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Lei Z, Chen X, Chen K, Liu P, Ao M, Gan L, Yu L. Exosome-like vesicles encapsulated with specific microRNAs accelerate burn wound healing and ameliorate scarring. J Nanobiotechnology 2025; 23:264. [PMID: 40176075 PMCID: PMC11963272 DOI: 10.1186/s12951-025-03337-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/16/2025] [Indexed: 04/04/2025] Open
Abstract
Burn injuries are prevalent, yet effective treatments remain elusive. Exosomes derived from mesenchymal stem cells (MSC-Ex) possess remarkable pro-regenerative properties for wound healing. Despite their potential, the challenge of mass production limits their clinical application. To address this, preparing exosome-like vesicles has become an international trend. In this study, 28 key microRNAs (miRNAs) with significant pro-proliferation, anti-inflammation, and anti-fibrosis functions were screened from MSC-Ex. These miRNAs were encapsulated into liposomes and then hybridized with extracellular vesicles derived from watermelon to create synthetic exosome-like vesicles. The fabricated vesicles exhibited similar particle size and zeta potential to MSC-Ex, demonstrating high serum stability and effectively resisting the degradation of miRNA by RNase. They were efficiently internalized by cells and enabled a high rate of lysosomal escape for miRNAs post cellular uptake, thereby effectively exerting their pro-proliferative, anti-inflammatory, and anti-fibrotic functions. Further experiments demonstrated that these vesicles efficiently accelerated burn wound healing and reduced scarring, with effects comparable to those of natural MSC-Ex. Based on these findings, the exosome-like vesicles fabricated in this study present a promising alternative to MSC-Ex in burn wound treatment.
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Affiliation(s)
- Zhiyong Lei
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hubei Engineering Research Center for Both Edible and Medicinal Resources, Wuhan, 430074, China
| | - Xiaojuan Chen
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hubei Engineering Research Center for Both Edible and Medicinal Resources, Wuhan, 430074, China
| | - Kezhuo Chen
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hubei Engineering Research Center for Both Edible and Medicinal Resources, Wuhan, 430074, China
| | - Pan Liu
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Mingzhang Ao
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Lu Gan
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Longjiang Yu
- Institute of Resource Biology and Biotechnology, Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
- Hubei Engineering Research Center for Both Edible and Medicinal Resources, Wuhan, 430074, China.
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Sadeghi M, Moghaddam A, Amiri AM, Charoghdoozi K, Mohammadi M, Dehnavi S, Orazizadeh M. Improving the Wound Healing Process: Pivotal role of Mesenchymal stromal/stem Cells and Immune Cells. Stem Cell Rev Rep 2025; 21:680-697. [PMID: 39921839 DOI: 10.1007/s12015-025-10849-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.
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Affiliation(s)
- Mahvash Sadeghi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Moghaddam
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Mohammad Amiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kianush Charoghdoozi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojgan Mohammadi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Orazizadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Ning J, Sah RK, Wang J. Coculture of mesenchymal stem cells and macrophage: A narrative review. J Pharmacol Exp Ther 2025; 392:103531. [PMID: 40154096 DOI: 10.1016/j.jpet.2025.103531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/24/2025] [Indexed: 04/01/2025] Open
Abstract
Stem cell transplantation is a promising treatment for repairing damaged tissues, but challenges like immune rejection and ethical concerns remain. Mesenchymal stem cells (MSCs) offer high differentiation potential and immune regulatory activity, showing promise in treating diseases such as gynecological, neurological, and kidney disorders. With scientific progress, MSC applications are overcoming traditional treatment limitations. In MSCs-macrophage coculture, MSCs transform macrophages into anti-inflammatory M2 macrophages, reducing inflammation, whereas macrophages enhance MSCs osteogenic differentiation. This coculture is vital for immune modulation and tissue repair, with models varying by contact type and dimensional arrangements. Factors such as coculture techniques and cell ratios influence outcomes. Benefits include improved heart function, wound healing, reduced lung inflammation, and accelerated bone repair. Challenges include optimizing coculture conditions. This study reviews the methodologies, factors, and mechanisms of MSC-macrophage coculture, providing a foundation for tissue engineering applications. SIGNIFICANCE STATEMENT: This review underlines the significant role of mesenchymal stem cell-macrophage coculture, providing a foundation for tissue engineering application.
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Affiliation(s)
- Jun Ning
- Department of General Gynecology II, Gynecology and Obstetrics Center, the First Hospital of Jilin University, Changchun, China
| | - Rajiv Kumar Sah
- Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas
| | - Jing Wang
- Department of Reproductive Medicine, Department of Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China.
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Zhang HA, Zhang BY, Tang HB. Effects of macrophages on the osteogenic differentiation of adipose tissue-derived stem cells in two-dimensional and three-dimensional cocultures. World J Stem Cells 2025; 17:99326. [DOI: 10.4252/wjsc.v17.i2.99326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Fracture is one of the most pervasive injuries in the musculoskeletal system, and there is a complex interaction between macrophages and adipose tissue-derived stem cells (ADSCs) in fracture healing. However, two-dimensional (2D) coculture of macrophages and ADSCs can not accurately mimic the in vivo cell microenvironment.
AIM To establish both 2D and 3D osteogenic coculture models to investigate the interaction between macrophages and ADSCs.
METHODS After obtaining ADSCs from surgery and inducing differentiation of the THP1 cell line, we established 2D and 3D osteogenic coculture models. To assess the level of osteogenic differentiation, we used alizarin red staining and measured the relative expression levels of osteogenic differentiation markers osteocalcin, Runt-related transcription factor 2, and alkaline phosphatase through polymerase chain reaction. Verification was conducted by analyzing the expression changes of N-cadherin and the activation of the Wnt/β-catenin signaling pathway using western blotting.
RESULTS In this study, it was discovered that macrophages in 3D culture inhibited osteogenic differentiation of ADSCs, contrary to the effect in 2D culture. This observation confirmed the significance of intricate intercellular connections in the 3D culture environment. Additionally, the 3D culture group exhibited significantly higher N-cadherin expression and showed reduced β-catenin and Wnt1 protein levels compared to the 2D culture group.
CONCLUSION Macrophages promoted ADSC osteogenic differentiation in 2D culture conditions but inhibited it in 3D culture. The 3D culture environment might inhibit the Wnt/β-catenin signaling pathway by upregulating N-cadherin expression, ultimately hindering the osteogenic differentiation of ADSCs. By investigating the process of osteogenesis in ADSCs, this study provides novel ideas for exploring 3D osteogenesis in ADSCs, fracture repair, and other bone trauma repair.
