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Song W, Liu W, Li SY, Yu Y, Xu H, Shi T, Yu HP, He Y, Zhu YJ, Yu W. Remodeling the Senescent Microenvironment for Promoting Osteoporotic Tendon-to-Bone Healing via Synergizing Senolytic Quercetin and Aligned Nanowire-Structured Hydrogels. ACS NANO 2025; 19:18364-18385. [PMID: 40325895 DOI: 10.1021/acsnano.5c01332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Osteoporotic tendon-to-bone healing remains a major challenge, as cellular senescence disrupts tissue regeneration and impairs repair outcomes. Although the role of cellular senescence in rotator cuff repair is increasingly recognized, current strategies often overlook the complex pathological context, particularly the dual impacts of senescence on both bone marrow-derived mesenchymal stem cells (BMSCs) and tendon-derived stem cells (TDSCs). This gap hampers effective tendon-to-bone healing and integration, especially under osteoporotic conditions. Herein, a composite hydrogel system, quercetin-loaded aligned ultralong hydroxyapatite nanowire/gelatin-hyaluronic acid hydrogel (Que-AHNW/GH), has been developed to address these challenges. By integrating senolytic quercetin as a biological cue with highly aligned ultralong hydroxyapatite (HAP) nanowires as a topographical cue, the system remodels the senescent microenvironment, alleviating senescence in both BMSCs and TDSCs and promoting osteogenesis and tenogenesis. Que-AHNW/GH suppresses the PI3K/AKT pathway, enhances autophagy, and reduces senescence in both cell types. In vivo, Que-AHNW/GH improves bone tunnel regeneration, tendon repair, and tendon-to-bone integration in osteoporotic rats with rotator cuff injury. This system enhances biomechanical strength and gait performance and demonstrates excellent biosafety. These findings highlight the promising potential of Que-AHNW/GH as a multifunctional biomaterial for effectively promoting senescence-related tendon-to-bone healing, offering a promising solution for treating osteoporotic tendon-to-bone injuries.
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Affiliation(s)
- Wei Song
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Wencai Liu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Si-Yi Li
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, PR China
| | - Yuhao Yu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Hui Xu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Tingwang Shi
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Han-Ping Yu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, PR China
| | - Yaohua He
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
| | - Ying-Jie Zhu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, PR China
| | - Weilin Yu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China
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2
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Garcia‐Aponte OF, Kahlenberg S, Kouroupis D, Egger D, Kasper C. Effects of Hydrogels on Mesenchymal Stem/Stromal Cells Paracrine Activity and Extracellular Vesicles Production. J Extracell Vesicles 2025; 14:e70057. [PMID: 40091440 PMCID: PMC11911545 DOI: 10.1002/jev2.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/10/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a valuable source of paracrine factors, as they have a remarkable secretory capacity, and there is a sizeable knowledge base to develop industrial and clinical production protocols. Promising cell-free approaches for tissue regeneration and immunomodulation are driving research towards secretome applications, among which extracellular vesicles (EVs) are steadily gaining attention. However, the manufacturing and application of EVs is limited by insufficient yields, knowledge gaps, and low standardization. Facing these limitations, hydrogels represent a versatile three-dimensional (3D) culture platform that can incorporate extracellular matrix (ECM) components to mimic the natural stem cell environment in vitro; via these niche-mimicking properties, hydrogels can regulate MSCs' morphology, adhesion, proliferation, differentiation and secretion capacities. However, the impact of the hydrogel's architectural, biochemical and biomechanical properties on the production of EVs remains poorly understood, as the field is still in its infancy and the interdependency of culture parameters compromises the comparability of the studies. Therefore, this review summarizes and discusses the reported effects of hydrogel encapsulation and culture on the secretion of MSC-EVs. Considering the effects of cell-material interactions on the overall paracrine activity of MSCs, we identify persistent challenges from low standardization and process control, and outline future paths of research, such as the synergic use of hydrogels and bioreactors to enhance MSC-EV generation.
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Affiliation(s)
- Oscar Fabian Garcia‐Aponte
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
| | - Simon Kahlenberg
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
- Diabetes Research Institute & Cell Transplant Center, Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Dominik Egger
- Institute of Cell Biology and BiophysicsLeibniz University HannoverHannoverGermany
| | - Cornelia Kasper
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
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Castilla-Casadiego DA, Loh DH, Pineda-Hernandez A, Rosales AM. Stimuli-Responsive Substrates to Control the Immunomodulatory Potential of Stromal Cells. Biomacromolecules 2024; 25:6319-6337. [PMID: 39283807 PMCID: PMC11506505 DOI: 10.1021/acs.biomac.4c00835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2024]
Abstract
Mesenchymal stromal cells (MSCs) have broad immunomodulatory properties that range from regulation, proliferation, differentiation, and immune cell activation to secreting bioactive molecules that inhibit inflammation and regulate immune response. These properties provide MSCs with high therapeutic potency that has been shown to be relevant to tissue engineering and regenerative medicine. Hence, researchers have explored diverse strategies to control the immunomodulatory potential of stromal cells using polymeric substrates or scaffolds. These substrates alter the immunomodulatory response of MSCs, especially through biophysical cues such as matrix mechanical properties. To leverage these cell-matrix interactions as a strategy for priming MSCs, emerging studies have explored the use of stimuli-responsive substrates to enhance the therapeutic value of stromal cells. This review highlights how stimuli-responsive materials, including chemo-responsive, microenvironment-responsive, magneto-responsive, mechano-responsive, and photo-responsive substrates, have specifically been used to promote the immunomodulatory potential of stromal cells by controlling their secretory activity.
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Affiliation(s)
- David A Castilla-Casadiego
- Mcketta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
| | - Darren H Loh
- Mcketta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
| | - Aldaly Pineda-Hernandez
- Mcketta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
| | - Adrianne M Rosales
- Mcketta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
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4
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Ju R, Gao X, Zhang C, Tang W, Tian W, He M. Exogenous MSC based tissue regeneration: a review of immuno-protection strategies from biomaterial scaffolds. J Mater Chem B 2024; 12:8868-8882. [PMID: 39171946 DOI: 10.1039/d4tb00778f] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Mesenchymal stem cell (MSC)-based tissue engineering holds great potential for regenerative medicine as a means of replacing damaged or lost tissues to restore their structure and function. However, the efficacy of MSC-based regeneration is frequently limited by the low survival rate and limited survival time of transplanted MSCs. Despite the inherent immune privileges of MSCs, such as low expression of major histocompatibility complex antigens, tolerogenic properties, local immunosuppressive microenvironment creation, and induction of immune tolerance, immune rejection remains a major obstacle to their survival and regenerative potential. Evidence suggests that immune protection strategies can enhance MSC therapeutic efficacy by prolonging their survival and maintaining their biological functions. Among various immune protection strategies, biomaterial-based scaffolds or cell encapsulation systems that mediate the interaction between transplanted MSCs and the host immune system or spatially isolate MSCs from the immune system for a specific time period have shown great promise. In this review, we provide a comprehensive overview of these biomaterial-based immune protection strategies employed for exogenous MSCs, highlighting the crucial role of modulating the immune microenvironment. Each strategy is critically examined, discussing its strengths, limitations, and potential applications in MSC-based tissue engineering. By elucidating the mechanisms behind immune rejection and exploring immune protection strategies, we aim to address the challenges faced by MSC-based tissue engineering and pave the way for enhancing the therapeutic outcomes of MSC therapies. The insights gained from this review will contribute to the development of more effective strategies to protect transplanted MSCs from immune rejection and enable their successful application in regenerative medicine.
