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Walker JT, Cooper TT, Dunmore-Buyze J, Serack FE, Brooks C, Grant A, Drangova M, Lajoie G, Dekaban GA, Flynn LE. Syngeneic adipose-derived stromal cells modulate the immune response but have limited persistence within decellularized adipose tissue implants in C57BL/6 mice. Acta Biomater 2025; 195:169-182. [PMID: 39922513 DOI: 10.1016/j.actbio.2025.02.015] [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: 10/18/2024] [Revised: 01/14/2025] [Accepted: 02/05/2025] [Indexed: 02/10/2025]
Abstract
The delivery of adipose-derived stromal cells (ASCs) on cell-instructive decellularized adipose tissue (DAT) scaffolds is a promising strategy for stimulating host-derived soft tissue regeneration. However, a better understanding of the mechanisms through which ASCs modulate regeneration in vivo is needed to harness these cells more effectively. In this study, DAT scaffolds, both with and without seeded syngeneic DsRED+ mouse ASCs, were implanted into immunocompetent C57BL/6 mice. Downstream analyses focused on assessing donor ASC persistence and phenotype, as well as the effects of ASC seeding on host macrophage polarization and the perfused host vascular network. Notably, most donor ASCs were cleared from the scaffolds by 2 weeks. Mass spectrometry-based proteomics indicated that the transplanted ASCs maintained their pre-implantation phenotype up to 1 week in vivo, suggesting that the cells were not undergoing programmed cell death. A higher fraction of the infiltrating host macrophages expressed CD68 and Arginase-1 in the ASC-seeded implants up to 1-week post-implantation. Interestingly, a small population of phagocytic macrophages, identified by uptake of DsRED protein, was present in the DAT implants in the first 2 weeks and showed enhanced expression of CD68, Arginase-1, and CD163, along with reduced expression of iNOS. MicroCT angiography revealed a similar perfused vessel network in the seeded and unseeded groups at 4- and 8-weeks post-implantation. Overall, seeding with syngeneic ASCs modulated the host macrophage response to the DAT bioscaffolds at early timepoints, but did not impact long-term regenerative outcomes, potentially due to the rapid clearance of the donor cell population in this model. STATEMENT OF SIGNIFICANCE: Decellularized adipose tissue (DAT) is a promising biomaterial for treating soft tissue defects. Seeding with adipose-derived stromal cells (ASCs) can augment fat regeneration within DAT in pre-clinical models, but our understanding of how ASCs contribute to tissue regeneration in vivo remains limited. Furthermore, ASC clearance from implanted biomaterials is well described, but poorly understood. Here, ASC-seeded DAT was implanted subcutaneously in immunocompetent mice to assess how ASCs altered the host macrophage response, functional vascular regeneration, and long-term integration with the host tissues. Additionally, ASC phenotype and persistence were assessed to determine how these cells might be cleared from the implants. Such understanding is critical to design biomaterials that can better harness the therapeutic benefits of ASCs.
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Affiliation(s)
- John T Walker
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Tyler T Cooper
- Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada
| | - Joy Dunmore-Buyze
- Robarts Research Institute, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Fiona E Serack
- School of Biomedical Engineering, Faculty of Engineering, The University of Western Ontario, London, Ontario N6A 3K7, Canada
| | - Courtney Brooks
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Aaron Grant
- Division of Plastic and Reconstructive Surgery, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1151 Richmond St, London, Ontario N6A 5C1, Canada
| | - Maria Drangova
- Robarts Research Institute, The University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Gilles Lajoie
- Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada
| | - Gregory A Dekaban
- Robarts Research Institute, The University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario N6A 3K7, Canada
| | - Lauren E Flynn
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada; School of Biomedical Engineering, Faculty of Engineering, The University of Western Ontario, London, Ontario N6A 3K7, Canada; Department of Chemical and Biochemical Engineering, Faculty of Engineering, The University of Western Ontario, London, Ontario N6A 5B9, Canada.
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Khazaeel K, Sadeghi A, Khademi Moghaddam F, Mohammadi T. The impact of graphene quantum dots on osteogenesis potential of Wharton's jelly mesenchymal stem cells in fibrin hydrogel scaffolds. Cytotechnology 2025; 77:14. [PMID: 39665046 PMCID: PMC11628478 DOI: 10.1007/s10616-024-00672-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024] Open
Abstract
Bone tissue engineering is a promising approach to overcome the limitations of traditional autograft bone transplantation. Graphene quantum dots (GQDs) have been suggested as an enhancement for osteogenic differentiation. This study aimed to investigate the ability of the fibrin hydrogel scaffold in the presence of graphene quantum dots to promote osteogenic differentiation of human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs). The hWJ-MSCs were isolated from the Wharton's jelly of the human umbilical cord using a mechanical method. Fibrin hydrogel scaffolds were prepared by mixing 15 µl of thrombin solution with fibrinogen solution. GQDs were incorporated into the scaffolds at concentrations of 0, 5, and 10 µg/ml. Cell viability was determined through DAPI staining and the MTT assay. Osteogenic differentiation was assessed by measuring alkaline phosphatase (ALP) activity, quantifying calcium deposition using Alizarin Red S staining, and analyzing the gene expression of BGLAP, COL1A1, Runx-2 and ALP via qPCR. Scanning electron microscopy (SEM) was employed to analyze the scaffold architecture. SEM analysis revealed that the fibrin hydrogel exhibited a suitable architecture for tissue engineering, and DAPI staining confirmed cell viability. The MTT results indicated that the GQDs and fibrin hydrogel scaffold exhibited no cytotoxic effects. Furthermore, the incorporation of GQDs at a concentration of 10 µg/ml significantly enhanced ALP activity, calcium deposition, and the expression of osteogenesis-related genes compared to the control. The findings suggest that the combination of fibrin hydrogel and GQDs can effectively promote the osteogenic differentiation of hWJ-MSCs, contributing to the advancement of bone tissue engineering.