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Affiliation(s)
- He-Ao Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Bo-Yu Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hong-Bo Tang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Ilić V, Biočanin V, Antonijević Đ, Petrović B, Jokanović V, Ilić D, Danilović V, Japundžić-Žigon N, Paraš S, Milutinović J, Milutinović-Smiljanić S. The intensity of subacute local biological effects after the implantation of ALBO-OS dental material based on hydroxyapatite and poly(lactide-co-glycolide): in vivo evaluation in rats. BIOMED ENG-BIOMED TE 2024; 69:563-574. [PMID: 39001571 DOI: 10.1515/bmt-2023-0640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 06/24/2024] [Indexed: 12/01/2024]
Abstract
OBJECTIVES This study aimed to evaluate the intensity of the subacute local biological effects after implantation and osseoconductive potential of novel hydroxyapatite-based bone substitute coated with poly (lactide-co-glycolide), named ALBO-OS, in comparison to Bio-Oss®. METHODS Fifteen male Wistar rats, randomly assigned into groups: 10, 20, and 30 days (n꞊5), were subcutaneously implanted with ALBO-OS and Bio-Oss®. Furthermore, artificially made bone defects on both rat's tibias were implanted with experimental materials. Unimplanted defects represented negative control. After the animals' euthanizing, tissue samples were prepared and analyzed histologically and histomorphometrically. RESULTS Normal healing of the epithelial tissue was observed, with no signs of infection or necrosis. Minimal vascular congestion was noted immediately around the graft, with no signs of tissue oedema, with a minimal capsule thickness. The applied material did not cause an inflammatory response (IR) of significant intensity, and 20 days after implantation, the IR was mainly assessed as minimal. The tibial specimen showed that ALBO-OS has good osseoconductive potential, similar to Bio-Oss®, as well as low levels of acute and subacute inflammation. CONCLUSIONS The tested material exhibits satisfying biocompatibility, similar to Bio-Oss®.
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Affiliation(s)
- Veljko Ilić
- Department of General and Oral Histology and Embryology, School of Dental Medicine, University of Belgrade, Beograd, Serbia
| | - Vladimir Biočanin
- Faculty of Dentistry in Pančevo, University of Business Academy, Novi Sad, Serbia
| | - Đorđe Antonijević
- Department of Anatomy, School of Dental Medicine, University of Belgrade, Beograd, Serbia
| | - Božana Petrović
- Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Belgrade University, Belgrade, Serbia
| | | | - Dragan Ilić
- Department for Restorative Dentistry and Endodontics, School of Dental Medicine, University of Belgrade, Beograd, Serbia
| | - Vesna Danilović
- Department of General and Oral Histology and Embryology, School of Dental Medicine, University of Belgrade, Beograd, Serbia
| | - Nina Japundžić-Žigon
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Beograd, Serbia
| | - Smiljana Paraš
- Faculty of Natural Sciences and Mathematics, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
| | - Jovana Milutinović
- Faculty of Dentistry in Pančevo, University of Business Academy, Novi Sad, Serbia
| | - Sanja Milutinović-Smiljanić
- Department of General and Oral Histology and Embryology, School of Dental Medicine, University of Belgrade, Beograd, Serbia
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Yang J, Xiao L, Zhang L, Luo G, Ma Y, Wang X, Zhang Y. Platelets: A Potential Factor that Offers Strategies for Promoting Bone Regeneration. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:631-643. [PMID: 38482796 DOI: 10.1089/ten.teb.2024.0004] [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: 04/13/2024]
Abstract
Bone defects represent a prevalent category of clinical injuries, causing significant pain and escalating health care burdens. Effectively addressing bone defects is thus of paramount importance. Platelets, formed from megakaryocyte lysis, have emerged as pivotal players in bone tissue repair, inflammatory responses, and angiogenesis. Their intracellular storage of various growth factors, cytokines, and membrane protein receptors contributes to these crucial functions. This article provides a comprehensive overview of platelets' roles in hematoma structure, inflammatory responses, and angiogenesis throughout the process of fracture healing. Beyond their application in conjunction with artificial bone substitute materials for treating bone defects, we propose the potential future use of anticoagulants such as heparin in combination with these materials to regulate platelet number and function, thereby promoting bone healing. Ultimately, we contemplate whether manipulating platelet function to modulate bone healing could offer innovative ideas and directions for the clinical treatment of bone defects. Impact statement Given that 5-10% of fracture patients with delayed bone healing or even bone nonunion, this review explores the potential role of platelets in bone healing (directly/indirectly) and proposes ideas and directions for the future as to whether it is possible to promote bone healing and improve fracture healing rates by modulating platelets.
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Affiliation(s)
- Jingjing Yang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
- Guizhou Provincial Key Laboratory of Medicinal Biotechnology in Colleges and Universities, Zunyi Medical University, Zunyi, China
| | - Lan Xiao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- School of Medicine and Dentistry, Griffith University, Queensland, Australia
| | - Lijia Zhang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
| | - Guochen Luo
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Guizhou Provincial Key Laboratory of Medicinal Biotechnology in Colleges and Universities, Zunyi Medical University, Zunyi, China
| | - Yi Zhang
- Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, China
- Key Laboratory of Maternal and Child Health and Exposure Science of Guizhou Higher Education Institutes, Zunyi Medical University, Zunyi, China
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Song C, Liu Y, Tao X, Cheng K, Cai W, Zhou D, Zhou Y, Wang L, Shi H, Hao Q, Liu Z. Immunomodulation Pathogenesis and Treatment of Bone Nonunion. Orthop Surg 2024; 16:1770-1782. [PMID: 38946017 PMCID: PMC11293939 DOI: 10.1111/os.14131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 07/02/2024] Open
Abstract
Fractures and bone nonunion commonly require surgical intervention. Serious outcomes of non-healing in the late stages of fracture place a significant financial burden on society and families. Bone nonunion occurs when a fracture stops healing, for many reasons, and leads to a variety of bad outcomes. Numerous factors, including biomechanics and immunology, are involved in the complicated mechanisms of bone nonunion. The immune-inflammatory response plays a significant part in the emergence of bone nonunion, and the occurrence, control, and remission of inflammation in the bone healing process have a significant influence on the ultimate success of bone tissue repair. In the bone microenvironment, immune cells and associated cytokines control bone repair, which is significantly influenced by macrophages, T cells, and fibroblast growth factor. To limit acute inflammation and balance osteogenesis and osteoblastogenesis for tissue repair and regeneration, immune cells and various cytokines in the local microenvironment must be precisely regulated. As a bad complication of late-stage fractures, bone nonunion has a significant effect on patients' quality of life and socioeconomic development. Therefore, in-depth research on its pathogenesis and treatment methods has important clinical value. To provide more precise, focused therapeutic options for the treatment of bone nonunion, we discuss the regulatory roles of the key immune cells engaged in bone healing within the microenvironment during bone healing and their effect on osteogenesis.
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Affiliation(s)
- Chao Song
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Yong Liu
- Department of Bone and Joint Sports MedicineXingguo People's Hospital, Gannan Medical CollegeXingguoChina
| | - Xingxing Tao
- College of Integrative Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Kang Cheng
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Weiye Cai
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Daqian Zhou
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Yang Zhou
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Liquan Wang
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Houyin Shi
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Qi Hao
- Orthopedic Surgery, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Zongchao Liu
- Department of Orthopedics and Traumatology (Trauma and Bone‐Setting), Laboratory of Integrated Chinese and Western Medicine for Orthopedic and Traumatic Diseases Prevention and Treatment, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
- Department of OrthopedicsLuzhou Longmatan District People's HospitalLuzhouChina
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Yang Y, He X, Zhao Z, Yi J. Macrophage-Centric Biomaterials for Bone Regeneration in Diabetes Mellitus: Contemporary Advancements, Challenges, and Future Trajectories. Cureus 2024; 16:e66621. [PMID: 39258053 PMCID: PMC11386247 DOI: 10.7759/cureus.66621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2024] [Indexed: 09/12/2024] Open
Abstract
Increased susceptibility to bone fragility and the diminution of bone regenerative capacity are recognized as significant and frequent sequelae of diabetes mellitus. Research has elucidated the pivotal role of macrophages in the pathogenesis and repair of diabetic bone defects. Notwithstanding this, the therapeutic efficacy of traditional interventions remains predominantly inadequate. Concomitant with substantial advancements in tissue engineering in recent epochs, there has been an escalation in the development of biomaterials designed to modulate macrophage activity, thereby augmenting osseous tissue regeneration in the context of hyperglycemia. This review amalgamates insights from extant research and delineates recent progressions in the domain of biomaterials that target macrophages for the regeneration of diabetic bone, whilst also addressing the clinical challenges and envisaging future directions within this field.