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Affiliation(s)
- Rongbai Ju
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinhui Gao
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chi Zhang
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wei Tang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Min He
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
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5
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Tai Z, Liu J, Wang B, Chen S, Liu C, Chen X. The Effect of Aligned and Random Electrospun Fibers Derived from Porcine Decellularized ECM on Mesenchymal Stem Cell-Based Treatments for Spinal Cord Injury. Bioengineering (Basel) 2024; 11:772. [PMID: 39199730 PMCID: PMC11351159 DOI: 10.3390/bioengineering11080772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 09/01/2024] Open
Abstract
The impact of traumatic spinal cord injury (SCI) can be extremely devastating, as it often results in the disruption of neural tissues, impeding the regenerative capacity of the central nervous system. However, recent research has demonstrated that mesenchymal stem cells (MSCs) possess the capacity for multi-differentiation and have a proven track record of safety in clinical applications, thus rendering them effective in facilitating the repair of spinal cord injuries. It is urgent to develop an aligned scaffold that can effectively load MSCs for promoting cell aligned proliferation and differentiation. In this study, we prepared an aligned nanofiber scaffold using the porcine decellularized spinal cord matrix (DSC) to induce MSCs differentiation for spinal cord injury. The decellularization method removed 87% of the immune components while retaining crucial proteins in DSC. The electrospinning technique was employed to fabricate an aligned nanofiber scaffold possessing biocompatibility and a diameter of 720 nm. In in vitro and in vivo experiments, the aligned nanofiber scaffold induces the aligned growth of MSCs and promotes their differentiation into neurons, leading to tissue regeneration and nerve repair after spinal cord injury. The approach exhibits promising potential for the future development of nerve regeneration scaffolds for spinal cord injury treatment.
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Affiliation(s)
| | | | | | | | | | - Xi Chen
- Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomaterials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China; (Z.T.); (C.L.)
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6
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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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Cheng HY, Anggelia MR, Liu SC, Lin CF, Lin CH. Enhancing Immunomodulatory Function of Mesenchymal Stromal Cells by Hydrogel Encapsulation. Cells 2024; 13:210. [PMID: 38334602 PMCID: PMC10854565 DOI: 10.3390/cells13030210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 02/10/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) showcase remarkable immunoregulatory capabilities in vitro, positioning them as promising candidates for cellular therapeutics. However, the process of administering MSCs and the dynamic in vivo environment may impact the cell-cell and cell-matrix interactions of MSCs, consequently influencing their survival, engraftment, and their immunomodulatory efficacy. Addressing these concerns, hydrogel encapsulation emerges as a promising solution to enhance the therapeutic effectiveness of MSCs in vivo. Hydrogel, a highly flexible crosslinked hydrophilic polymer with a substantial water content, serves as a versatile platform for MSC encapsulation. Demonstrating improved engraftment and heightened immunomodulatory functions in vivo, MSCs encapsulated by hydrogel are at the forefront of advancing therapeutic outcomes. This review delves into current advancements in the field, with a focus on tuning various hydrogel parameters to elucidate mechanistic insights and elevate functional outcomes. Explored parameters encompass hydrogel composition, involving monomer type, functional modification, and co-encapsulation, along with biomechanical and physical properties like stiffness, viscoelasticity, topology, and porosity. The impact of these parameters on MSC behaviors and immunomodulatory functions is examined. Additionally, we discuss potential future research directions, aiming to kindle sustained interest in the exploration of hydrogel-encapsulated MSCs in the realm of immunomodulation.
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Affiliation(s)
- Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (M.R.A.)
| | - Madonna Rica Anggelia
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (M.R.A.)
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Shiao-Chin Liu
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (M.R.A.)
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chih-Fan Lin
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (M.R.A.)
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (M.R.A.)
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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Liu W, Hao M, Xu Y, Ren X, Hu J, Wang L, Chen X, Lv Q. Exploration of eMSCs with HA-GEL system in repairing damaged endometrium after endometrial cancer with fertility-sparing treatment. Cell Tissue Res 2023; 394:379-392. [PMID: 37759141 DOI: 10.1007/s00441-023-03831-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 08/28/2023] [Indexed: 09/29/2023]
Abstract
Despite the high complete response rate of fertility-sparing treatment in early-stage endometrial cancer (EC), the low pregnancy rate is a clinical challenge. Whether endometrium-derived mesenchymal stem cells (eMSCs) can repair damaged endometrium after EC reversal remains unclear. This study explored the potential therapeutic effects of eMSCs with suitable scaffold materials on endometrial damage caused by EC. Here, appropriate engineering scaffold materials were compared to identify the most suitable materials to carry eMSCs. Then, safety and efficacy evaluations of eMSCs with a suitable hyaluronic acid hydrogel (eMSCs/HA-GEL) were investigated in in vivo experiments with subcutaneous xenotransplantation in Balb/C nude mice and a model of endometrial mechanical injury in rats. HA-GEL has minimal cytotoxicity to eMSCs compared to other materials. Then, in vitro experiments demonstrate that eMSCs/HA-GEL enhance the inhibitory effects of progestins on EC cell biological behaviors. eMSCs/HA-GEL significantly inhibit EC cell growth and have no potential safety hazards of spontaneous tumorigenesis in Balb/C nude mouse subcutaneous xenotransplantation assays. eMSCs/HA-GEL intrauterine transplantation effectively increases endometrial thickness and glandular number, improves endometrial blood supply, reduces fibrotic areas, and improves pregnancy rates in a rat endometrial mechanical injury model. GFP-eMSCs/HA-GEL intrauterine transplantation in rats shows more GFP-eMSCs in the endometrium than GFP-eMSCs transplantation alone, and no tumor formation or suspicious cell nodules are found in the liver, kidney, or lung tissues. Our results reveal the safety and efficacy of eMSCs/HA-GEL in animal models and provide preliminary evidence for the use of eMSCs/HA-GEL as a treatment for EC-related endometrial damage.
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Affiliation(s)
- Wei Liu
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Mengxin Hao
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Yuhui Xu
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Xiaojun Ren
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Jiali Hu
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Lulu Wang
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Xiaojun Chen
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
| | - Qiaoying Lv
- Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
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Kim OH, Jeon TJ, So YI, Shin YK, Lee HJ. Applications of Bioinspired Platforms for Enhancing Immunomodulatory Function of Mesenchymal Stromal Cells. Int J Stem Cells 2023; 16:251-259. [PMID: 37385634 PMCID: PMC10465339 DOI: 10.15283/ijsc22211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 07/01/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have attracted scientific and medical interest due to their self-renewing properties, pluripotency, and paracrine function. However, one of the main limitations to the clinical application of MSCs is their loss of efficacy after transplantation in vivo. Various bioengineering technologies to provide stem cell niche-like conditions have the potential to overcome this limitation. Here, focusing on the stem cell niche microenvironment, studies to maximize the immunomodulatory potential of MSCs by controlling biomechanical stimuli, including shear stress, hydrostatic pressure, stretch, and biophysical cues, such as extracellular matrix mimetic substrates, are discussed. The application of biomechanical forces or biophysical cues to the stem cell microenvironment will be beneficial for enhancing the immunomodulatory function of MSCs during cultivation and overcoming the current limitations of MSC therapy.
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Affiliation(s)
- Ok-Hyeon Kim
- Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Tae Jin Jeon
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Korea
| | - Young In So
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Korea
| | - Yong Kyoo Shin
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Hyun Jung Lee
- Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Korea
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10
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Fadilah NIM, Riha SM, Mazlan Z, Wen APY, Hao LQ, Joseph B, Maarof M, Thomas S, Motta A, Fauzi MB. Functionalised-biomatrix for wound healing and cutaneous regeneration: future impactful medical products in clinical translation and precision medicine. Front Bioeng Biotechnol 2023; 11:1160577. [PMID: 37292094 PMCID: PMC10245056 DOI: 10.3389/fbioe.2023.1160577] [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: 02/07/2023] [Accepted: 05/08/2023] [Indexed: 06/10/2023] Open
Abstract
Skin tissue engineering possesses great promise in providing successful wound injury and tissue loss treatments that current methods cannot treat or achieve a satisfactory clinical outcome. A major field direction is exploring bioscaffolds with multifunctional properties to enhance biological performance and expedite complex skin tissue regeneration. Multifunctional bioscaffolds are three-dimensional (3D) constructs manufactured from natural and synthetic biomaterials using cutting-edge tissue fabrication techniques incorporated with cells, growth factors, secretomes, antibacterial compounds, and bioactive molecules. It offers a physical, chemical, and biological environment with a biomimetic framework to direct cells toward higher-order tissue regeneration during wound healing. Multifunctional bioscaffolds are a promising possibility for skin regeneration because of the variety of structures they provide and the capacity to customise the chemistry of their surfaces, which allows for the regulated distribution of bioactive chemicals or cells. Meanwhile, the current gap is through advanced fabrication techniques such as computational designing, electrospinning, and 3D bioprinting to fabricate multifunctional scaffolds with long-term safety. This review stipulates the wound healing processes used by commercially available engineered skin replacements (ESS), highlighting the demand for a multifunctional, and next-generation ESS replacement as the goals and significance study in tissue engineering and regenerative medicine (TERM). This work also scrutinise the use of multifunctional bioscaffolds in wound healing applications, demonstrating successful biological performance in the in vitro and in vivo animal models. Further, we also provided a comprehensive review in requiring new viewpoints and technological innovations for the clinical application of multifunctional bioscaffolds for wound healing that have been found in the literature in the last 5 years.