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Affiliation(s)
- Kaveh Khazaeel
- Department of Basic Sciences, Division of Anatomy and Embryology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Stem Cells and Transgenic Technology Research Center (STTRC), Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Abbas Sadeghi
- Department of Basic Sciences, Division of Anatomy and Embryology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Tayebeh Mohammadi
- Department of Basic Sciences, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
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Gallo MC, Elias A, Reynolds J, Ball JR, Lieberman JR. Regional Gene Therapy for Bone Tissue Engineering: A Current Concepts Review. Bioengineering (Basel) 2025; 12:120. [PMID: 40001640 PMCID: PMC11852166 DOI: 10.3390/bioengineering12020120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
The management of segmental bone defects presents a complex reconstruction challenge for orthopedic surgeons. Current treatment options are limited by efficacy across the spectrum of injury, morbidity, and cost. Regional gene therapy is a promising tissue engineering strategy for bone repair, as it allows for local implantation of nucleic acids or genetically modified cells to direct specific protein expression. In cell-based gene therapy approaches, a variety of different cell types have been described including mesenchymal stem cells (MSCs) derived from multiple sources-bone marrow, adipose, skeletal muscle, and umbilical cord tissue, among others. MSCs, in particular, have been well studied, as they serve as a source of osteoprogenitor cells in addition to providing a vehicle for transgene delivery. Furthermore, MSCs possess immunomodulatory properties, which may support the development of an allogeneic "off-the-shelf" gene therapy product. Identifying an optimal cell type is paramount to the successful clinical translation of cell-based gene therapy approaches. Here, we review current strategies for the management of segmental bone loss in orthopedic surgery, including bone grafting, bone graft substitutes, and operative techniques. We also highlight regional gene therapy as a tissue engineering strategy for bone repair, with a focus on cell types and cell sources suitable for this application.
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Affiliation(s)
- Matthew C. Gallo
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Aura Elias
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Julius Reynolds
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Jacob R. Ball
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
| | - Jay R. Lieberman
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; (M.C.G.); (A.E.); (J.R.); (J.R.B.)
- Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA
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Hwang HS, Lee CS. Exosome-Integrated Hydrogels for Bone Tissue Engineering. Gels 2024; 10:762. [PMID: 39727520 DOI: 10.3390/gels10120762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 12/28/2024] Open
Abstract
Exosome-integrated hydrogels represent a promising frontier in bone tissue engineering, leveraging the unique biological properties of exosomes to enhance the regenerative capabilities of hydrogels. Exosomes, as naturally occurring extracellular vesicles, carry a diverse array of bioactive molecules that play critical roles in intercellular communication and tissue regeneration. When combined with hydrogels, these exosomes can be spatiotemporally delivered to target sites, offering a controlled and sustained release of therapeutic agents. This review aims to provide a comprehensive overview of the recent advancements in the development, engineering, and application of exosome-integrated hydrogels for bone tissue engineering, highlighting their potential to overcome current challenges in tissue regeneration. Furthermore, the review explores the mechanistic pathways by which exosomes embedded within hydrogels facilitate bone repair, encompassing the regulation of inflammatory pathways, enhancement of angiogenic processes, and induction of osteogenic differentiation. Finally, the review addresses the existing challenges, such as scalability, reproducibility, and regulatory considerations, while also suggesting future directions for research in this rapidly evolving field. Thus, we hope this review contributes to advancing the development of next-generation biomaterials that synergistically integrate exosome and hydrogel technologies, thereby enhancing the efficacy of bone tissue regeneration.
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Affiliation(s)
- Hee Sook Hwang
- Department of Pharmaceutical Engineering, Dankook University, Cheonan 31116, Republic of Korea
| | - Chung-Sung Lee
- Department of Pharmaceutical Engineering, Soonchunhyang University, Asan 31538, Republic of Korea
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Wang J, Liu M, Yang C, Pan Y, Ji S, Han N, Sun G. Biomaterials for bone defect repair: Types, mechanisms and effects. Int J Artif Organs 2024; 47:75-84. [PMID: 38166512 DOI: 10.1177/03913988231218884] [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: 01/04/2024]
Abstract
Bone defects or bone discontinuities caused by trauma, infection, tumours and other diseases have led to an increasing demand for bone grafts and biomaterials. Autologous bone grafts, bone grafts with vascular tips, anastomosed vascular bone grafts and autologous bone marrow components are all commonly used in clinical practice, while oversized bone defects require the use of bone tissue engineering-related biomaterials to repair bone defects and promote bone regeneration. Currently, inorganic components such as polysaccharides and bioceramics, as well as a variety of bioactive proteins, metal ions and stem cells can be loaded into hydrogels or 3D printed scaffold materials to achieve better therapeutic results. In this review, we provide an overview of the types of materials, applications, potential mechanisms and current developments in the repair of bone defects.