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Affiliation(s)
- Yiyan Yang
- Department of Orthodontics, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, CHN
| | - Xiaoli He
- Department of Orthodontics, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, CHN
| | - Zhihe Zhao
- Department of Orthodontics, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, CHN
| | - Jianru Yi
- Department of Orthodontics, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, CHN
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Jeffery EC. The role of hematopoiesis in bone repair: an update. Curr Opin Hematol 2024; 31:163-167. [PMID: 38723188 DOI: 10.1097/moh.0000000000000821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
PURPOSE OF REVIEW The repair of bone after injury requires the participation of many different immune cell populations, which are derived from the hematopoietic lineage. The field of osteoimmunology, or the study of the interactions between bone and the immune system, is a growing field with emerging impact on both the basic science and clinical aspects of fracture healing. RECENT FINDINGS Despite previous focus on the innate immune system in fracture healing, recent studies have revealed an important role for the adaptive immune system in bone repair. The composition of adaptive and innate immune cell populations present at the fracture site is significantly altered during aging and diet-induced obesity, which may contribute to delayed healing. Recent data also suggest a complicated relationship between fracture repair and systemic inflammation, raising the possibility that immune populations from distant sites such as the gut can impact the bone repair process. SUMMARY These findings have important implications for the treatment of fracture patients with antibiotics or anti-inflammatory drugs. Furthermore, the effects of systemic inflammation on fracture repair in the contexts of aging or obesity should be carefully interpreted, as they may not be uniformly detrimental.
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Affiliation(s)
- Elise C Jeffery
- Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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10
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Zhang H, Xiang L, Yuan H, Yu H. PTPRO inhibition ameliorates spinal cord injury through shifting microglial M1/M2 polarization via the NF-κB/STAT6 signaling pathway. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167141. [PMID: 38565385 DOI: 10.1016/j.bbadis.2024.167141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 04/04/2024]
Abstract
Spinal cord injury (SCI) induces severe neuroinflammation, and subsequently neurological dysfunction. Activated microglia are critical for modulation of neuroinflammation. Protein tyrosine phosphatase receptor type O (PTPRO), a member of protein tyrosine phosphatases (PTPs), exerts a pro-inflammatory role in multiple human diseases; however, its role in SCI remains unclarified. Here, a T7 spinal cord compression injury model was established in Sprague-Dawley (SD) rats, and PTPRO expression was upregulated in injured spinal cord and microglia after SCI. Microglia M1 and M2 polarization in vitro were induced using LPS/IFN-γ and IL-4, respectively. PTPRO expression was elevated in M1-polarized microglia, and PTPRO downregulation mediated by PTPRO shRNA (shPTPRO) decreased CD86+ cell proportion, iNOS, TNF-α, IL-1β, and IL-6 levels, and p65 phosphorylation. PTPRO was downregulated in M2 microglia, and PTPRO upregulation by PTPRO overexpression plasmid (OE-PTPRO) reduced CD206+ cell percentage, Arg-1, IL-10, and TGF-β1 levels and STAT6 phosphorylation. Mechanistically, the transcription factor SOX4 elevated PTPRO expression and its promoter activity. SOX4 overexpression enhanced M1 polarization and p65 phosphorylation, while its knockdown promoted M2 polarization and STAT6 phosphorylation. PTPRO might mediate the function of SOX4 in BV2 microglia polarization. Furthermore, lentivirus-mediated downregulation of PTPRO following SCI improved locomotor functional recovery, demonstrated by elevated BBB scores, incline angle, consistent hindlimb coordination, and reduced lesion area and neuronal apoptosis. PTPRO downregulation promoted microglia M2 polarization, NF-κB inactivation and STAT6 activation after injury. In conclusion, PTPRO inhibition improves spinal cord injury through facilitating M2 microglia polarization via the NF-κB/STAT6 signaling pathway, which is probably controlled by SOX4.
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Affiliation(s)
- Haocong Zhang
- Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China
| | - Liangbi Xiang
- Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China
| | - Hong Yuan
- Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China
| | - Hailong Yu
- Department of Orthopaedics, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China.
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Sun Y, Sheng R, Cao Z, Liu C, Li J, Zhang P, Du Y, Mo Q, Yao Q, Chen J, Zhang W. Bioactive fiber-reinforced hydrogel to tailor cell microenvironment for structural and functional regeneration of myotendinous junction. SCIENCE ADVANCES 2024; 10:eadm7164. [PMID: 38657071 PMCID: PMC11042749 DOI: 10.1126/sciadv.adm7164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/18/2024] [Indexed: 04/26/2024]
Abstract
Myotendinous junction (MTJ) injuries are prevalent in clinical practice, yet the treatment approaches are limited to surgical suturing and conservative therapy, exhibiting a high recurrence rate. Current research on MTJ tissue engineering is scarce and lacks in vivo evaluation of repair efficacy. Here, we developed a three-dimensional-printed bioactive fiber-reinforced hydrogel containing mesenchymal stem cells (MSCs) and Klotho for structural and functional MTJ regeneration. In a rat MTJ defect model, the bioactive fiber-reinforced hydrogel promoted the structural restoration of muscle, tendon, and muscle-tendon interface and enhanced the functional recovery of injured MTJ. In vivo proteomics and in vitro cell cultures elucidated the regenerative mechanisms of the bioactive fiber-reinforced hydrogel by modulating oxidative stress and inflammation, thus engineering an optimized microenvironment to support the survival and differentiation of transplanted MSCs and maintain the functional phenotype of resident cells within MTJ tissues, including tendon/muscle cells and macrophages. This strategy provides a promising treatment for MTJ injuries.
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Affiliation(s)
- Yuzhi Sun
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Renwang Sheng
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Zhicheng Cao
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Chuanquan Liu
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Jiaxiang Li
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Po Zhang
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Yan Du
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Qingyun Mo
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Qingqiang Yao
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310000 Hangzhou, China
| | - Jialin Chen
- School of Medicine, Southeast University, 210009 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310000 Hangzhou, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
| | - Wei Zhang
- School of Medicine, Southeast University, 210009 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310000 Hangzhou, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
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12
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Zhang FF, Hao Y, Zhang KX, Yang JJ, Zhao ZQ, Liu HJ, Li JT. Interplay between mesenchymal stem cells and macrophages: Promoting bone tissue repair. World J Stem Cells 2024; 16:375-388. [PMID: 38690513 PMCID: PMC11056637 DOI: 10.4252/wjsc.v16.i4.375] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.