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Affiliation(s)
- Nur Izzah Md Fadilah
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Shaima Maliha Riha
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Zawani Mazlan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Adzim Poh Yuen Wen
- Department of Surgery, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Looi Qi Hao
- My Cytohealth Sdn Bhd Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Blessy Joseph
- Business Innovation and Incubation Centre, Mahatma Gandhi University, Kottayam, Kerala, India
| | - Manira Maarof
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Sabu Thomas
- International and Inter University Centre for Nanosciences and Nanotechnology, Mahatma Gandhi University, Kottayam, Kerala, India
| | - Antonella Motta
- Department of Industrial Engineering, University of Trento, Trento, Italy
| | - Mh Busra Fauzi
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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12
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Nikolits I, Radwan S, Liebner F, Dietrich W, Egger D, Chariyev-Prinz F, Kasper C. Hydrogels from TEMPO-Oxidized Nanofibrillated Cellulose Support In Vitro Cultivation of Encapsulated Human Mesenchymal Stem Cells. ACS APPLIED BIO MATERIALS 2023; 6:543-551. [PMID: 36745634 PMCID: PMC9945099 DOI: 10.1021/acsabm.2c00854] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) are the most prominent type of adult stem cells for clinical applications. Three-dimensional (3D) cultivation of MSCs in biomimetic hydrogels provides a more physiologically relevant cultivation microenvironment for in vitro testing and modeling, thus overcoming the limitations of traditional planar cultivation methods. Cellulose nanofibers are an excellent candidate biomaterial for synthesis of hydrogels for this application, due to their biocompatibility, tunable properties, availability, and low cost. Herein, we demonstrate the capacity of hydrogels prepared from 2,2,6,6-tetramethylpiperidine-1-oxyl -oxidized and subsequently individualized cellulose-nanofibrils to support physiologically relevant 3D in vitro cultivation of human MSCs at low solid contents (0.2-0.5 wt %). Our results show that MSCs can spread, proliferate, and migrate inside the cellulose hydrogels, while the metabolic activity and proliferative capacity of the cells as well as their morphological characteristics benefit more in the lower bulk cellulose concentration hydrogels.
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Affiliation(s)
- Ilias Nikolits
- Institute
of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences
BOKU Vienna, Muthgasse 18, 1190 Vienna, Austria
| | - Sara Radwan
- Department
of Life Science Engineering, University
of Applied Sciences Technikum Vienna, Höchstädtplatz 6, 1200 Vienna, Austria
| | - Falk Liebner
- Institute
of Chemistry of Renewable Resources, Department of Chemistry, University of Natural Resources and Life Sciences
BOKU Vienna, Konrad Lorenz Straße 24, 3430 Tulln, Austria
| | - Wolf Dietrich
- Department
of Gynecology and Obstetrics, Karl Landsteiner
University of Health Sciences, Alter Ziegelweg 10, 3430 Tulln, Austria
| | - Dominik Egger
- Institute
of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences
BOKU Vienna, Muthgasse 18, 1190 Vienna, Austria
| | - Farhad Chariyev-Prinz
- Institute
of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences
BOKU Vienna, Muthgasse 18, 1190 Vienna, Austria
| | - Cornelia Kasper
- Institute
of Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences
BOKU Vienna, Muthgasse 18, 1190 Vienna, Austria,
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13
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Immunomodulating Hydrogels as Stealth Platform for Drug Delivery Applications. Pharmaceutics 2022; 14:pharmaceutics14102244. [PMID: 36297679 PMCID: PMC9610165 DOI: 10.3390/pharmaceutics14102244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/23/2022] [Accepted: 10/05/2022] [Indexed: 11/23/2022] Open
Abstract
Non-targeted persistent immune activation or suppression by different drug delivery platforms can cause adverse and chronic physiological effects including cancer and arthritis. Therefore, non-toxic materials that do not trigger an immunogenic response during delivery are crucial for safe and effective in vivo treatment. Hydrogels are excellent candidates that can be engineered to control immune responses by modulating biomolecule release/adsorption, improving regeneration of lymphoid tissues, and enhancing function during antigen presentation. This review discusses the aspects of hydrogel-based systems used as drug delivery platforms for various diseases. A detailed investigation on different immunomodulation strategies for various delivery options and deliberate upon the outlook of such drug delivery platforms are conducted.
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14
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Tendon 3D Scaffolds Establish a Tailored Microenvironment Instructing Paracrine Mediated Regenerative Amniotic Epithelial Stem Cells Potential. Biomedicines 2022; 10:biomedicines10102578. [PMID: 36289840 PMCID: PMC9599634 DOI: 10.3390/biomedicines10102578] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/06/2022] [Accepted: 10/12/2022] [Indexed: 11/28/2022] Open
Abstract
Tendon tissue engineering aims to develop effective implantable scaffolds, with ideally the native tissue’s characteristics, able to drive tissue regeneration. This research focused on fabricating tendon-like PLGA 3D biomimetic scaffolds with highly aligned fibers and verifying their influence on the biological potential of amniotic epithelial stem cells (AECs), in terms of tenodifferentiation and immunomodulation, with respect to fleeces. The produced 3D scaffolds better resemble native tendon tissue, both macroscopically, microscopically, and biomechanically. From a biological point of view, these constructs were able to instruct AECs genotypically and phenotypically. In fact, cells engineered on 3D scaffolds acquired an elongated tenocyte-like morphology; this was different from control AECs, which retained their polygonal morphology. The boosted AECs tenodifferentiation by 3D scaffolds was confirmed by the upregulation of tendon-related genes (SCX, COL1 and TNMD) and TNMD protein expression. The produced constructs also prompted AECs’ immunomodulatory potential, both at the gene and paracrine level. This enhanced immunomodulatory profile was confirmed by a greater stimulatory effect on THP-1-activated macrophages. These biological effects have been related to the mechanotransducer YAP activation evidenced by its nuclear translocation. Overall, these results support the biomimicry of PLGA 3D scaffolds, revealing that not only fiber alignment but also scaffold topology provide an in vitro favorable tenodifferentiative and immunomodulatory microenvironment for AECs that could potentially stimulate tendon regeneration.
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15
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Abstract
The efficacy of implanted biomaterials is largely dependent on the response of the host's immune and stromal cells. Severe foreign body response (FBR) can impede the integration of the implant into the host tissue and compromise the intended mechanical and biochemical function. Many features of FBR, including late-stage fibrotic encapsulation of implants, parallel the formation of fibrotic scar tissue after tissue injury. Regenerative organisms like zebrafish and salamanders can avoid fibrosis after injury entirely, but FBR in these research organisms is rarely investigated because their immune competence is much lower than humans. The recent characterization of a regenerative mammal, the spiny mouse (Acomys), has inspired us to take a closer look at cellular regulation in regenerative organisms across the animal kingdom for insights into avoiding FBR in humans. Here, we highlight how major features of regeneration, such as blastema formation, macrophage polarization, and matrix composition, can be modulated across a range of regenerative research organisms to elucidate common features that may be harnessed to minimize FBR. Leveraging a deeper understanding of regenerative biology for biomaterial design may help to reduce FBR and improve device integration and performance.
