed significantly greater capacity for tendon regeneration than GMSCs or hBMMSCs (P < 0.05). Altogether, these findings indicate that periodontal ligament and gingival tissues can be considered as suitable stem cell sources for tendon engineering. PDLSCs and GMSCs encapsulated in TGF-β3-loaded RGD-modified alginate microspheres are promising candidates for tendon regeneration.
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Affiliation(s)
- Alireza Moshaverinia
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
| | - Xingtian Xu
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
| | - Chider Chen
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
| | - Sahar Ansari
- Laboratory for Immunoregulation and Tissue Engineering (LITE), Ostrow School of Dentistry of USC, University of Southern California, Los Angeles, CA, USA
| | - Homayoun H Zadeh
- Laboratory for Immunoregulation and Tissue Engineering (LITE), Ostrow School of Dentistry of USC, University of Southern California, Los Angeles, CA, USA
| | - Malcolm L Snead
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
| | - Songtao Shi
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
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Cantu DA, Kao WJ. Combinatorial biomatrix/cell-based therapies for restoration of host tissue architecture and function. Adv Healthc Mater 2013; 2:1544-63. [PMID: 23828863 PMCID: PMC3896550 DOI: 10.1002/adhm.201300063] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 03/08/2013] [Indexed: 12/13/2022]
Abstract
This Progress Report reviews recent advances in the utility of extracellular matrix (ECM)-mimic biomaterials in presenting and delivering therapeutic cells to promote tissue healing. This overview gives a brief introduction of different cell types being used in regenerative medicine and tissue engineering while addressing critical issues that must be overcome before cell-based approaches can be routinely employed in the clinic. A selection of five commonly used cell-associated, biomaterial platforms (collagen, hyaluronic acid, fibrin, alginate, and poly(ethylene glycol)) are reviewed for treatment of a number of acute injury or diseases with emphasis on animal models and clinical trials. This article concludes with current challenges and future perspectives regarding foreign body host response to biomaterials and immunological reactions to allogeneic or xenogeneic cells, vascularization and angiogenesis, matching mechanical strength and anisotropy of native tissues, as well as other non-technical issues regarding the clinical translation of biomatrix/cell-based therapies.
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Affiliation(s)
- David Antonio Cantu
- School of Pharmacy, Division of Pharmaceutical Sciences University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - W. John Kao
- School of Pharmacy, Division of Pharmaceutical Sciences University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA
- Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
- Univeristy of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
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Moshaverinia A, Xu X, Chen C, Akiyama K, Snead ML, Shi S. Dental mesenchymal stem cells encapsulated in an alginate hydrogel co-delivery microencapsulation system for cartilage regeneration. Acta Biomater 2013; 9:9343-50. [PMID: 23891740 PMCID: PMC3818395 DOI: 10.1016/j.actbio.2013.07.023] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 06/13/2013] [Accepted: 07/19/2013] [Indexed: 01/09/2023]
Abstract
Dental-derived mesenchymal stem cells (MSCs) are promising candidates for cartilage regeneration, with a high capacity for chondrogenic differentiation. This property helps make dental MSCs an advantageous therapeutic option compared to current treatment modalities. The MSC delivery vehicle is the principal determinant for the success of MSC-mediated cartilage regeneration therapies. The objectives of this study were to: (1) develop a novel co-delivery system based on TGF-β1 loaded RGD-coupled alginate microspheres encapsulating periodontal ligament stem cells (PDLSCs) or gingival mesenchymal stem cells (GMSCs); and (2) investigate dental MSC viability and chondrogenic differentiation in alginate microspheres. The results revealed the sustained release of TGF-β1 from the alginate microspheres. After 4 weeks of chondrogenic differentiation in vitro, PDLSCs and GMSCs as well as human bone marrow mesenchymal stem cells (hBMMSCs) (as positive control) revealed chondrogenic gene expression markers (Col II and Sox-9) via qPCR, as well as matrix positively stained by Toluidine Blue and Safranin-O. In animal studies, ectopic cartilage tissue regeneration was observed inside and around the transplanted microspheres, confirmed by histochemical and immunofluorescent staining. Interestingly, PDLSCs showed more chondrogenesis than GMSCs and hBMMSCs (p<0.05). Taken together, these results suggest that RGD-modified alginate microencapsulating dental MSCs make a promising candidate for cartilage regeneration. Our results highlight the vital role played by the microenvironment, as well as value of presenting inductive signals for viability and differentiation of MSCs.