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Affiliation(s)
- Fei-Fan Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yang Hao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Kuai-Xiang Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Jiang-Jia Yang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhi-Qiang Zhao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
| | - Hong-Jian Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ji-Tian Li
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
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13
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Liu X, Gao J, Liu J, Cheng J, Han Z, Li Z, Chang Z, Zhang L, Li M, Tang P. Three-Dimensional-Printed Spherical Hollow Structural Scaffolds for Guiding Critical-Sized Bone Regeneration. ACS Biomater Sci Eng 2024; 10:2581-2594. [PMID: 38489227 DOI: 10.1021/acsbiomaterials.3c01956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
The treatment of bone tissue defects continues to be a complex medical issue. Recently, three-dimensional (3D)-printed scaffold technology for bone tissue engineering (BTE) has emerged as an important therapeutic approach for bone defect repair. Despite the potential of BTE scaffolds to contribute to long-term bone reconstruction, there are certain challenges associated with it including the impediment of bone growth within the scaffolds and vascular infiltration. These difficulties can be resolved by using scaffold structural modification strategies that can effectively guide bone regeneration. This study involved the preparation of biphasic calcium phosphate spherical hollow structural scaffolds (SHSS) with varying pore sizes using 3D printing (photopolymerized via digital light processing). The chemical compositions, microscopic morphologies, mechanical properties, biocompatibilities, osteogenic properties, and impact on repairing critical-sized bone defects of SHSS were assessed through characterization analyses, in vitro cytological assays, and in vivo biological experiments. The results revealed the biomimetic properties of SHSS and their favorable biocompatibility. The scaffolds stimulated cell adhesion, proliferation, differentiation, and migration and facilitated the expression of osteogenic genes and proteins, including Col-1, OCN, and OPN. Furthermore, they could effectively repair a critical-sized bone defect in a rabbit femoral condyle by establishing an osteogenic platform and guiding bone regeneration in the defect region. This innovative strategy presents a novel therapeutic approach for assessing critical-sized bone defects.
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Affiliation(s)
- Xiao Liu
- Medical School of Chinese PLA, Beijing 100853, China
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Jianpeng Gao
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Jianheng Liu
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Junyao Cheng
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Zhenchuan Han
- Medical School of Chinese PLA, Beijing 100853, China
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Zijian Li
- Medical School of Chinese PLA, Beijing 100853, China
| | | | - Licheng Zhang
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Ming Li
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
| | - Peifu Tang
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing 100853, China
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14
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Liu X, Gao J, Liu J, Zhang L, Li M. Inhibiting the "isolated island" effect in simulated bone defect repair using a hollow structural scaffold design. Front Bioeng Biotechnol 2024; 12:1362913. [PMID: 38633663 PMCID: PMC11022659 DOI: 10.3389/fbioe.2024.1362913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
The treatment of bone tissue defects remains a complicated clinical challenge. Recently, the bone tissue engineering (BTE) technology has become an important therapeutic approach for bone defect repair. Researchers have improved the scaffolds, cells, and bioactive factors used in BTE through various existing bone repair material preparation strategies. However, due to insufficient vascularization, inadequate degradation, and fibrous wrapping, most BTE scaffolds impede new bone ingrowth and the reconstruction of grid-like connections in the middle and late stages of bone repair. These non-degradable scaffolds become isolated and disordered like independent "isolated islands", which leads to the failure of osteogenesis. Consequently, we hypothesized that the "island effect" prevents successful bone repair. Accordingly, we proposed a new concept of scaffold modification-osteogenesis requires a bone temporary shelter (also referred to as the empty shell osteogenesis concept). Based on this concept, we consider that designing hollow structural scaffolds is the key to mitigating the "isolated island" effect and enabling optimal bone regeneration and reconstruction.
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Affiliation(s)
- Xiao Liu
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China
| | - Jianpeng Gao
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China
| | - Jianheng Liu
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China
| | - Licheng Zhang
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China
| | - Ming Li
- Department of Orthopaedics, The Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China
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15
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Yan W, Xia Y, Zhao H, Xu X, Ma X, Tao L. Stem cell-based therapy in cardiac repair after myocardial infarction: Promise, challenges, and future directions. J Mol Cell Cardiol 2024; 188:1-14. [PMID: 38246086 DOI: 10.1016/j.yjmcc.2023.12.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/09/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024]
Abstract
Stem cells represent an attractive resource for cardiac regeneration. However, the survival and function of transplanted stem cells is poor and remains a major challenge for the development of effective therapies. As two main cell types currently under investigation in heart repair, mesenchymal stromal cells (MSCs) indirectly support endogenous regenerative capacities after transplantation, while induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) functionally integrate into the damaged myocardium and directly contribute to the restoration of its pump function. These two cell types are exposed to a common microenvironment with many stressors in ischemic heart tissue. This review summarizes the research progress on the mechanisms and challenges of MSCs and iPSC-CMs in post-MI heart repair, introduces several randomized clinical trials with 3D-mapping-guided cell therapy, and outlines recent findings related to the factors that affect the survival and function of stem cells. We also discuss the future directions for optimization such as biomaterial utilization, cell combinations, and intravenous injection of engineered nucleus-free MSCs.
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Affiliation(s)
- Wenjun Yan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yunlong Xia
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Huishou Zhao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xiaoming Xu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Xinliang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States of America
| | - Ling Tao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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16
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Pan Q, Zhang P, Xue F, Zhang J, Fan Z, Chang Z, Liang Z, Zhou G, Ren W. Subcutaneously Engineered Decalcified Bone Matrix Xenografts Promote Bone Repair by Regulating the Immune Microenvironment, Prevascularization, and Stem Cell Homing. ACS Biomater Sci Eng 2024; 10:515-524. [PMID: 38150512 DOI: 10.1021/acsbiomaterials.3c01331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Immunoregulatory and vascularized microenvironments play an important role in bone regeneration; however, the precise regulation for vascularization and inflammatory reactions remains elusive during bone repair. In this study, by means of subcutaneous preimplantation, we successfully constructed demineralized bone matrix (DBM) grafts with immunoregulatory and vascularized microenvironments. According to the current results, at the early time points (days 1 and 3), subcutaneously implanted DBM grafts recruited a large number of pro-inflammatory M1 macrophages with positive expression of CD68 and iNOS, while at the later time points (days 7 and 14), these inflammatory cells gradually subsided, accompanying increased presence of anti-inflammatory M2 macrophages with positive expression of CD206 and Arg-1, indicating a gradually enhanced anti-inflammatory microenvironment. At the same time, the gradually increased angiogenesis was observed in the DBM grafts with implantation time. In addition, the positive cells of CD105, CD73, and CD90 were observed in the inner region of the DBM grafts, implying the homing of mesenchymal stem cells. The repair results of cranial bone defects in a rat model further confirmed that the subcutaneous DBM xenografts at 7 days significantly improved bone regeneration. In summary, we developed a simple and novel strategy for bone regeneration mediated by anti-inflammatory microenvironment, prevascularization, and endogenous stem cell homing.