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Affiliation(s)
- Sunaina Sapru
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, Florida 32611, United States
| | - Michele N Dill
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida 32611, United States
| | - Chelsey S Simmons
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, Florida 32611, United States.,J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida 32611, United States
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16
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Patrick MD, Annamalai RT. Licensing microgels prolong the immunomodulatory phenotype of mesenchymal stromal cells. Front Immunol 2022; 13:987032. [PMID: 36059508 PMCID: PMC9433901 DOI: 10.3389/fimmu.2022.987032] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSC) are sensors of inflammation, and they exert immunomodulatory properties through the secretion of cytokines and exosomes and direct cell-cell interactions. MSC are routinely used in clinical trials and effectively resolve inflammatory conditions. Nevertheless, inconsistent clinical outcomes necessitate the need for more robust therapeutic phenotypes. The immunomodulatory properties of MSC can be enhanced and protracted by priming (aka licensing) them with IFNγ and TNFα. Yet these enhanced properties rapidly diminish, and prolonged stimulation could tolerize their response. Hence a balanced approach is needed to enhance the therapeutic potential of the MSC for consistent clinical performance. Here, we investigated the concentration-dependent effects of IFNγ and TNFα and developed gelatin-based microgels to sustain a licensed MSC phenotype. We show that IFNγ treatment is more beneficial than TNFα in promoting an immunomodulatory MSC phenotype. We also show that the microgels possess integrin-binding sites to support adipose tissue-derived MSC (AD-MSC) attachment and a net positive charge to sequester the licensing cytokines electrostatically. Microgels are enzymatically degradable, and the rate is dependent on the enzyme concentration and matrix density. Our studies show that one milligram of microgels by dry mass can sequester up to 641 ± 81 ng of IFNγ. Upon enzymatic degradation, microgels exhibited a sustained release of IFNγ that linearly correlated with their degradation rate. The AD-MSC cultured on the IFNγ sequestered microgels displayed efficient licensing potential comparable to or exceeding the effects of bolus IFNγ treatment. When cultured with proinflammatory M1-like macrophages, the AD-MSC-seeded on licensing microgel showed an enhanced immunomodulatory potential compared to untreated AD-MSC and AD-MSC treated with bolus IFNγ treatment. Specifically, the AD-MSC seeded on licensing microgels significantly upregulated Arg1, Mrc1, and Igf1, and downregulated Tnfα in M1-like macrophages compared to other treatment conditions. These licensing microgels are a potent immunomodulatory approach that shows substantial promise in elevating the efficacy of current MSC therapies and may find utility in treating chronic inflammatory conditions.
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17
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Holkar K, Kale V, Ingavle G. Well-orchestrated physico-chemical and biological factors for enhanced secretion of osteogenic and angiogenic extracellular vesicles by mesenchymal stem cells in a 3D culture format. Biomater Sci 2022; 10:4458-4473. [PMID: 35815723 DOI: 10.1039/d2bm00750a] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The secretome of mesenchymal stem cells (MSCs) is being studied for its regenerative potential for the treatment of various disorders, including bone diseases. However, mimicking the physiological parameters of native bone could further improve MSCs' secretory profile. The proteomic analysis revealed that MSCs have a diverse secretory profile depending on the cell formats used to grow them, such as two-dimensional (2D) or three-dimensional (3D) microenvironments. Stem cells are given biochemical and biophysical stimuli in a 3D milieu that mimics in vivo situations. Compared to the gold standard monolayer culture, extracellular vesicles (EVs) released under 3D conditions improved the EV cargo numerically and qualitatively. The higher requirements of EVs in clinical trials with consistent therapeutic potential are challenging. This review discusses the impact of cell culture formats on the regenerative potential of MSCs, specifically in bone regeneration. The poor yield and heterogeneity issues have hampered the therapeutic usage of EVs. Therefore, this review further explores various engineering approaches that could enhance EVs' scalability from MSCs and their therapeutic effectiveness beyond their native utility in bone tissue regeneration. This review also highlights some of the upcoming 3D approaches/models that might be useful for the enhanced secretion of therapeutic EVs from stem cells. Finally, we discuss possible future directions and conclusions in this domain.
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Affiliation(s)
- Ketki Holkar
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis International (Deemed University), Pune 412115, India. .,Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune 412115, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis International (Deemed University), Pune 412115, India. .,Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune 412115, India
| | - Ganesh Ingavle
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis International (Deemed University), Pune 412115, India. .,Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune 412115, India
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18
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Abstract
Human mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are important adult stem cells for regenerative medicine, largely due to their regenerative characteristics such as self-renewal, secretion of trophic factors, and the capability of inducing mesenchymal cell lineages. MSCs also possess homing and trophic properties modulating immune system, influencing microenvironment around damaged tissues and enhancing tissue repair, thus offering a broad perspective in cell-based therapies. Therefore, it is not surprising that MSCs have been the broadly used adult stem cells in clinical trials. To gain better insights into the current applications of MSCs in clinical applications, we perform a comprehensive review of reported data of MSCs clinical trials conducted globally. We summarize the biological effects and mechanisms of action of MSCs, elucidating recent clinical trials phases and findings, highlighting therapeutic effects of MSCs in several representative diseases, including neurological, musculoskeletal diseases and most recent Coronavirus infectious disease. Finally, we also highlight the challenges faced by many clinical trials and propose potential solutions to streamline the use of MSCs in routine clinical applications and regenerative medicine.
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19
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McKinney JM, Pucha KA, Doan TN, Wang L, Weinstock LD, Tignor BT, Fowle KL, Levit RD, Wood LB, Willett NJ. Sodium alginate microencapsulation of human mesenchymal stromal cells modulates paracrine signaling response and enhances efficacy for treatment of established osteoarthritis. Acta Biomater 2022; 141:315-332. [PMID: 34979327 PMCID: PMC11898789 DOI: 10.1016/j.actbio.2021.12.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 01/15/2023]
Abstract
Mesenchymal stromal cells (MSCs) have shown promise as osteoarthritis (OA) treatments; however, effective translation has been limited by high variability and heterogeneity of MSCs, suboptimal delivery strategies, and poor understanding of critical quality and potency attributes. Furthermore, most pre-clinical studies of MSC therapeutics for OA have focused on delaying OA development and not on treating established OA, which brings added clinical relevance. Thus, the objective of the current study was to assess the effects of sodium alginate microencapsulation on human MSC (hMSC) secretion of immunomodulatory cytokines in an OA microenvironment and therapeutic efficacy in treating established OA. A Medial Meniscal Transection (MMT) pre-clinical model of OA was implemented. Three weeks post-surgery, after OA was established, intra-articular injections of encapsulated hMSCs or nonencapsulated hMSCs were administered. Six weeks post-surgery, microstructural changes in the knee joint were quantified using microCT. Encapsulated hMSCs reduced articular cartilage degeneration and subchondral bone remodeling. A multiplexed immunoassay panel was used to profile the in vitro secretome of hMSCs in response to IL-1β. Nonencapsulated hMSCs showed an indiscriminate increase in all cytokines in response to IL-1β while encapsulated hMSCs showed a targeted secretory response with increased expression of pro-inflammatory (IL-1β, IL-6, IL-7, IL-8), anti-inflammatory (IL-1RA), and chemotactic (G-CSF, MDC, IP10) cytokines. These data show that sodium alginate microencapsulation can modulate hMSC paracrine signaling and enhance the therapeutic efficacy of the hMSCs in treating established OA. This cytokine profile provides a foundation for the identification of key factors affecting the overall potency of hMSC therapeutics for OA. STATEMENT OF SIGNIFICANCE: While there has been considerable interest in material based MSC encapsulation for treatment of OA, there are critical gaps in our translational understanding of these biomaterial-based technologies for OA. More specifically, previous studies have several important limitations: (1) they have been largely focused on preventing OA development, which limits their translational utility and (2) little prior work has been done to delineate potential routes/mechanisms by which material encapsulation alters MSC therapeutic action. In our manuscript, we aimed to fill these gaps in knowledge by testing the hypotheses that: (1) hMSC encapsulation can attenuate established disease progression, which is a more clinically relevant scenario and (2) hMSC encapsulation significantly changes the secreted paracrine factors from hMSCs.