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Affiliation(s)
- Jiaming Wang
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Mingchong Liu
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chensong Yang
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yutao Pan
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shengchao Ji
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ning Han
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Guixin Sun
- Department of Traumatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Salem S, Leach L. Umbilical cord mesenchymal stem cells from gestational diabetes show impaired ability to up-regulate paracellular permeability from sub-endothelial niche. Clin Sci (Lond) 2024; 138:87-102. [PMID: 38168704 PMCID: PMC10794701 DOI: 10.1042/cs20230657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 12/14/2023] [Accepted: 01/02/2024] [Indexed: 01/05/2024]
Abstract
In vitro studies have shown that Wharton's jelly mesenchymal stem cells (WJ-MSCs) can cross umbilical and uterine endothelial barriers and up-regulate endothelial junctional integrity from sub-endothelial niches. This pericytic behaviour may be lost in pregnancies complicated by gestational diabetes (GDM), where increased vascular permeability and junctional disruption are reported. The aim of the present study was to investigate whether WJ-MSCs isolated from GDM pregnancies displayed any changes in morphology, proliferation, VEGF-A secretion, and their ability to influence paracellular junctional composition and permeability. WJ-MSCs were isolated from human umbilical cords from normal pregnancies (nWJ-MSCs, n=13) and those complicated by GDM (gWJ-MSCs), either diet-controlled (d-GDM, n=13) or metformin-treated (m-GDM, n=9). We recorded that 4-fold more WJ-MSCs migrated from m-GDM, and 2.5-fold from d-GDM cord samples compared with the normal pregnancy. gWJ-MSCs showed a less predominance of spindle-shaped morphology and secreted 3.8-fold more VEGF-A compared with nWJ-MSCs. The number of cells expressing CD105 (Endoglin) was higher in gWJ-MSCs compared with nWJ-MSCs (17%) at P-2. The tracer leakage after 24 h across the HUVEC + gWJ-MSCs bilayer was 22.13% and 11.2% higher in the m-GDM and d-GDM, respectively, HUVEC + nWJ-MSCs. Transfection studies with siRNAs that target Endoglin were performed in n-WJ-MSCs; transfected cells were co-cultured with HUVEC followed by permeability studies and VE-cadherin analyses. Loss of Endoglin also led to increased VEGF-A secretion, increased permeability and affected endothelial stabilization. These results reinforce the pericytic role of nWJ-MSCs to promote vascular repair and the deficient ability of gWJ-MSCs to maintain endothelial barrier integrity.
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Affiliation(s)
- Samar Salem
- School of Life Sciences, Division of Physiology, Pharmacology and Neuroscience, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, U.K
| | - Lopa Leach
- School of Life Sciences, Division of Physiology, Pharmacology and Neuroscience, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, U.K
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Diaz-Solano D, Sadri B, Peshkova M, Shpichka A, Smirnova O, Shams R, Timashev P, Vosough M. Advanced Therapeutic Medicinal Products in Bone and Cartilage Defects. Curr Rev Clin Exp Pharmacol 2024; 19:355-369. [PMID: 38275042 DOI: 10.2174/0127724328274436231207062008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/20/2023] [Accepted: 11/01/2023] [Indexed: 01/27/2024]
Abstract
The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.
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Affiliation(s)
- Dylana Diaz-Solano
- Unidad de Terapia Celular - Laboratorio de Patología Celular y Molecular, Centro de Medicina Regenerativa, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela
| | - Bahareh Sadri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maria Peshkova
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Anastasia Shpichka
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Olga Smirnova
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Roshanak Shams
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Wang W, Li X, Cui C, Yin G, Ren W, Wang X. Autophagy of umbilical cord mesenchymal stem cells induced by rapamycin conduces to pro-angiogenic function of the conditioned medium. Biochem Biophys Rep 2023; 36:101583. [PMID: 38053620 PMCID: PMC10694647 DOI: 10.1016/j.bbrep.2023.101583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/26/2023] [Accepted: 11/13/2023] [Indexed: 12/07/2023] Open
Abstract
Angiogenesis is critical for wound healing and tissue repair. Umbilical cord mesenchymal stem cells (UCMSCs)-conditioned medium has certain actions to promote angiogenesis, and is expected for wound healing and tissue repair. However, recent studies showed that the pro-angiogenic efficacy of unprocessed MSCs-conditioned medium is low, and insufficient for tissue repair. Autophagy is a process for protein recycling and a contributor for cell exocrine, which may enhance pro-angiogenic efficacy of the conditioned medium by stimulating cytokine release from UCMSCs. Therefore, in this study we attempted to obtain enhanced autophagy in UCMSCs using different concentrations of rapamycin and compared pro-angiogenic functions of the conditioned media. The in vitro data showed that although 100 nM-10 μM rapamycin all could induce autophagy in UCMSCs, 100 nM was the best dose to optimize the angiogenic effect of the conditioned medium. The in vivo data also showed that pro-angiogenic effect of the optimized conditioned medium was more obvious than that of the control conditioned medium (0 nM group) in the injected matrigel plaques. Further, the expressions of VEGF, FGF-2, MMP-9, PDGF-α and PDGF-β were markedly increased in UCMSCs treated with 100 nM rapamycin. In conclusion, appropriately enhancing autophagy of UCMSC can improve pro-angiogenic efficacy of the conditioned medium, which may optimize therapeutic applications of UCMSCs-conditioned medium in wound healing and tissue repair.