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Affiliation(s)
- Alireza Moshaverinia
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
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Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for three-dimensional mesenchymal stromal/stem cell administration to cutaneous wounds. Acta Biomater 2013; 9:8802-14. [PMID: 23811217 DOI: 10.1016/j.actbio.2013.06.021] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 06/09/2013] [Accepted: 06/14/2013] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are considered promising cellular therapeutics in the fields of tissue engineering and regenerative medicine. MSCs secrete high concentrations of immunomodulatory cytokines and growth factors, which exert paracrine effects on infiltrating immune and resident cells in the wound microenvironment that could favorably promote healing after acute injury. However, better spatial delivery and improved retention at the site of injury are two factors that could improve the clinical application of MSCs. In this study, we utilized thiol-ene Michael-type addition for rapid encapsulation of MSCs within a gelatin/poly(ethylene glycol) biomatrix. This biomatrix was also applied as a provisional dressing to full thickness wounds in Sprague-Dawley rats. The three-way interaction of MSCs, gelatin/poly(ethylene glycol) biomatrices, and host immune cells and adjacent resident cells in the wound microenvironment favorably modulated wound progression and host response. In this model we observed attenuated immune cell infiltration, lack of foreign giant cell (FBGC) formation, accelerated wound closure and re-epithelialization, as well as enhanced neovascularization and granulation tissue formation by 7 days. The MSC entrapped in the gelatin/poly(ethylene glycol) biomatrix localized cell presentation adjacent to the wound microenvironment and thus mediated the early resolution of inflammatory events and facilitated the proliferative phases in wound healing.
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Abstract
INTRODUCTION Organ/tissue replacement therapy is inherently difficult for application in the tissue engineering field due to immune rejection that limits the long-term efficacy of implanted devices. As the application of tissue engineering in the biomedical field has steadily expanded, stem cells have emerged as a viable option to promote the immune acceptance of implantable devices and to expedite alleviation of the pathological conditions. With various novel scaffolds being introduced, nanofibers which have a three-dimensional architecture can be considered as an efficient carrier for stem cells. AREAS COVERED This article reviews the novel tissue engineering processes involved with nanofiber and stem cells. Topics such as the fabrication of nanofiber via electrospinning techniques, the interaction between nanofiber scaffold and specific cell and advanced techniques to enhance the stability of stem cells are delineated in detail. In addition, cardiovascular applications of nanofiber scaffolds loaded with stem cells are examined from a clinical perspective. EXPERT OPINION Electrospun nanofibers have been intensively explored as a tool for the architecture control of cardiovascular tissue engineering due to their tunable physicochemical properties. The modification of nanofiber with biological cues, which provide rapid differentiation of stem cells into a specific lineage and protect stem cells under the harsh conditions (i.e., hypoxia), will significantly enhance therapeutic efficacies of transplanted cells. A combination of nanofiber carriers and stem cell therapy for tissue regeneration seems to pose enormous potential for the treatment of cardiac diseases including atherosclerosis and myocardial infarction.