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Affiliation(s)
- Jay M McKinney
- Research Division, VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Department of Orthopaedics, Emory University, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA
| | - Krishna A Pucha
- Research Division, VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA
| | - Thanh N Doan
- Research Division, VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Department of Orthopaedics, Emory University, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303, USA
| | - Lanfang Wang
- Department of Medicine, Division of Cardiology, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
| | - Laura D Weinstock
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA
| | - Benjamin T Tignor
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA
| | - Kelsey L Fowle
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA
| | - Rebecca D Levit
- Department of Medicine, Division of Cardiology, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA
| | - Levi B Wood
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, North Ave NW, Atlanta, GA 30332, USA.
| | - Nick J Willett
- Research Division, VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Department of Orthopaedics, Emory University, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; Phil and Penny Knight Campus for Accelerating Scientific Impact, 6231 University of Oregon, Eugene, Oregon, USA.
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20
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Yang Y, Chu C, Xiao W, Liu L, Man Y, Lin J, Qu Y. Strategies for advanced particulate bone substitutes regulating the osteo-immune microenvironment. Biomed Mater 2022; 17. [PMID: 35168224 DOI: 10.1088/1748-605x/ac5572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 02/15/2022] [Indexed: 02/05/2023]
Abstract
The usage of bone substitute granule materials has improved the clinical results of alveolar bone deficiencies treatment and thus broadened applications in implant dentistry. However, because of the complicated mechanisms controlling the foreign body response, no perfect solution can avoid the fibrotic encapsulation of materials till now, which may impair the results of bone regeneration, even cause the implant materials rejection. Recently, the concept of 'osteoimmunology' has been stressed. The outcomes of bone regeneration are proved to be related to the bio-physicochemical properties of biomaterials, which allow them to regulate the biological behaviours of both innate and adaptive immune cells. With the development of single cell transcriptome, the truly heterogeneity of osteo-immune cells has been clarifying, which is helpful to overcome the limitations of traditional M1/M2 macrophage nomenclature and drive the advancements of particulate biomaterials applications. This review aims at introducing the mechanisms of optimal osseointegration regulated by immune systems and provides feasible strategies for the design of next generation 'osteoimmune-smart' particulate bone substitute materials in dental clinic.
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Affiliation(s)
- Yang Yang
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Chenyu Chu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Wenlan Xiao
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Li Liu
- State Key Laboratory of Biotherapy and Laboratory, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yi Man
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Jie Lin
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yili Qu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
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21
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Fibrin, Bone Marrow Cells and Macrophages Interactively Modulate Cardiomyoblast Fate. Biomedicines 2022; 10:biomedicines10030527. [PMID: 35327330 PMCID: PMC8945703 DOI: 10.3390/biomedicines10030527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/17/2022] [Accepted: 02/19/2022] [Indexed: 02/05/2023] Open
Abstract
Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). We hypothesized that cell-based treatments might modulate these interactions. After validating that bone marrow cells (BMC) associated with fibrin lowered the infarct extent and improved cardiac function, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation. In vitro, BMC were primed with fibrin (F-BMC). RT-PCR and proteomic analyses showed that fibrin profoundly influenced the gene expression and the secretome of BMCs. Consequently, the secretome of F-BMC increased the spreading of cardiomyoblasts and showed an alleviated immunomodulatory capacity. Indeed, the proliferation of anti-inflammatory macrophages was augmented, and the phenotype of pro-inflammatory switched as shown by downregulated Nos2, Il6 and IL1b and upregulated Arg1, CD163, Tgfb and IL10. Interestingly, the secretome of F-BMC educated-macrophages stimulated the incorporation of EdU in cardiomyoblasts. In conclusion, our study provides evidence that BMC/fibrin-based treatment improved cardiac structure and function following MI. In vitro proofs-of-concept reveal that the F-BMC secretome increases cardiac cell size and promotes an anti-inflammatory response. Thenceforward, the F-BMC educated macrophages sequentially stimulated cardiac cell proliferation.
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22
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Alvites R, Branquinho M, Sousa AC, Lopes B, Sousa P, Maurício AC. Mesenchymal Stem/Stromal Cells and Their Paracrine Activity-Immunomodulation Mechanisms and How to Influence the Therapeutic Potential. Pharmaceutics 2022; 14:381. [PMID: 35214113 PMCID: PMC8875256 DOI: 10.3390/pharmaceutics14020381] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration.
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Affiliation(s)
- Rui Alvites
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Mariana Branquinho
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana C. Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Bruna Lopes
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Patrícia Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana Colette Maurício
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
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23
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Rana N, Suliman S, Al-Sharabi N, Mustafa K. Extracellular Vesicles Derived from Primed Mesenchymal Stromal Cells Loaded on Biphasic Calcium Phosphate Biomaterial Exhibit Enhanced Macrophage Polarization. Cells 2022; 11:470. [PMID: 35159282 PMCID: PMC8834243 DOI: 10.3390/cells11030470] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stromal cells (MSC) loaded on biphasic calcium phosphate biomaterial (MSC + BCP) have been used as an advanced therapy medicinal product to treat complex maxillofacial bone defects in patients. Further, MSC-derived extracellular vesicles (EVs) are established vehicles of paracrine factors, supporting inter-cellular communication between MSC and other interacting cell types, such as monocytes/macrophages. However, the information about the immunomodulatory potential of EVs derived from MSC and biomaterial constructs (MSC + BCP:EV) and inflammatory primed constructs (MSCp + BCP:EV) are scarce. Hence, we isolated and characterized EVs from these different systems, and compared their cytokine contents with plastic-adherent MSC-derived EVs (MSC:EV). When EVs from all three MSC systems were added to the primary blood-derived macrophages in vitro, significantly higher numbers of M0 (naive) macrophages shifted to M2-like (anti-inflammatory) by MSCp + BCP:EV treatment. Further, this treatment led to enhanced switching of M1 polarized macrophages to M2 polarized, and conversely, M2 to M1, as evaluated by determining the M1/M2 ratios after treatment. The enhanced macrophage modulation by MSCp + BCP:EV was attributed to their higher immunomodulatory (TNFα, IL1β, IL5), angiogenic (VEGF), and chemokine-rich (RANTES, MCP1, MIP1β) cytokine cargo. In conclusion, we successfully isolated and characterized EVs from MSC + BCP constructs and demonstrated that, depending upon the tissue microenvironment, these EVs contribute towards modulating the macrophage-mediated inflammation and healing responses. The study offers new insights into the use of biomaterial-induced EVs for MSC secretome delivery, as a step towards future 'cell-free' bone regenerative therapies.
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Affiliation(s)
| | | | | | - Kamal Mustafa
- Center for Translational Oral Research (TOR), Tissue Engineering Group, Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway; (N.R.); (S.S.); (N.A.-S.)
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24
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Russo V, El Khatib M, Prencipe G, Cerveró-Varona A, Citeroni MR, Mauro A, Berardinelli P, Faydaver M, Haidar-Montes AA, Turriani M, Di Giacinto O, Raspa M, Scavizzi F, Bonaventura F, Liverani L, Boccaccini AR, Barboni B. Scaffold-Mediated Immunoengineering as Innovative Strategy for Tendon Regeneration. Cells 2022; 11:cells11020266. [PMID: 35053383 PMCID: PMC8773518 DOI: 10.3390/cells11020266] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
Tendon injuries are at the frontier of innovative approaches to public health concerns and sectoral policy objectives. Indeed, these injuries remain difficult to manage due to tendon’s poor healing ability ascribable to a hypo-cellularity and low vascularity, leading to the formation of a fibrotic tissue affecting its functionality. Tissue engineering represents a promising solution for the regeneration of damaged tendons with the aim to stimulate tissue regeneration or to produce functional implantable biomaterials. However, any technological advancement must take into consideration the role of the immune system in tissue regeneration and the potential of biomaterial scaffolds to control the immune signaling, creating a pro-regenerative environment. In this context, immunoengineering has emerged as a new discipline, developing innovative strategies for tendon injuries. It aims at designing scaffolds, in combination with engineered bioactive molecules and/or stem cells, able to modulate the interaction between the transplanted biomaterial-scaffold and the host tissue allowing a pro-regenerative immune response, therefore hindering fibrosis occurrence at the injury site and guiding tendon regeneration. Thus, this review is aimed at giving an overview on the role exerted from different tissue engineering actors in leading immunoregeneration by crosstalking with stem and immune cells to generate new paradigms in designing regenerative medicine approaches for tendon injuries.