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Affiliation(s)
- Wenya Wang
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Xiao Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Chaochu Cui
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Guotian Yin
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Wenjie Ren
- Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Xianwei Wang
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
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Fan W, Zhou M, Zheng S, Liu Y, Pan S, Guo P, Xu M, Hu C, Ding A, Wang Z, Yin S, Zuo K, Xie X. Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-β1 signaling pathway. Diabetol Metab Syndr 2023; 15:234. [PMID: 37968711 PMCID: PMC10652470 DOI: 10.1186/s13098-023-01191-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 10/12/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood. METHODS hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-β1 in exosomes were evaluated by Western blot. RESULTS Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-β1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-β1 in exosomes, and the results showed that exosomes had high expression of TGF-β1. CONCLUSION By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-β1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TβR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.
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Affiliation(s)
- Weijian Fan
- Department of Interventional & Vascular Surgery, Hefei Second People's Hospital, Hefei Hospital Affiliated to Anhui Medical University, Anhui, 230011, China
| | - Mengdie Zhou
- Geriatric department, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, 201600, China
| | - Shaoqiu Zheng
- Department of Urinary Surgery Shanghai Pudong New District Zhoupu Hospital, Shanghai, 200100, China
| | - Yang Liu
- Department of Geriatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Songsong Pan
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Peng Guo
- Department of Vascular Surgery, The Fifth Affiliated Hospital of ZhengZhou University, ZhengZhou, 450052, China
| | - Minjie Xu
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Chao Hu
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Anle Ding
- AnHui University of Science and Technology, Huainan, 232001, China
| | - Zan Wang
- AnHui University of Science and Technology, Huainan, 232001, China
| | - Shiwu Yin
- Department of Interventional & Vascular Surgery, Hefei Second People's Hospital, Hefei Hospital Affiliated to Anhui Medical University, Anhui, 230011, China
| | - Keqiang Zuo
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Xiaoyun Xie
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Baron M, Drohat P, Crawford B, Hornicek FJ, Best TM, Kouroupis D. Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients. Bioengineering (Basel) 2023; 10:1187. [PMID: 37892917 PMCID: PMC10604230 DOI: 10.3390/bioengineering10101187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Osteosarcoma (OS) is a type of bone cancer that is derived from primitive mesenchymal cells typically affecting children and young adults. The current standard of treatment is a combination of neoadjuvant chemotherapy and surgical resection of the cancerous bone. Post-resection challenges in bone regeneration arise. To determine the appropriate amount of bone to be removed, preoperative imaging techniques such as bone and CT scans are employed. To prevent local recurrence, the current standard of care suggests maintaining bony and soft tissue margins from 3 to 7 cm beyond the tumor. The amount of bone removed in an OS patient leaves too large of a deficit for bone to form on its own and requires reconstruction with metal implants or allografts. Both methods require the bone to heal, either to the implant or across the allograft junction, often in the setting of marrow-killing chemotherapy. Therefore, the issue of bone regeneration within the surgically resected margins remains an important challenge for the patient, family, and treating providers. Mesenchymal stem/stromal cells (MSCs) are potential agents for enhancing bone regeneration post tumor resection. MSCs, used with scaffolds and growth factors, show promise in fostering bone regeneration in OS cases. We spotlight two MSC types-bone marrow-derived (BM-MSCs) and adipose tissue-derived (ASCs)-highlighting their bone regrowth facilitation and immunomodulatory effects on immune cells like macrophages and T cells, enhancing therapeutic outcomes. The objective of this review is two-fold: review work demonstrating any ability of MSCs to target the deranged immune system in the OS microenvironment, and synthesize the available literature on the use of MSCs as a therapeutic option for stimulating bone regrowth in OS patients post bone resection. When it comes to repairing bone defects, both MB-MSCs and ASCs hold great potential for stimulating bone regeneration. Research has showcased their effectiveness in reconstructing bone defects while maintaining a non-tumorigenic role following wide resection of bone tumors, underscoring their capability to enhance bone healing and regeneration following tumor excisions.
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Affiliation(s)
- Max Baron
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Philip Drohat
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Brooke Crawford
- Sarcoma Biology Laboratory, Department of Orthopedics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (B.C.); (F.J.H.)