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Affiliation(s)
- Byeongtaek Oh
- University of Missouri-Kansas, School of Pharmacy, Division of Pharmaceutical Sciences , Kansas City, MO 64108 , USA
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King SN, Hanson SE, Chen X, Kim J, Hematti P, Thibeault SL. In vitro characterization of macrophage interaction with mesenchymal stromal cell-hyaluronan hydrogel constructs. J Biomed Mater Res A 2013; 102:890-902. [PMID: 23564555 DOI: 10.1002/jbm.a.34746] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/22/2013] [Accepted: 03/28/2013] [Indexed: 11/12/2022]
Abstract
Macrophages play a critical role in mediating not only normal tissue healing, but also the host reaction against biomaterial scaffolds. There is increasing interest in regenerative medicine to combine mesenchymal stromal/stem cells (MSCs) with biomaterial scaffolds to modulate inflammatory response while restoring tissue architecture. The objective of the current study was to investigate the interaction between MSCs (derived from bone marrow, adipose or vocal fold tissue) encapsulated in hyaluronan-based hydrogel and differentiating macrophages as measured by extracellular matrix (ECM) gene expression and cytokine, chemokine, and growth factor concentrations. Gene expression was analyzed using real-time polymerase chain reaction from MSCs embedded in Carbylan-GSX after 7 days of coculture with or without CD14+ cells. Protein concentrations were measured using a Bio-plex assay from cell culture supernatants on days 3 and 7 for all conditions. Following 7 days, we identified upregulation of collagen-I, collagen-III, procollagen, and matrix metalloproteinase-9 genes compared to control conditions. We demonstrate increased concentrations of immunoregulatory cytokines [interleukin (IL)-1β, tumor necrosis factor-α, macrophage inflammatory protein-1α, IFN-γ, IL-12, and IL-10] and remodeling growth factors (vascular endothelial growth factor, hepatocyte growth factor) in MSC-3D constructs cocultured with macrophages compared to control conditions, with some temporal variation. Our results indicate an alteration of expression of ECM proteins important to tissue regeneration and cytokines critical to the inflammatory cascade when 3D constructs were cultured with differentiating macrophages.
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Affiliation(s)
- Suzanne N King
- Division of Otolaryngology - Head and Neck Surgery, University of Wisconsin-Madison, Madison, Wisconsin
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Moshaverinia A, Ansari S, Chen C, Xu X, Akiyama K, Snead ML, Zadeh HH, Shi S. Co-encapsulation of anti-BMP2 monoclonal antibody and mesenchymal stem cells in alginate microspheres for bone tissue engineering. Biomaterials 2013; 34:6572-9. [PMID: 23773817 DOI: 10.1016/j.biomaterials.2013.05.048] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 05/23/2013] [Indexed: 12/19/2022]
Abstract
Recently, it has been shown that tethered anti-BMP2 monoclonal antibodies (mAbs) can trap BMP ligands and thus provide BMP inductive signals for osteo-differentiation of progenitor cells. The objectives of this study were to: (1) develop a co-delivery system based on murine anti-BMP2 mAb-loaded alginate microspheres encapsulating human bone marrow mesenchymal stem cells (hBMMSCs); and (2) investigate osteogenic differentiation of encapsulated stem cells in alginate microspheres in vitro and in vivo. Alginate microspheres of 1 ± 0.1 mm diameter were fabricated with 2 × 10(6) hBMMSCs per mL of alginate. Critical-size calvarial defects (5 mm diameter) were created in immune-compromised mice and alginate microspheres preloaded with anti-BMP mAb encapsulating hBMMSCs were transplanted into defect sites. Alginate microspheres pre-loaded with isotype-matched non-specific antibody were used as the negative control. After 8 weeks, micro CT and histologic analyses were used to analyze bone formation. In vitro analysis demonstrated that anti-BMP2 mAbs tethered BMP2 ligands that can activate the BMP receptors on hBMMSCs. The co-delivery system described herein, significantly enhanced hBMMSC-mediated osteogenesis, as confirmed by the presence of BMP signal pathway-activated osteoblast determinants Runx2 and ALP. Our results highlight the importance of engineering the microenvironment for stem cells, and particularly the value of presenting inductive signals for osteo-differentiation of hBMMSCs by tethering BMP ligands using mAbs. This strategy of engineering the microenvironment with captured BMP signals is a promising modality for repair and regeneration of craniofacial, axial and appendicular bone defects.
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Affiliation(s)
- Alireza Moshaverinia
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry of USC, University of Southern California, Los Angeles, CA 90089, USA
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