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Affiliation(s)
- Valentina Russo
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
- Correspondence:
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Maria Rita Citeroni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Annunziata Mauro
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Paolo Berardinelli
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Melisa Faydaver
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Arlette A. Haidar-Montes
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Maura Turriani
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Marcello Raspa
- Institute of Biochemistry and Cellular Biology (IBBC), Council of National Research (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Ferdinando Scavizzi
- Institute of Biochemistry and Cellular Biology (IBBC), Council of National Research (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Fabrizio Bonaventura
- Institute of Biochemistry and Cellular Biology (IBBC), Council of National Research (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Liliana Liverani
- Department of Materials Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (L.L.); (A.R.B.)
| | - Aldo R. Boccaccini
- Department of Materials Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany; (L.L.); (A.R.B.)
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (A.C.-V.); (M.R.C.); (A.M.); (P.B.); (M.F.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
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Zhao Y, Wang M, Liang F, Li J. Recent strategies for enhancing the therapeutic efficacy of stem cells in wound healing. Stem Cell Res Ther 2021; 12:588. [PMID: 34823579 PMCID: PMC8614023 DOI: 10.1186/s13287-021-02657-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 11/03/2021] [Indexed: 01/09/2023] Open
Abstract
Skin wound healing is a multi-stage process that depends on the coordination of multiple cells and mediators. Chronic or non-healing wounds resulting from the dysregulation of this process represent a challenge for the healthcare system. For skin wound management, there are various approaches to tissue recovery. For decades, stem cell therapy has made outstanding achievements in wound regeneration. Three major types of stem cells, including embryonic stem cells, adult stem cells, and induced pluripotent stem cells, have been explored intensely. Mostly, mesenchymal stem cells are thought to be an extensive cell type for tissue repair. However, the limited cell efficacy and the underutilized therapeutic potential remain to be addressed. Exploring novel and advanced treatments to enhance stem cell efficacy is an urgent need. Diverse strategies are applied to maintain cell survival and increase cell functionality. In this study, we outline current approaches aiming to improve the beneficial outcomes of cell therapy to better grasp clinical cell transformation.
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Affiliation(s)
- Yongqing Zhao
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Min Wang
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Feng Liang
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, Jilin, China.
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26
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El Khatib M, Russo V, Prencipe G, Mauro A, Wyrwa R, Grimm G, Di Mattia M, Berardinelli P, Schnabelrauch M, Barboni B. Amniotic Epithelial Stem Cells Counteract Acidic Degradation By-Products of Electrospun PLGA Scaffold by Improving Their Immunomodulatory Profile In Vitro. Cells 2021; 10:cells10113221. [PMID: 34831443 PMCID: PMC8623927 DOI: 10.3390/cells10113221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/25/2022] Open
Abstract
Electrospun poly(lactic-co-glycolic acid) (PLGA) scaffolds with highly aligned fibers (ha-PLGA) represent promising materials in the field of tendon tissue engineering (TE) due to their characteristics in mimicking fibrous extracellular matrix (ECM) of tendon native tissue. Among these properties, scaffold biodegradability must be controlled allowing its replacement by a neo-formed native tendon tissue in a controlled manner. In this study, ha-PLGA were subjected to hydrolytic degradation up to 20 weeks, under di-H2O and PBS conditions according to ISO 10993-13:2010. These were then characterized for their physical, morphological, and mechanical features. In vitro cytotoxicity tests were conducted on ovine amniotic epithelial stem cells (oAECs), up to 7 days, to assess the effect of non-buffered and buffered PLGA by-products at different concentrations on cell viability and their stimuli on oAECs’ immunomodulatory properties. The ha-PLGA scaffolds degraded slowly as evidenced by a slight decrease in mass loss (14%) and average molecular weight (35%), with estimated degradation half-time of about 40 weeks under di-H2O. The ultrastructure morphology of the scaffolds showed no significant fiber degradation even after 20 weeks, but alteration of fiber alignment was already evident at week 1. Moreover, mechanical properties decreased throughout the degradation times under wet as well as dry PBS conditions. The influence of acid degradation media on oAECs was dose-dependent, with a considerable effect at 7 days’ culture point. This effect was notably reduced by using buffered media. To a certain level, cells were able to compensate the generated inflammation-like microenvironment by upregulating IL-10 gene expression and favoring an anti-inflammatory rather than pro-inflammatory response. These in vitro results are essential to better understand the degradation behavior of ha-PLGA in vivo and the effect of their degradation by-products on affecting cell performance. Indeed, buffering the degradation milieu could represent a promising strategy to balance scaffold degradation. These findings give good hope with reference to the in vivo condition characterized by physiological buffering systems.
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Affiliation(s)
- Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
| | - Giuseppe Prencipe
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
- Correspondence:
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
| | - Ralf Wyrwa
- Department of Biomaterials, INNOVENT e.V., 07745 Jena, Germany; (R.W.); (G.G.); (M.S.)
| | - Gabriele Grimm
- Department of Biomaterials, INNOVENT e.V., 07745 Jena, Germany; (R.W.); (G.G.); (M.S.)
| | - Miriam Di Mattia
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
| | - Paolo Berardinelli
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
| | | | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (V.R.); (A.M.); (M.D.M.); (P.B.); (B.B.)
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27
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Functional heterogeneity of IFN-γ-licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials. Proc Natl Acad Sci U S A 2021; 118:2105972118. [PMID: 34446555 DOI: 10.1073/pnas.2105972118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are increasingly combined with biomaterials to enhance their therapeutic properties, including their immunosuppressive function. However, clinical trials utilizing MSCs with or without biomaterials have shown limited success, potentially due to their functional heterogeneity across different donors and among different subpopulations of cells. Here, we evaluated the immunosuppressive capacity, as measured by the ability to reduce T-cell proliferation and activation, of interferon-gamma (IFN-γ)-licensed MSCs from multiple donors on fibrin and collagen hydrogels, the two most commonly utilized biomaterials in combination with MSCs in clinical trials worldwide according to ClinicalTrials.gov Variations in the immunosuppressive capacity between IFN-γ-licensed MSC donors on the biomaterials correlated with the magnitude of indoleamine-2,3-dioxygenase activity. Immunosuppressive capacity of the IFN-γ-licensed MSCs depended on the αV/α5 integrins when cultured on fibrin and on the α2/β1 integrins when cultured on collagen. While all tested MSCs were nearly 100% positive for these integrins, sorted MSCs that expressed higher levels of αV/α5 integrins demonstrated greater immunosuppressive capacity with IFN-γ licensing than MSCs that expressed lower levels of these integrins on fibrin. These findings were equivalent for MSCs sorted based on the α2/β1 integrins on collagen. These results demonstrate the importance of integrin engagement to IFN-γ licensed MSC immunosuppressive capacity and that IFN-γ-licensed MSC subpopulations of varying immunosuppressive capacity can be identified by the magnitude of integrin expression specific to each biomaterial.
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28
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Mesenchymal stem cells from biology to therapy. Emerg Top Life Sci 2021; 5:539-548. [PMID: 34355761 PMCID: PMC8639183 DOI: 10.1042/etls20200303] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/30/2021] [Accepted: 07/21/2021] [Indexed: 01/07/2023]
Abstract
Mesenchymal stem cells are as fascinating as they are enigmatic. They appear capable of performing a wide array of functions that cross skeletal biology, immunology and haematology. As therapeutics, mesenchymal stem cells or even just their secreted products may be used to regenerate tissue lost through injury or disease and suppress damaging immune reactions. However, these cells lack unique markers and are hard to identify and isolate as pure cell populations. They are often grown in laboratories using basic and undefined culture conditions. We cannot even agree on their name. While mesenchymal stem cells may lack the developmental understanding and defined differentiation hierarchies of their more illustrious stem cell cousins, they offer a compelling scientific challenge. In depth understanding of mesenchymal stem cell biology will enable us to exploit fully one of the most clinically valuable cell sources.