| | - Francis J. Hornicek
- Sarcoma Biology Laboratory, Department of Orthopedics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (B.C.); (F.J.H.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
- Diabetes Research Institute, Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Moradi N, Soufi-Zomorrod M, Hosseinzadeh S, Soleimani M. Poly (acrylic acid)/tricalcium phosphate nanoparticles scaffold enriched with exosomes for cell-free therapy in bone tissue engineering: An in vivo evaluation. BIOIMPACTS : BI 2023; 14:27510. [PMID: 38938758 PMCID: PMC11199929 DOI: 10.34172/bi.2023.27510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 12/09/2022] [Accepted: 01/30/2023] [Indexed: 06/29/2024]
Abstract
Introduction This study aimed to assess the potential of poly (acrylic acid)/tricalcium phosphate nanoparticles (PAA/triCaPNPs) scaffold in terms of biocompatibility and osteoconductivity properties the in-vivo evaluation as well as to investigate the performance of PAA/triCaPNPs scaffold (with or without exosomes derived from UC-MSCs) for bone regeneration of rat critical-sized defect. Methods PAA/triCaPNPs scaffold was made from acrylic acid (AA) monomer, N,N'-methylenebisacrylamide (MBAA), sodium bicarbonate (SBC), and ammonium persulfate (APS) through freeze-drying method. For in vivo evaluation, we randomly divided 24 rats into three groups. The rat calvarial bone defects were treated as follows: (1) Control group: defects without any treatment, (2) scaffold group: defects treated with scaffold only, (3) scaffold+exo group: defects treated with scaffold enriched with exosomes (1 μg/μL, 150 μg per rat). Eight- and 12-weeks post-surgery, half of the animals were sacrificed and bone regeneration was examined through micro-computerized tomography (µ-CT), histological staining, and immunohistochemistry (IHC). Results Quantitative analysis based on µ-CT scan images at 8 and 12 weeks post-implantation clearly indicated that healing rate for defects that were filled with scaffold enriched with exosome was significantly higher than defects filled with scaffold without exosome. The H&E and Masson staining results revealed that more new bone-like form developed in the scaffold+exo group than that in control and scaffold groups. Further, IHC staining for osteocalcin and CD31 confirmed that more bone healing in the scaffold+exo group at 12 weeks could be associated with osteogenesis and angiogenesis concurrently. Conclusion In the present study, we aimed to investigate the therapeutic potential of PAA/triCaPNPs scaffold as a carrier of human UC-MSC-derived exosome to achieve the exosome-controlled release on calvarial bone defect. The in vivo results indicated that the exosome-enriched scaffold could effectively minify the defect area and improve the bone healing in rat model, and as such it could be an option for exosome-based therapy.
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Affiliation(s)
- Nahid Moradi
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mina Soufi-Zomorrod
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Simzar Hosseinzadeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Rosner M, Horer S, Feichtinger M, Hengstschläger M. Multipotent fetal stem cells in reproductive biology research. Stem Cell Res Ther 2023; 14:157. [PMID: 37287077 DOI: 10.1186/s13287-023-03379-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Due to the limited accessibility of the in vivo situation, the scarcity of the human tissue, legal constraints, and ethical considerations, the underlying molecular mechanisms of disorders, such as preeclampsia, the pathological consequences of fetomaternal microchimerism, or infertility, are still not fully understood. And although substantial progress has already been made, the therapeutic strategies for reproductive system diseases are still facing limitations. In the recent years, it became more and more evident that stem cells are powerful tools for basic research in human reproduction and stem cell-based approaches moved into the center of endeavors to establish new clinical concepts. Multipotent fetal stem cells derived from the amniotic fluid, amniotic membrane, chorion leave, Wharton´s jelly, or placenta came to the fore because they are easy to acquire, are not associated with ethical concerns or covered by strict legal restrictions, and can be banked for autologous utilization later in life. Compared to adult stem cells, they exhibit a significantly higher differentiation potential and are much easier to propagate in vitro. Compared to pluripotent stem cells, they harbor less mutations, are not tumorigenic, and exhibit low immunogenicity. Studies on multipotent fetal stem cells can be invaluable to gain knowledge on the development of dysfunctional fetal cell types, to characterize the fetal stem cells migrating into the body of a pregnant woman in the context of fetomaternal microchimerism, and to obtain a more comprehensive picture of germ cell development in the course of in vitro differentiation experiments. The in vivo transplantation of fetal stem cells or their paracrine factors can mediate therapeutic effects in preeclampsia and can restore reproductive organ functions. Together with the use of fetal stem cell-derived gametes, such strategies could once help individuals, who do not develop functional gametes, to conceive genetically related children. Although there is still a long way to go, these developments regarding the usage of multipotent fetal stem cells in the clinic should continuously be accompanied by a wide and detailed ethical discussion.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | - Stefanie Horer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | | | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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13
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Liu P, An Y, Zhu T, Tang S, Huang X, Li S, Fu F, Chen J, Xuan K. Mesenchymal stem cells: Emerging concepts and recent advances in their roles in organismal homeostasis and therapy. Front Cell Infect Microbiol 2023; 13:1131218. [PMID: 36968100 PMCID: PMC10034133 DOI: 10.3389/fcimb.2023.1131218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/03/2023] [Indexed: 03/11/2023] Open
Abstract
Stem cells play a crucial role in re-establishing homeostasis in the body, and the search for mechanisms by which they interact with the host to exert their therapeutic effects remains a key question currently being addressed. Considering their significant regenerative/therapeutic potential, research on mesenchymal stem cells (MSCs) has experienced an unprecedented advance in recent years, becoming the focus of extensive works worldwide to develop cell-based approaches for a variety of diseases. Initial evidence for the effectiveness of MSCs therapy comes from the restoration of dynamic microenvironmental homeostasis and endogenous stem cell function in recipient tissues by systemically delivered MSCs. The specific mechanisms by which the effects are exerted remain to be investigated in depth. Importantly, the profound cell-host interplay leaves persistent therapeutic benefits that remain detectable long after the disappearance of transplanted MSCs. In this review, we summarize recent advances on the role of MSCs in multiple disease models, provide insights into the mechanisms by which MSCs interact with endogenous stem cells to exert therapeutic effects, and refine the interconnections between MSCs and cells fused to damaged sites or differentiated into functional cells early in therapy.