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Affiliation(s)
- Qingqing Pan
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Pei Zhang
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Fei Xue
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Jingxuan Zhang
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Zhenlin Fan
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Zhanyu Chang
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Zhuo Liang
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
| | - Guangdong Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Tissue Engineering, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Wenjie Ren
- Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang 453003, China
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17
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Liu Y, Han J, Fang J, Li R. The Beneficial Effects of Mesenchymal Stem Cells in Acute Kidney Injury: A Narrative Review. Curr Stem Cell Res Ther 2024; 19:200-209. [PMID: 36748221 PMCID: PMC10680085 DOI: 10.2174/1574888x18666230206115046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 02/08/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) is a multifaced disease characterized by a rapid decline in renal function. However, with growing insight into the pathophysiologic mechanisms of AKI, currently available interventions for AKI are merely supportive. Thus, novel therapies are urgently needed to improve the outcomes of patients with AKI. This narrative review aims to explore enhancing the beneficial effects of Mesenchymal Stem Cells(MSCs) in AKI. METHODS The authors examined all studies regarding the role of MSCs in AKI. And the authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. The most relevant and up-to-date research was included. RESULTS AND DISCUSSION Based on encouraging preclinical results, stem cell therapy has been widely explored over the last decade. Among the various stem cell types investigated, mesenchymal stem cells are being intensely investigated by virtue of their numerous strengths, such as easy derivation, undemanding cell culture conditions, anti-apoptosis, immunomodulation, and anti-inflammation effects. Mounting evidence suggests that MSCs hold great potential in accelerating kidney repair following AKI in various preclinical models. Unfortunately, low engrafting efficiency and poor survival rate of injected MSCs in the injured renal tissue are major obstacles MSCs clinical application faces. CONCLUSION Various strategies, including genetic manipulation, mimicking the cellular microenvironment with different culture conditions, optimizing MSCs preparation and administration schedule, and screening patients who may more like benefit from MSCs therapy, have been developed to enhance the therapeutic potential of MSCs in AKI.
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Affiliation(s)
- Yuxiang Liu
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, 030012, Shanxi, China
- Department of the Fifth Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, Taiyuan, 030012, Shanxi, China
| | - Jibin Han
- Department of Critical Care Medicine, First Hospital of Shanxi Medical University, Taiyuan, 030012, Shanxi, China
| | - Jingai Fang
- Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, Taiyuan, 030012, Shanxi, China
| | - Rongshan Li
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, 030012, Shanxi, China
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18
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Zhang Y, Wei J, Yu X, Chen L, Ren R, Dong Y, Wang S, Zhu M, Ming N, zhu Z, Gao C, Xiong W. CXCL chemokines-mediated communication between macrophages and BMSCs on titanium surface promotes osteogenesis via the actin cytoskeleton pathway. Mater Today Bio 2023; 23:100816. [PMID: 37859997 PMCID: PMC10582501 DOI: 10.1016/j.mtbio.2023.100816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 09/06/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023] Open
Abstract
The refined functional cell subtypes in the immune microenvironment of specific titanium (Ti) surface and their collaborative role in promoting bone marrow mesenchymal stem cells (BMSCs) driven bone integration need to be comprehensively characterized. This study employed a simplified co-culture system to investigate the dynamic, temporal crosstalk between macrophages and BMSCs on the Ti surface. The M2-like sub-phenotype of macrophages, characterized by secretion of CXCL chemokines, emerges as a crucial mediator for promoting BMSC osteogenic differentiation and bone integration in the Ti surface microenvironment. Importantly, these two cells maintain their distinct functional phenotypes through a mutually regulatory interplay. The secretion of CXCL3, CXCL6, and CXCL14 by M2-like macrophages plays a pivotal role. The process activates CXCR2 and CCR1 receptors, triggering downstream regulatory effects on the actin cytoskeleton pathway within BMSCs, ultimately fostering osteogenic differentiation. Reciprocally, BMSCs secrete pleiotrophin (PTN), a key player in regulating macrophage differentiation. This secretion maintains the M2-like phenotype via the Sdc3 receptor-mediated cell adhesion molecules pathway. Our findings provide a novel insight into the intricate communication and mutual regulatory mechanisms operating between BMSCs and macrophages on the Ti surface, highlight specific molecular events governing cell-cell interactions in the osteointegration, inform the surface design of orthopedic implants, and advance our understanding of osteointegration.
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Affiliation(s)
- Yayun Zhang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
- Trauma Center/Department of Emergency and Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Jiemao Wei
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Xingbang Yu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Liangxi Chen
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Ranyue Ren
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yimin Dong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Sibo Wang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Meipeng Zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Nannan Ming
- The State Key Laboratory of Refractories and Metallurgy Institute of Advanced Materials and Nanotechnology Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Ziwei zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Chenghao Gao
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Wei Xiong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
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19
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Otsu Y, Hatakeyama M, Kanayama T, Akiyama N, Ninomiya I, Omae K, Kato T, Onodera O, Fukushima M, Shimohata T, Kanazawa M. Oxygen-Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke. Neurotherapeutics 2023; 20:1369-1387. [PMID: 37335500 PMCID: PMC10480381 DOI: 10.1007/s13311-023-01398-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2023] [Indexed: 06/21/2023] Open
Abstract
Stroke is the leading cause of severe long-term disability. Cell therapy has recently emerged as an approach to facilitate functional recovery in stroke. Although administration of peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation (OGD-PBMCs) has been shown to be a therapeutic strategy for ischemic stroke, the recovery mechanisms remain largely unknown. We hypothesised that cell-cell communications within PBMCs and between PBMCs and resident cells are necessary for a polarising protective phenotype. Here, we investigated the therapeutic mechanisms underlying the effects of OGD-PBMCs through the secretome. We compared levels of transcriptomes, cytokines, and exosomal microRNA in human PBMCs by RNA sequences, Luminex assay, flow cytometric analysis, and western blotting under normoxic and OGD conditions. We also performed microscopic analyses to assess the identification of remodelling factor-positive cells and evaluate angiogenesis, axonal outgrowth, and functional recovery by blinded examination by administration of OGD-PBMCs after ischemic stroke in Sprague-Dawley rats. We found that the therapeutic potential of OGD-PBMCs was mediated by a polarised protective state through decreased levels of exosomal miR-155-5p, and upregulation of vascular endothelial growth factor and a pluripotent stem cell marker stage-specific embryonic antigen-3 through the hypoxia-inducible factor-1α axis. After administration of OGD-PBMCs, microenvironment changes in resident microglia by the secretome promoted angiogenesis and axonal outgrowth, resulting in functional recovery after cerebral ischemia. Our findings revealed the mechanisms underlying the refinement of the neurovascular unit by secretome-mediated cell-cell communications through reduction of miR-155-5p from OGD-PBMCs, highlighting the therapeutic potential carrier of this approach against ischemic stroke.
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Affiliation(s)
- Yutaka Otsu
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Takeshi Kanayama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Natsuki Akiyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Kaoru Omae
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 1-5-4 Minatojima-Minamimachi, Kobe, 650-0047, Japan
| | - Taisuke Kato
- Department of System Pathology for Neurological Disorders, Brain Science Branch, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Masanori Fukushima
- Foundation of Learning Health Society Institute, 8F, Nagoya Mitsui Bussan Bldg. 1-16-21 Meiekiminami, Nakamura-ku, Nagoya, 450-003, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan.