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29
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Kronstadt SM, Pottash AE, Levy D, Wang S, Chao W, Jay SM. Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment. ADVANCED THERAPEUTICS 2021; 4:2000259. [PMID: 34423113 PMCID: PMC8378673 DOI: 10.1002/adtp.202000259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Indexed: 12/14/2022]
Abstract
Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
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Affiliation(s)
- Stephanie M Kronstadt
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Alex E Pottash
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Daniel Levy
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Sheng Wang
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Steven M Jay
- Fischell Department of Bioengineering and Program in Molecular and, Cell Biology, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
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30
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Zhang K, Feng Q, Fang Z, Gu L, Bian L. Structurally Dynamic Hydrogels for Biomedical Applications: Pursuing a Fine Balance between Macroscopic Stability and Microscopic Dynamics. Chem Rev 2021; 121:11149-11193. [PMID: 34189903 DOI: 10.1021/acs.chemrev.1c00071] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Owing to their unique chemical and physical properties, hydrogels are attracting increasing attention in both basic and translational biomedical studies. Although the classical hydrogels with static networks have been widely reported for decades, a growing number of recent studies have shown that structurally dynamic hydrogels can better mimic the dynamics and functions of natural extracellular matrix (ECM) in soft tissues. These synthetic materials with defined compositions can recapitulate key chemical and biophysical properties of living tissues, providing an important means to understanding the mechanisms by which cells sense and remodel their surrounding microenvironments. This review begins with the overall expectation and design principles of dynamic hydrogels. We then highlight recent progress in the fabrication strategies of dynamic hydrogels including both degradation-dependent and degradation-independent approaches, followed by their unique properties and use in biomedical applications such as regenerative medicine, drug delivery, and 3D culture. Finally, challenges and emerging trends in the development and application of dynamic hydrogels are discussed.
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Affiliation(s)
- Kunyu Zhang
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.,Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Qian Feng
- Bioengineering College, Chongqing University, Chongqing 400044, People's Republic of China
| | - Zhiwei Fang
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.,Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Luo Gu
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.,Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Liming Bian
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, People's Republic of China.,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, People's Republic of China.,Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, People's Republic of China.,Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, People's Republic of China.,Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, People's Republic of China
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31
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Lian M, Sun B, Han Y, Yu B, Xin W, Xu R, Ni B, Jiang W, Hao Y, Zhang X, Shen Y, Qiao Z, Dai K. A low-temperature-printed hierarchical porous sponge-like scaffold that promotes cell-material interaction and modulates paracrine activity of MSCs for vascularized bone regeneration. Biomaterials 2021; 274:120841. [PMID: 33984633 DOI: 10.1016/j.biomaterials.2021.120841] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSCs) secrete paracrine trophic factors that are beneficial for tissue regeneration. In this study, a sponge-like scaffold with hierarchical and interconnected pores was developed using low-temperature deposition modeling (LDM) printing. Its effects on the cellular behavior, especially on the paracrine secretion patterns of MSCs, were comprehensively investigated. We found that compared with the scaffolds printed via the fused deposition modeling (FDM) technique, the LDM-printed sponges enhanced the adhesion, retention, survival, and ingrowth of MSCs and promoted cell-material interactions. Moreover, the paracrine functions of the cultured MSCs on the LDM-printed sponges were improved, with significant secretion of upregulated immunomodulatory, angiogenic, and osteogenic factors. MSCs on the LDM-printed sponges exert beneficial paracrine effects on multiple regenerative processes, including macrophage polarization, tube formation, and osteogenesis, verifying the enhanced immunomodulatory, angiogenic, and osteogenic potential. Further protein function assays indicated that focal adhesion kinase (FAK), downstream AKT, and yes-associated-protein (YAP) signaling might participate in the required mechanotransductive pathways, through which the hierarchical porous structures stimulated the paracrine effects of MSCs. In a rat distal femoral defect model, the MSC-laden LDM-printed sponges significantly promoted vascularized bone regeneration. The results of the present study demonstrate that the hierarchical porous biomimetic sponges prepared via LDM printing have potential applications in tissue engineering based on their cell-material interaction promotion and MSC paracrine function modulation effects. Furthermore, our findings suggest that the optimization of biomaterial properties to direct the paracrine signaling of MSCs would enhance tissue regeneration.
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Affiliation(s)
- Meifei Lian
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Prosthodontics, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Binbin Sun
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yu Han
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Bin Yu
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Weiwei Xin
- Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201112, China
| | - Ruida Xu
- Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201112, China
| | - Bing Ni
- School of Life Science, East China Normal University, Shanghai, 200241, China
| | - Wenbo Jiang
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yongqiang Hao
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Xiuyin Zhang
- Department of Prosthodontics, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yi Shen
- Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201112, China.
| | - Zhiguang Qiao
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201112, China.
| | - Kerong Dai
- Clinical and Translational Research Center for 3D Printing Technology, Medical 3D Printing Innovation Research Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China; Department of Orthopaedic Surgery, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
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Kim D, Lee AE, Xu Q, Zhang Q, Le AD. Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review. Front Immunol 2021; 12:667221. [PMID: 33936109 PMCID: PMC8085523 DOI: 10.3389/fimmu.2021.667221] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/30/2021] [Indexed: 12/15/2022] Open
Abstract
A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.
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Affiliation(s)
- Dane Kim
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Alisa E Lee
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Qilin Xu
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Qunzhou Zhang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Anh D Le
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, United States
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Towards Physiologic Culture Approaches to Improve Standard Cultivation of Mesenchymal Stem Cells. Cells 2021; 10:cells10040886. [PMID: 33924517 PMCID: PMC8069108 DOI: 10.3390/cells10040886] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are of great interest for their use in cell-based therapies due to their multipotent differentiation and immunomodulatory capacities. In consequence of limited numbers following their isolation from the donor tissue, MSCs require extensive expansion performed in traditional 2D cell culture setups to reach adequate amounts for therapeutic use. However, prolonged culture of MSCs in vitro has been shown to decrease their differentiation potential and alter their immunomodulatory properties. For that reason, preservation of these physiological characteristics of MSCs throughout their in vitro culture is essential for improving the efficiency of therapeutic and in vitro modeling applications. With this objective in mind, many studies already investigated certain parameters for enhancing current standard MSC culture protocols with regard to the effects of specific culture media components or culture conditions. Although there is a lot of diversity in the final therapeutic uses of the cells, the primary stage of standard isolation and expansion is imperative. Therefore, we want to review on approaches for optimizing standard MSC culture protocols during this essential primary step of in vitro expansion. The reviewed studies investigate and suggest improvements focused on culture media components (amino acids, ascorbic acid, glucose level, growth factors, lipids, platelet lysate, trace elements, serum, and xenogeneic components) as well as culture conditions and processes (hypoxia, cell seeding, and dissociation during passaging), in order to preserve the MSC phenotype and functionality during the primary phase of in vitro culture.
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Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22073397. [PMID: 33806241 PMCID: PMC8037333 DOI: 10.3390/ijms22073397] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been developed as cell therapeutics for various immune disorders using their immunoregulatory properties mainly exerted by their paracrine functions. However, variation among cells from different donors, as well as rapid clearance after transplantation have impaired the uniform efficacy of MSCs and limited their application. Recently, several strategies to overcome this limitation have been suggested and proven in pre-clinical settings. Therefore, in this review article, we will update the knowledge on bioengineering strategies to improve the immunomodulatory functions of MSCs, including genetic modification and physical engineering.
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Najar M, Martel-Pelletier J, Pelletier JP, Fahmi H. Novel insights for improving the therapeutic safety and efficiency of mesenchymal stromal cells. World J Stem Cells 2020; 12:1474-1491. [PMID: 33505596 PMCID: PMC7789128 DOI: 10.4252/wjsc.v12.i12.1474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/13/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have attracted great interest in the field of regenerative medicine. They can home to damaged tissue, where they can exert pro-regenerative and anti-inflammatory properties. These therapeutic effects involve the secretion of growth factors, cytokines, and chemokines. Moreover, the functions of MSCs could be mediated by extracellular vesicles (EVs) that shuttle various signaling messengers. Although preclinical studies and clinical trials have demonstrated promising therapeutic results, the efficiency and the safety of MSCs need to be improved. After transplantation, MSCs face harsh environmental conditions, which likely dampen their therapeutic efficacy. A possible strategy aiming to improve the survival and therapeutic functions of MSCs needs to be developed. The preconditioning of MSCs ex vivo would strength their capacities by preparing them to survive and to better function in this hostile environment. In this review, we will discuss several preconditioning approaches that may improve the therapeutic capacity of MSCs. As stated above, EVs can recapitulate the beneficial effects of MSCs and may help avoid many risks associated with cell transplantation. As a result, this novel type of cell-free therapy may be safer and more efficient than the whole cell product. We will, therefore, also discuss current knowledge regarding the therapeutic properties of MSC-derived EVs.