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Affiliation(s)
- Peisheng Liu
- The College of Life Science, Northwest University, Xi’an, Shaanxi, China
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yongqian An
- Department of Stomatology, 962 Hospital of People's Liberation Army of China, Harbin, Heilongjiang, China
| | - Ting Zhu
- The College of Life Science, Northwest University, Xi’an, Shaanxi, China
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Siyuan Tang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- School of Basic Medicine, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xiaoyao Huang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shijie Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Fei Fu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ji Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Oral Implantology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Ji Chen, ; Kun Xuan,
| | - Kun Xuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, The Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Ji Chen, ; Kun Xuan,
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14
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Dwivedi S, Choudhary P, Gupta A, Singh S. Therapeutical growth in oligodendroglial fate induction via transdifferentiation of stem cells for neuroregenerative therapy. Biochimie 2023; 211:35-56. [PMID: 36842627 DOI: 10.1016/j.biochi.2023.02.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/20/2022] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
The merits of stem cell therapy and research are undisputed due to their widespread usage in the treatment of neurodegenerative diseases and demyelinating disorders. Cell replacement therapy especially revolves around stem cells and their induction into different cell lineages both adult and progenitor - belonging to each germ layer, prior to transplantation or disease modeling studies. The nervous system is abundant in glial cells and among these are oligodendrocytes capable of myelinating new-born neurons and remyelination of axons with lost or damaged myelin sheath. But demyelinating diseases generate tremendous deficit between myelin loss and recovery. To compensate for this loss, analyze the defects in remyelination mechanisms as well as to trigger full recovery in such patients mesenchymal stem cells (MSCs) have been induced to transdifferentiate into oligodendrocytes. But such experiments are riddled with problems like prolonged, tenuous and complicated protocols that stretch longer than the time taken for the spread of demyelination-associated after-effects. This review delves into such protocols and the combinations of different molecules and factors that have been recruited to derive bona fide oligodendrocytes from in vitro differentiation of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and MSCs with special focus on MSC-derived oligodendrocytes.
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Affiliation(s)
- Shrey Dwivedi
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Princy Choudhary
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Ayushi Gupta
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Sangeeta Singh
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India.
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15
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Vascularized Tissue Organoids. Bioengineering (Basel) 2023; 10:bioengineering10020124. [PMID: 36829618 PMCID: PMC9951914 DOI: 10.3390/bioengineering10020124] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023] Open
Abstract
Tissue organoids hold enormous potential as tools for a variety of applications, including disease modeling and drug screening. To effectively mimic the native tissue environment, it is critical to integrate a microvasculature with the parenchyma and stroma. In addition to providing a means to physiologically perfuse the organoids, the microvasculature also contributes to the cellular dynamics of the tissue model via the cells of the perivascular niche, thereby further modulating tissue function. In this review, we discuss current and developing strategies for vascularizing organoids, consider tissue-specific vascularization approaches, discuss the importance of perfusion, and provide perspectives on the state of the field.
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16
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Chen YC, Fu YS, Tsai SW, Wu PK, Chen CM, Chen WM, Chen CF. IL-1b in the Secretomes of MSCs Seeded on Human Decellularized Allogeneic Bone Promotes Angiogenesis. Int J Mol Sci 2022; 23:ijms232315301. [PMID: 36499629 PMCID: PMC9737155 DOI: 10.3390/ijms232315301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis plays an important role in the development of bone and bone regeneration to provide the required molecules. Mesenchymal stem cells (MSCs) are pluripotent, self-renewing, and spindle-shaped cells, which can differentiate into multiple lineages such as chondrocytes, osteocytes, and adipocytes. MSCs derived from bone marrow (BMMSCs), adipose tissue (ADMSCs), and Wharton's jelly (UCMSCs) are popular in the field of tissue regeneration. MSCs have been proposed that can promote bone regeneration by enhancing vascularization. In this study, the angiogenic potential of secretomes of undifferentiated and osteo-differentiated BMMSCs, ADMSCs, and UCMSCs seeded on human decellularized allogeneic bone were compared. Human umbilical vein endothelial cells (HUVECs) were treated with MSC secretomes. Cell growth, cell migration, and angiogenesis of HUVECs were analyzed by MTT, wound healing, and tube formation assays. Angiogenic gene expression levels of MSCs were evaluated using real-time quantitative PCR. Antibody neutralization was performed to validate the candidate target. Our study demonstrates that the angiogenic gene expression profile is tissue-dependent and the angiogenic ability of secretomes is independent of the state of differentiation. We also explore that IL-1b is important for MSC angiogenic potential. Taken together, this study proves that IL-1b in the secretomes plays a vital role in angiogenesis.
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Affiliation(s)
- Yi-Chun Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Yu-Show Fu
- Department of Anatomy and Cell Biology, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shang-Wen Tsai
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Orthopaedics, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Po-Kuei Wu
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Orthopaedics, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chao-Ming Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Orthopaedics, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Wei-Ming Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Orthopaedics, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Cheng-Fong Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Department of Orthopaedics, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan
- Correspondence:
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17
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Zhu Q, Ding L, Yue R. Skeletal stem cells: a game changer of skeletal biology and regenerative medicine? LIFE MEDICINE 2022; 1:294-306. [PMID: 36811113 PMCID: PMC9938637 DOI: 10.1093/lifemedi/lnac038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/13/2022] [Indexed: 11/12/2022]
Abstract
Skeletal stem cells (SSCs) were originally discovered in the bone marrow stroma. They are capable of self-renewal and multilineage differentiation into osteoblasts, chondrocytes, adipocytes, and stromal cells. Importantly, these bone marrow SSCs localize in the perivascular region and highly express hematopoietic growth factors to create the hematopoietic stem cell (HSC) niche. Thus, bone marrow SSCs play pivotal roles in orchestrating osteogenesis and hematopoiesis. Besides the bone marrow, recent studies have uncovered diverse SSC populations in the growth plate, perichondrium, periosteum, and calvarial suture at different developmental stages, which exhibit distinct differentiation potential under homeostatic and stress conditions. Therefore, the current consensus is that a panel of region-specific SSCs collaborate to regulate skeletal development, maintenance, and regeneration. Here, we will summarize recent advances of SSCs in long bones and calvaria, with a special emphasis on the evolving concept and methodology in the field. We will also look into the future of this fascinating research area that may ultimately lead to effective treatment of skeletal disorders.