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Chen R, Long S, Ren L, Xu S, Liu X, Shi J, Liu J, Ma D, Zhou P, Ren L. The Role of Macrophage Phenotype in the Vascularization of Prevascularized Human Bone Marrow Mesenchymal Stem Cell Sheets. Stem Cells Dev 2023; 32:504-514. [PMID: 37119121 DOI: 10.1089/scd.2022.0268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023] Open
Abstract
With the development of tissue engineering and regenerative medicine, prevascularized bone marrow mesenchymal stem cell (BMSC) sheets have been regarded as a promising method for tissue regeneration. Furthermore, the inflammatory response is one of the main regulators of vascularization and the restoration of engineered tissue function; among them, macrophages and cytokines produced by them are considered to be the decisive factors of the downstream outcomes. This study investigated the effect of macrophages on the formation of microvascular-like structures of human umbilical vein endothelial cells (HUVECs) in BMSC sheets. First, a human monocytic leukemia cell line (THP-1 cells) was differentiated into derived macrophages (M0) with phorbol 12-myristate 13-acetate and further activated into proinflammatory macrophages (M1 macrophages) with interferon-γ and lipopolysaccharide or anti-inflammatory macrophages (M2 macrophages) with interleukin-4. Then, HUVECs and prevascularized sheets were treated with conditioned media (CM) from different macrophages, and the impact of macrophage phenotypes on vascularized network formation in prevascularized cell sheets was examined by hematoxylin and eosin staining, CD31 immunofluorescence staining and enzyme-linked immunosorbent assay. Our study showed that macrophages may guide the arrangement of endothelial cells through a paracrine pathway. Cell sheets that were cultured in the CM from M2 macrophages were thinner than those cultured in other media. At various time points, the levels of tumor necrosis factor alpha and vascular endothelial growth factor in prevascularized sheets cultured with CM(M1) was higher than that in sheets cultured with other media; however, the levels of platelet-derived growth factor in prevascularized sheets cultured with CM(M2) was higher than that in sheets cultured with other media. These findings suggest that the paracrine effect of macrophages can influence the formation of microvascular networks in prevascularized sheets by regulating the arrangement of cells, the thickness of the cell sheet and the secretion of cytokines related to angiogenesis. Macrophages with different phenotypes have unique effects on prevascularized sheets.
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Affiliation(s)
- Rui Chen
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Siqi Long
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
- Department of Orthodontics, West China School of Stomatology, Sichuan University, Chengdu, PR China
| | - Lina Ren
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Sen Xu
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Xiaoning Liu
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Jiamin Shi
- College of Life Sciences, Lanzhou University, Lanzhou, PR China
| | - Jiaxin Liu
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Dongyang Ma
- Department of Oral and Maxillofacial Surgery, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, PR China
| | - Ping Zhou
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
| | - Liling Ren
- Department of Orthodontics, School and Hospital of Stomatology, Lanzhou University, Lanzhou, PR China
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Pinto-Cardoso R, Bessa-Andrês C, Correia-de-Sá P, Bernardo Noronha-Matos J. Could hypoxia rehabilitate the osteochondral diseased interface? Lessons from the interplay of hypoxia and purinergic signals elsewhere. Biochem Pharmacol 2023:115646. [PMID: 37321413 DOI: 10.1016/j.bcp.2023.115646] [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: 04/07/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
The osteochondral unit comprises the articular cartilage (90%), subchondral bone (5%) and calcified cartilage (5%). All cells present at the osteochondral unit that is ultimately responsible for matrix production and osteochondral homeostasis, such as chondrocytes, osteoblasts, osteoclasts and osteocytes, can release adenine and/or uracil nucleotides to the local microenvironment. Nucleotides are released by these cells either constitutively or upon plasma membrane damage, mechanical stress or hypoxia conditions. Once in the extracellular space, endogenously released nucleotides can activate membrane-bound purinoceptors. Activation of these receptors is fine-tuning regulated by nucleotides' breakdown by enzymes of the ecto-nucleotidase cascade. Depending on the pathophysiological conditions, both the avascular cartilage and the subchondral bone subsist to significant changes in oxygen tension, which has a tremendous impact on tissue homeostasis. Cell stress due to hypoxic conditions directly influences the expression and activity of several purinergic signalling players, namely nucleotide release channels (e.g. Cx43), NTPDase enzymes and purinoceptors. This review gathers experimental evidence concerning the interplay between hypoxia and the purinergic signalling cascade contributing to osteochondral unit homeostasis. Reporting deviations to this relationship resulting from pathological alterations of articular joints may ultimately unravel novel therapeutic targets for osteochondral rehabilitation. At this point, one can only hypothesize how hypoxia mimetic conditions can be beneficial to the ex vivo expansion and differentiation of osteo- and chondro-progenitors for auto-transplantation and tissue regenerative purposes.
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Affiliation(s)
- Rui Pinto-Cardoso
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Catarina Bessa-Andrês
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP)
| | - José Bernardo Noronha-Matos
- Laboratório de Farmacologia e Neurobiologia; Center for Drug Discovery and Innovative Medicines (MedInUP), Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto (ICBAS-UP).
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22
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Li S, Zhang L, Liu C, Kim J, Su K, Chen T, Zhao L, Lu X, Zhang H, Cui Y, Cui X, Yuan F, Pan H. Spontaneous immunomodulation and regulation of angiogenesis and osteogenesis by Sr/Cu-borosilicate glass (BSG) bone cement to repair critical bone defects. Bioact Mater 2023; 23:101-117. [DOI: 10.1016/j.bioactmat.2022.10.021] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022] Open
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Li Y, Xu Z, Wang J, Pei X, Chen J, Wan Q. Alginate-based biomaterial-mediated regulation of macrophages in bone tissue engineering. Int J Biol Macromol 2023; 230:123246. [PMID: 36649862 DOI: 10.1016/j.ijbiomac.2023.123246] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 12/06/2022] [Accepted: 01/09/2023] [Indexed: 01/15/2023]
Abstract
Many studies in the bone tissue engineering field have focused on the interactions between materials and bone marrow stem cells. With the development of osteoimmunology, the immune cells' essential role in biomaterial-mediated osteogenesis has increasingly been recognized. As a promising therapeutic candidate for bone defects due to their prominent biocompatibility, tuneability, and versatility, it is necessary to develop alginate-based biomaterials that can regulate immune cells, especially macrophages. Moreover, modified alginate-based biomaterials may facilitate better regulation of macrophage phenotypes by the newly endowed physicochemical properties, including stiffness, porosity, hydrophilicity, and electrical properties. This review summarizes the role of macrophages in bone regeneration and the recent research progress related to the effects of alginate-based biomaterials on macrophages applied in bone tissue engineering. This review also emphasizes the strategies adopted by material design to regulate macrophage phenotypes, the corresponding macrophage responses, and their contribution to osteogenesis.
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Affiliation(s)
- Yuanyuan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zhengyi Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Jian Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xibo Pei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China
| | - Junyu Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Qianbing Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; West China School of Stomatology, Sichuan University, Chengdu 610041, China.