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Affiliation(s)
- Mehdi Najar
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada.
| | - Johanne Martel-Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Jean Pierre Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Hassan Fahmi
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
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Lech W, Sarnowska A, Kuczynska Z, Dabrowski F, Figiel-Dabrowska A, Domanska-Janik K, Buzanska L, Zychowicz M. Biomimetic microenvironmental preconditioning enhance neuroprotective properties of human mesenchymal stem cells derived from Wharton's Jelly (WJ-MSCs). Sci Rep 2020; 10:16946. [PMID: 33037314 PMCID: PMC7547118 DOI: 10.1038/s41598-020-74066-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Tuning stem cells microenvironment in vitro may influence their regenerative properties. In this study Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) were encapsulated in 3D hydrogels derived from human fibrin (FB) or platelet lysate (PL) and the oxygen level was adjusted to physiological normoxia (5% O2). The influence of the type of the scaffold and physiological normoxia conditions was tested on the WJ-MSCs' survivability, proliferation, migratory potential, the level of expression of selected trophic factors, cytokines, and neural markers. Encapsulated WJ-MSCs revealed high survivability, stable proliferation rate, and ability to migrate out of the hydrogel and the up-regulated expression of all tested factors, as well as the increased expression of neural differentiation markers. Physiological normoxia stimulated proliferation of encapsulated WJ-MSCs and significantly enhanced their neuronal, but not glial, differentiation. Ex vivo studies with indirect co-culture of organotypic hippocampal slices and cell-hydrogel bio-constructs revealed strong neuroprotective effect of WJ-MSCs against neuronal death in the CA1 region of the rat hippocampus. This effect was potentiated further by FB scaffolds under 5% O2 conditions. Our results indicating significant effect of oxygen and 3D cytoarchitecture suggest the urgent need for further optimization of the microenvironmental conditions to improve therapeutical competence of the WJ-MSCs population.
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Affiliation(s)
- Wioletta Lech
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Anna Sarnowska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland.,Translational Platform for Regenerative Medicine, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Zuzanna Kuczynska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Filip Dabrowski
- 1st Department of Obstetrics and Gynecology, Faculty of Medicine, Medical University of Warsaw, Starynkiewicza Square 1/3, 02-015, Warsaw, Poland
| | - Anna Figiel-Dabrowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Krystyna Domanska-Janik
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Leonora Buzanska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Marzena Zychowicz
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland.
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37
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Goodman SB, Lin T. Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches. Front Bioeng Biotechnol 2020; 8:641. [PMID: 32671040 PMCID: PMC7328340 DOI: 10.3389/fbioe.2020.00641] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022] Open
Abstract
Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.
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Affiliation(s)
- Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA, United States.,Department of Bioengineering, Stanford University, Stanford, CA, United States
| | - Tzuhua Lin
- Orthopaedic Research Laboratories, Stanford University, Stanford, CA, United States
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El Khatib M, Mauro A, Di Mattia M, Wyrwa R, Schweder M, Ancora M, Lazzaro F, Berardinelli P, Valbonetti L, Di Giacinto O, Polci A, Cammà C, Schnabelrauch M, Barboni B, Russo V. Electrospun PLGA Fiber Diameter and Alignment of Tendon Biomimetic Fleece Potentiate Tenogenic Differentiation and Immunomodulatory Function of Amniotic Epithelial Stem Cells. Cells 2020; 9:cells9051207. [PMID: 32413998 PMCID: PMC7290802 DOI: 10.3390/cells9051207] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022] Open
Abstract
Injured tendons are challenging in their regeneration; thus, tissue engineering represents a promising solution. This research tests the hypothesis that the response of amniotic epithelial stem cells (AECs) can be modulated by fiber diameter size of tendon biomimetic fleeces. Particularly, the effect of electrospun poly(lactide-co-glycolide) (PLGA) fleeces with highly aligned microfibers possessing two different diameter sizes (1.27 and 2.5 µm: ha1- and ha2-PLGA, respectively) was tested on the ability of AECs to differentiate towards the tenogenic lineage by analyzing tendon related markers (Collagen type I: COL1 protein and mRNA Scleraxis: SCX, Tenomodulin: TNMD and COL1 gene expressions) and to modulate their immunomodulatory properties by investigating the pro- (IL-6 and IL-12) and anti- (IL-4 and IL-10) inflammatory cytokines. It was observed that fiber alignment and not fiber size influenced cell morphology determining the morphological change of AECs from cuboidal to fusiform tenocyte-like shape. Instead, fleece mechanical properties, cell proliferation, tenogenic differentiation, and immunomodulation were regulated by changing the ha-PLGA microfiber diameter size. Specifically, higher DNA quantity and better penetration within the fleece were found on ha2-PLGA, while ha1-PLGA fleeces with small fiber diameter size had better mechanical features and were more effective on AECs trans-differentiation towards the tenogenic lineage by significantly translating more efficiently SCX into the downstream effector TNMD. Moreover, the fiber diameter of 1.27 µm induced higher expression of pro-regenerative, anti-inflammatory interleukins mRNA expression (IL-4 and IL-10) with favorable IL-12/IL-10 ratio with respect to the fiber diameter of 2.5 µm. The obtained results demonstrate that fiber diameter is a key factor to be considered when designing tendon biomimetic fleece for tissue repair and provide new insights into the importance of controlling matrix parameters in enhancing cell differentiation and immunomodulation either for the cells functionalized within or for the transplanted host tissue.
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Affiliation(s)
- Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
- Correspondence:
| | - Miriam Di Mattia
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Ralf Wyrwa
- Department of Biomaterials, INNOVENT e. V., 07745 Jena, Germany; (R.W.); (M.S.)
| | - Martina Schweder
- Department of Surface Engineering, INNOVENT e. V., 07745 Jena, Germany;
| | - Massimo Ancora
- Laboratory of Molecular Biology and Genomic, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy; (M.A.); (C.C.)
| | - Francesco Lazzaro
- Research & Development Department, Assut Europe S.p.A., Magliano dei Marsi, 67062 L’Aquila, Italy;
| | - Paolo Berardinelli
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Luca Valbonetti
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Andrea Polci
- Laboratory of Diagnosis and surveillance of foreign diseases, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy;
| | - Cesare Cammà
- Laboratory of Molecular Biology and Genomic, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy; (M.A.); (C.C.)
| | | | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (M.E.K.); (M.D.M.); (P.B.); (L.V.); (O.D.G.); (B.B.); (V.R.)
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He J, Chen G, Liu M, Xu Z, Chen H, Yang L, Lv Y. Scaffold strategies for modulating immune microenvironment during bone regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 108:110411. [PMID: 31923946 DOI: 10.1016/j.msec.2019.110411] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 10/21/2019] [Accepted: 11/07/2019] [Indexed: 12/18/2022]
Abstract
Implanted bone scaffolds often fail to successfully integrate with the host tissue because they do not elicit a favorable immune reaction. Properties of bone scaffold not only provide mechanical and chemical signals to support cell adhesion, migration, proliferation and differentiation, but also play a pivotal role in determining the extent of immune response during bone regeneration. Appropriate design parameters of bone scaffold are of great significance in the process of developing a new generation of bone implants. Herein, this article addresses the recent advances in the field of bone scaffolds for immune response, particularly focusing on the physical and chemical properties of bone scaffold in manipulating the host response. Furthermore, incorporation of bioactive molecules and cells with immunoregulatory function in bone scaffolds are also presented. Finally, continuing challenges and future directions of scaffold-based strategies for modulating immune microenvironment are discussed.
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Affiliation(s)
- Jianhua He
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
| | - Guobao Chen
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China
| | - Mengying Liu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China
| | - Zhiling Xu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
| | - Hua Chen
- College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, PR China.
| | - Li Yang
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
| | - Yonggang Lv
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
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