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Affiliation(s)
- Qiaoling Zhu
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Lei Ding
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine and Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
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Chetty S, Yarani R, Swaminathan G, Primavera R, Regmi S, Rai S, Zhong J, Ganguly A, Thakor AS. Umbilical cord mesenchymal stromal cells-from bench to bedside. Front Cell Dev Biol 2022; 10:1006295. [PMID: 36313578 PMCID: PMC9597686 DOI: 10.3389/fcell.2022.1006295] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022] Open
Abstract
In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.
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Affiliation(s)
- Shashank Chetty
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Reza Yarani
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Ganesh Swaminathan
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Rosita Primavera
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Shobha Regmi
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Sravanthi Rai
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Jim Zhong
- Department of Diagnostic and Interventional Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Abantika Ganguly
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Avnesh S Thakor
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
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Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying MicroRNA-181c-5p Promote BMP2-Induced Repair of Cartilage Injury through Inhibition of SMAD7 Expression. Stem Cells Int 2022; 2022:1157498. [PMID: 35782228 PMCID: PMC9249498 DOI: 10.1155/2022/1157498] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/29/2022] [Indexed: 12/14/2022] Open
Abstract
The therapy role of mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) in cartilage regeneration has been well studied. Herein, we tried to analyze the role of human umbilical cord MSC- (hUCMSC-) EVs carrying microRNA- (miR-) 181c-5p in repair of cartilage injury. After successful isolation of hUCMSCs, the multidirectional differentiation abilities were analyzed. Then, the EVs were isolated and identified. After coculture of PKH26-labled EVs with bone marrow MSCs (BMSCs), the biological behaviors of which were detected. The relationship between the predicted early posttraumatic osteoarthritis-associated miRNA, miR-181c-5p, and SMAD7 was verified. Gain- and loss-of functions were performed for investing the role of miR-181c-5p and SMAD7 in BMP-induced chondrogenesis in vitro and in vivo. hUCMSC-EVs could be internalized by BMSCs and promote the proliferative, migratory, and chondrogenic differentiation potentials of BMSCs. Additionally, miR-181c-5p could target and inhibit SMAD7 expression to promote the bone morphogenic protein 2- (BMP2-) induced proliferative, migratory, and chondrogenic differentiation potentials of BMSCs. Also, overexpression of SMAD7 inhibited the repairing effect of BMP2, and overexpression of BMP2 and miR-181c-5p further promoted the repair of cartilage injury in vivo. Our present study highlighted the repairing effect of hUCMSC-EVs carrying miR-181c-5p on cartilage injury.
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Genç D, Günaydın B, Sezgin S, Aladağ A, Tarhan EF. The Comparison of the Differentiation Potential of Periodontal Ligament and Dental Pulp Mesenchymal Stem Cells in the Inflammatory Synovium Microenvironment. CYPRUS JOURNAL OF MEDICAL SCIENCES 2022. [DOI: 10.4274/cjms.2022.2021-192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Yi H, Wang Y, Liang Q, Mao X. Preclinical and Clinical Amelioration of Bone Fractures with Mesenchymal Stromal Cells: a Systematic Review and Meta-Analysis. Cell Transplant 2022; 31:9636897211051743. [PMID: 35916286 PMCID: PMC9350497 DOI: 10.1177/09636897211051743] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Even though reunion of bone fracture confronts clinicians, mesenchymal stromal
cells (MSCs) are investigated to be curative in bone fracture. This study aimed
to explore the application potential of MSCs for healing bone fractures. By
inputting search terms and retrieving studies published up to March 2021,
multiple databases, including PubMed, EMBASE, Web of Science, and Cochrane
Library, were searched to identify eligible studies. The mean difference (MD)
and 95% confidence interval (95% CI) were calculated to analyze the main results
in the meta-analysis. Data analysis was performed using Engauge Digitizer 10.8
and R Software. Of the 31 articles, 26 were preclinical studies
(n = 913), and 5 were clinical trials (n =
335). Preclinically, MSCs therapy significantly augmented the progress of bone
regeneration [(bone volume over tissue volume (MD7.35, p <
0.01)], despite some non-significant effects (on the callus index, bone
strength, work to failure, and stiffness). Clinically, the MSC group had a
significantly reduced incidence of poor recovery (odds ratio (OR) 0.30,
p < 0.01); however, a significant decrease in healing
time was not observed in the MSC group (MD 2.47, p = 0.26). In
summary, our data suggest that patients with bone fractures benefited from MSC
administration and that MSCs are a potentially useful agent for bone
regeneration. Despite these satisfactory outcomes, larger randomised clinical
trials (RCTs) are necessary to confirm these findings.