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24
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Zheng A, Wang X, Xin X, Peng L, Su T, Cao L, Jiang X. Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment. Bioact Mater 2023; 21:403-421. [PMID: 36185741 PMCID: PMC9483602 DOI: 10.1016/j.bioactmat.2022.08.031] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 08/07/2022] [Accepted: 08/14/2022] [Indexed: 11/25/2022] Open
Abstract
Injectable hydrogel is suitable for the repair of lacunar bone deficiency. This study fabricated an injectable, self-adaptive silk fibroin/mesoporous bioglass/sodium alginate (SMS) composite hydrogel system. With controllable and adjustable physical and chemical properties, the SMS hydrogel could be easily optimized adaptively to different clinical applications. The SMS hydrogel effectively showed great injectability and shapeability, allowing defect filling with no gap. Moreover, the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation, responsive to the concentration of Ca2+ and inflammatory-like pH value in the microenvironment of bone deficiency, respectively. In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway. The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells. Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2, which could create a specific favorable environment to induce new bone formation and angiogenesis. Meanwhile, SMS hydrogel was proved to be antibacterial, especially for gram-negative bacteria. Furthermore, in vivo study indicated that SMS could be easily applied for maxillary sinus elevation, inducing sufficient new bone formation. Thus, it is convincing that SMS hydrogel could be potent in a simple, minimally invasive and efficient treatment for the repair of lacunar bone deficiency.
Mesoporous bioglass was used as the crosslinking agent and in-situ porogen to form a porous injectable hydrogel. The composite hydrogel had suitable injectability and self-adaptability for lacunar bone regeneration. The composite hydrogel can simultaneously regulate macrophage polarization and osteogenic differentiation.
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25
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Li H, He Z, Li W, Yao J, Lyu C, Du Y, Xing D, Lin J. Exploring the Mechanism of Microfracture in the Treatment of Porcine Full-Thickness Cartilage Defect. Am J Sports Med 2023; 51:1033-1046. [PMID: 36802853 DOI: 10.1177/03635465231153630] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
BACKGROUND Microfracture has the most extensive clinical application because of its advantages of a single operation, unified process, and low operation cost. Because research on the repair mechanism of microfractures in the treatment of cartilage defects is not in-depth, this study aimed to elucidate the mechanism. PURPOSE To identify the characteristic cell subsets at different repair stages after microfracture, systematically analyze the repair process of the defect area after microfracture, and investigate the mechanism of fibrocartilage repair. STUDY DESIGN Descriptive laboratory study. METHODS Full-thickness articular cartilage defects and microfractures was established in the right knee of Bama miniature pigs. Single-cell transcriptional assays were used to identify the characteristics of cells isolated from healthy articular cartilage and regenerated tissues. RESULTS Microfractures induced mature fibrous repair in the full-thickness cartilage defect six months after surgery, while early stages of repair occurred within six weeks. Based on single-cell sequencing results, eight subsets and specific marker genes were identified. Two processes may occur after microfracture: normal hyaline cartilage regeneration and abnormal fibrocartilage repair. Regulatory chondrocytes, proliferative chondrocytes and cartilage progenitor cells (CPCs) may play important roles in the normal regeneration process. During abnormal repair, CPCs and skeletal stem cells may have different functions, and macrophages and endothelial cells may play important regulatory roles in the formation of fibrochondrocytes. CONCLUSIONS Using single-cell transcriptome sequencing, this study investigated the tissue regeneration process and identified key cell subsets after microfracture. CLINICAL RELEVANCE These results provide future targets for optimizing the repair effect of microfracture.
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Affiliation(s)
- Hui Li
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
| | - Zihao He
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
| | - Wenjing Li
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China
| | - Jiaying Yao
- Annoroad Gene Technology (Beijing) Co Ltd, Beijing, China
| | - Cheng Lyu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
| | - Jianhao Lin
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
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Mesenchymal stem cells and macrophages and their interactions in tendon-bone healing. J Orthop Translat 2023; 39:63-73. [PMID: 37188000 PMCID: PMC10175706 DOI: 10.1016/j.jot.2022.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/24/2022] [Accepted: 12/29/2022] [Indexed: 01/21/2023] Open
Abstract
Tendon-bone insertion injuries (TBI), such as anterior cruciate ligament (ACL) and rotator cuff injuries, are common degenerative or traumatic pathologies with a negative impact on the patient's daily life, and they cause huge economic losses every year. The healing process after an injury is complex and is dependent on the surrounding environment. Macrophages accumulate during the entire process of tendon and bone healing and their phenotypes progressively transform as they regenerate. As the "sensor and switch of the immune system", mesenchymal stem cells (MSCs) respond to the inflammatory environment and exert immunomodulatory effects during the tendon-bone healing process. When exposed to appropriate stimuli, they can differentiate into different tissues, including chondrocytes, osteocytes, and epithelial cells, promoting reconstruction of the complex transitional structure of the enthesis. It is well known that MSCs and macrophages communicate with each other during tissue repair. In this review, we discuss the roles of macrophages and MSCs in TBI injury and healing. Reciprocal interactions between MSCs and macrophages and some biological processes utilizing their mutual relations in tendon-bone healing are also described. Additionally, we discuss the limitations in our understanding of tendon-bone healing and propose feasible ways to exploit MSC-macrophage interplay to develop an effective therapeutic strategy for TBI injuries. The Translational potential of this article This paper reviewed the important functions of macrophages and mesenchymal stem cells in tendon-bone healing and described the reciprocal interactions between them during the healing process. By managing macrophage phenotypes, mesenchymal stem cells and the interactions between them, some possible novel therapies for tendon-bone injury may be proposed to promote tendon-bone healing after restoration surgery.
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27
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Zhang D, Dang Y, Deng R, Ma Y, Wang J, Ao J, Wang X. Research Progress of Macrophages in Bone Regeneration. J Tissue Eng Regen Med 2023; 2023:1512966. [PMID: 40226416 PMCID: PMC11919137 DOI: 10.1155/2023/1512966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/07/2022] [Accepted: 12/17/2022] [Indexed: 04/15/2025]
Abstract
Bone tissue regeneration plays an increasingly important role in contemporary clinical treatment. The reconstruction of bone defects remains a huge challenge for clinicians. Bone regeneration is regulated by the immune system, in which inflammation is an important regulating factor in bone formation and remodeling. As the main cells involved in inflammation, macrophages play a key role in osteogenesis by polarizing into different phenotypes during different stages of bone regeneration. Considering this, this review mainly summarizes the function of macrophage in bone regeneration based on mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, and vascular cells. In conclusion, anti-inflammatory macrophages (M2) have a greater potentiality to promote bone regeneration than M0 and classically activated proinflammatory macrophages (M1). In the fracture and bone defect models, tissue engineering materials can induce the transition from M1 to M2, alter the bone microenvironment, and promote bone regeneration through interactions with bone-related cells and blood vessels. The review provides a further understanding of macrophage polarization behavior in the evolving field of bone immunology.
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Affiliation(s)
- Dingmei Zhang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yi Dang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Renli Deng
- Nurse Department, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jing Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jun Ao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
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Zhou J, Ou MH, Wei XL, Lan BY, Chen WJ, Song SJ, Chen WX. The role of different macrophages-derived conditioned media in dental pulp tissue regeneration. Tissue Cell 2022; 79:101944. [DOI: 10.1016/j.tice.2022.101944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/21/2022] [Accepted: 09/21/2022] [Indexed: 10/14/2022]
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Chai H, Wang W, Yuan X, Zhu C. Bio-Activated PEEK: Promising Platforms for Improving Osteogenesis through Modulating Macrophage Polarization. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9120747. [PMID: 36550953 PMCID: PMC9774947 DOI: 10.3390/bioengineering9120747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/30/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022]
Abstract
The attention on orthopedic biomaterials has shifted from their direct osteogenic properties to their osteoimmunomodulation, especially the modulation of macrophage polarization. Presently, advanced technologies endow polyetheretherketone (PEEK) with good osteoimmunomodulation by modifying PEEK surface characteristics or incorporating bioactive substances with regulating macrophage polarization. Recent studies have demonstrated that the fabrication of a hydrophilic surface and the incorporation of bioactive substances into PEEK (e.g., zinc, calcium, and phosphate) are good strategies to promote osteogenesis by enhancing the polarization of M2 macrophages. Furthermore, the modification by other osteoimmunomodulatory composites (e.g., lncRNA-MM2P, IL-4, IL-10, and chitosan) and their controlled and desired release may make PEEK an optimal bio-activated implant for regulating and balancing the osteogenic system and immune system. The purpose of this review is to comprehensively evaluate the potential of bio-activated PEEK in polarizing macrophages into M2 phenotype to improve osteogenesis. For this objective, we retrieved and discussed different kinds of bio-activated PEEK regarding improving osteogenesis through modulating macrophage polarization. Meanwhile, the relevant challenges and outlook were presented. We hope that this review can shed light on the development of bio-activated PEEK with more favorable osteoimmunomodulation.
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Affiliation(s)
- Haobu Chai
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei 230001, China
| | - Wenzhi Wang
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei 230001, China
| | - Xiangwei Yuan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233, China
- Correspondence: (X.Y.); (C.Z.)
| | - Chen Zhu
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei 230001, China
- Correspondence: (X.Y.); (C.Z.)
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Chow SKH, Wong CHW, Cui C, Li MMC, Wong RMY, Cheung WH. Modulating macrophage polarization for the enhancement of fracture healing, a systematic review. J Orthop Translat 2022; 36:83-90. [PMID: 35979176 PMCID: PMC9364046 DOI: 10.1016/j.jot.2022.05.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 12/04/2022] Open
Abstract
Background All fracture repairs start with the innate immune system with the inflammatory response known as the inflammatory stage guided and driven by the secretion of chemokine by the ruptured tissue, followed by the sequential recruitment of neutrophils, monocytes and macrophages. These innate immune cells would infiltrate the fracture site and secrete inflammatory cytokines to stimulate recruitment of more immune cells to arrive at the fracture site coordinating subsequent stages of the repair process. In which, subsidence of pro-inflammatory M1 macrophage and transformation to anti-inflammatory M2 macrophages promotes osteogenesis that marks the start of the anabolic endochondral stage. Methods Literature search was performed on Pubmed, Embase, and Web of Science databases (last accessed 15th April 2021) using “macrophage AND fracture”. Review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Results Eleven pre-clinical animal studies out of 429 articles were included in this systematic review according to our inclusion and exclusion criteria. All of which investigated interventions targeting to modulate the acute inflammatory response and macrophage polarization as evident by various markers in association with fracture healing outcomes. Conclusion This systematic review summarizes attempts to modulate the innate immune response with focuses on promoting macrophage polarization from M1 to M2 phenotype targeting the enhancement of fracture injury repair. Methods used to achieve the goal may include applications of damage-associated molecular pattern (DAMP), pathogen-associated molecular pattern (PAMP) or mechanical stimulation that hold high translational potentials for clinical application in the near future.
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Affiliation(s)
- Simon Kwoon-Ho Chow
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Carissa Hing-Wai Wong
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Can Cui
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Michelle Meng-Chen Li
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ronald Man Yeung Wong
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wing-Hoi Cheung
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
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Ding Y, Liu X, Zhang J, Lv Z, Meng X, Yuan Z, Long T, Wang Y. 3D printing polylactic acid polymer-bioactive glass loaded with bone cement for bone defect in weight-bearing area. Front Bioeng Biotechnol 2022; 10:947521. [PMID: 35957643 PMCID: PMC9358041 DOI: 10.3389/fbioe.2022.947521] [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: 05/18/2022] [Accepted: 06/27/2022] [Indexed: 11/30/2022] Open
Abstract
The treatment of bone defects in weight-bearing areas is mainly to transplant filling materials into the defect area, to provide immediate and strong support for weight-bearing. At present, the commonly used filling material is bone cement, which can only provide physical support without bone regeneration effect. The long-term stress at the interface may cause the loosening of bone cement. The ideal filling material should provide not only strong mechanical support but also promote bone regeneration. We introduce a 3D printing frame-filling structure in this study. The structure was printed with polylactic acid/bioactive glass as the frame, and bone cement as the filler. In this system, bone cement was used to provide immediate fixation, and the frame provided long-term fixation by promoting osteogenic induction and conduction between the interface. The results showed that the degradation of bioactive glass in the frame promoted osteogenic metabolism, induced M2 polarization of macrophages, and inhibited local inflammatory response. The in vivo study revealed that implantation of the frame-filling structure significantly promoted bone regeneration in the femoral bone defect area of New Zealand white rabbits. For a bone defect in a weight-bearing area, long-term stability could be obtained by bone integration through this frame-filling structure.
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32
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Long C, Guo R, Han R, Li K, Wan Y, Xu J, Gong X, Zhao Y, Yao X, Liu J. Effects of macrophages on the proliferation and cardiac differentiation of human induced pluripotent stem cells. Cell Commun Signal 2022; 20:108. [PMID: 35850719 PMCID: PMC9290307 DOI: 10.1186/s12964-022-00916-1] [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: 03/04/2022] [Accepted: 06/09/2022] [Indexed: 12/03/2022] Open
Abstract
Background Macrophage phenotypes switch from proinflammatory (M1) to anti-inflammatory (M2) following myocardial injury. Implanted stem cells (e.g., induced pluripotent stem cells (iPSCs)) for cardiomyogenesis will inevitably contact the inflammatory environment at the myocardial infarction site. To understand how the macrophages affect the behavior of iPSCs, therefore, improve the therapeutic efficacy, we generated three macrophage subtypes and assessed their effects on the proliferation, cardiac differentiation, and maturation of iPSCs. Methods M0, M1, and M2 macrophages were polarized using cytokines, and their properties were confirmed by the expression of specific markers using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The effects of macrophages on iPSCs were studied using Transwell co-culture models. The proliferative ability of iPSCs was investigated by cell counting and CCK-8 assays. The cardiac differentiation ability of iPSCs was determined by the cardiomyocyte (CM) yield. The maturation of CM was analyzed by the expression of cardiac-specific genes using RT-qPCR, the sarcomere organization using immunofluorescence, and the mitochondrial function using oxidative respiration analysis. Results The data showed that the co-culture of iPSCs with M0, M1, or M2 macrophages significantly decreased iPSCs’ proliferative ability. M2 macrophages did not affect the CM yield during the cardiac differentiation of iPSCs. Still, they promoted the maturation of CM by improving sarcomeric structures, increasing contractile- and ion transport-associated gene expression, and enhancing mitochondrial respiration. M0 macrophages did not significantly affect the cardiomyogenesis ability of iPSCs during co-culture. In contrast, co-culture with M1 macrophages significantly reduced the cardiac differentiation and maturation of iPSCs. Conclusions M1- or M2-polarized macrophages play critical roles in the proliferation, cardiac differentiation, and maturation of iPSCs, providing knowledge to improve the outcomes of stem cell regeneration therapy.
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