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Affiliation(s)
- Hanxiao Yi
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yang Wang
- Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Qunying Liang
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoqun Mao
- Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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22
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Ahani-Nahayati M, Niazi V, Moradi A, Pourjabbar B, Roozafzoon R, Baradaran-Rafii A, Keshel SH. Umbilical cord mesenchymal stem/stromal cells potential to treat organ disorders; an emerging strategy. Curr Stem Cell Res Ther 2021; 17:126-146. [PMID: 34493190 DOI: 10.2174/1574888x16666210907164046] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 11/22/2022]
Abstract
Currently, mesenchymal stem/stromal cells (MSCs) have attracted growing attention in the context of cell-based therapy in regenerative medicine. Following the first successful procurement of human MSCs from bone marrow (BM), these cells isolation has been conducted from various origins, in particular, the umbilical cord (UC). Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) can be acquired by a non-invasive plan and simply cultured, and thereby signifies their superiority over MSCs derived from other sources for medical purposes. Due to their unique attributes, including self-renewal, multipotency, and accessibility concomitant with their immunosuppressive competence and lower ethical concerns, UC-MSCs therapy is described as encouraging therapeutic options in cell-based therapies. Regardless of their unique aptitude to adjust inflammatory response during tissue recovery and delivering solid milieu for tissue restoration, UC-MSCs can be differentiated into a diverse spectrum of adult cells (e.g., osteoblast, chondrocyte, type II alveolar, hepatocyte, and cardiomyocyte). Interestingly, they demonstrate a prolonged survival and longer telomeres compared with MSCs derived from other sources, suggesting that UC-MSCs are desired source to use in regenerative medicine. In the present review, we deliver a brief review of UC-MSCs isolation, expansion concomitantly with immunosuppressive activities, and try to collect and discuss recent pre-clinical and clinical researches based on the use of UC-MSCs in regenerative medicine, focusing on with special focus on in vivo researches.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Alireza Moradi
- Department of Physiology, School of Medicine, Iran University of Medical Science, Tehran. Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Reza Roozafzoon
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | | | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
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23
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Integration of Umbilical Cord Mesenchymal Stem Cell Application in Hydroxyapatite-Based Scaffolds in the Treatment of Vertebral Bone Defect due to Spondylitis Tuberculosis: A Translational Study. Stem Cells Int 2021; 2021:9928379. [PMID: 34475959 PMCID: PMC8407992 DOI: 10.1155/2021/9928379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/01/2021] [Accepted: 08/01/2021] [Indexed: 11/23/2022] Open
Abstract
Background Vertebral bone defect represents one of the most commonly found skeletal problems in the spine. Progressive increase of vertebral involvement of skeletal tuberculosis (TB) is reported as the main cause, especially in developed countries. Conventional spinal fusion using bone graft has been associated with donor-site morbidity and complications. We reported the utilization of umbilical cord mesenchymal stem cells (UC-MSCs) combined with hydroxyapatite (HA) based scaffolds in treating vertebral bone defect due to spondylitis tuberculosis. Materials and Methods Three patients with tuberculous spondylitis in the thoracic, thoracolumbar, or lumbar region with vertebral body collapse of more than 50 percent were included. The patient underwent a 2-stage surgical procedure, consisting of debridement, decompression, and posterior stabilization in the first stage followed by anterior fusion using the lumbotomy approach at the second stage. Twenty million UC-MSCs combined with HA granules in 2 cc of saline were transplanted to fill the vertebral bone defect. Postoperative alkaline phosphatase level, quality of life, and radiological healing were evaluated at one-month, three-month, and six-month follow-up. Results The initial mean ALP level at one-month follow-up was 48.33 ± 8.50 U/L. This value increased at the three-month follow-up but decreased at the six-month follow-up time, 97 ± 8.19 U/L and 90.33 ± 4.16 U/L, respectively. Bone formation of 50-75% of the defect site with minimal fracture line was found. Increased bone formation comprising 75-100% of the total bone area was reported six months postoperation. A total score of the SF-36 questionnaire showed better progression in all 8 domains during the follow-up with the mean total score at six months of 2912.5 ± 116.67 from all patients. Conclusion Umbilical cord mesenchymal stem cells combined with hydroxyapatite-based scaffold utilization represent a prospective alternative therapy for bone formation and regeneration of vertebral bone defect due to spondylitis tuberculosis. Further clinical investigations are needed to evaluate this new alternative.
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24
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Microenvironment Influences on Human Umbilical Cord Mesenchymal Stem Cell-Based Bone Regeneration. Stem Cells Int 2021; 2021:4465022. [PMID: 34447439 PMCID: PMC8384552 DOI: 10.1155/2021/4465022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/26/2021] [Indexed: 01/08/2023] Open
Abstract
The microenvironment, or niche, regulates stem cell fate and improves differentiation efficiency. Human umbilical cord mesenchymal stem cells (hUC-MSCs) are ideal cell source for bone tissue engineering. However, the role of the microenvironments in hUC-MSC-based bone regeneration is not yet fully understood. This study is aimed at investigating the effects of the in vitro culture microenvironment (hUC-MSCs, nano-hydroxyapatite/collagen/poly (L-lactide) (nHAC/PLA), osteogenic media (OMD), and recombinant human bone morphogenetic protein-7 (rhBMP-7)) and the in vivo transplanted microenvironment (ectopic and orthotopic) on bone regeneration ability of hUC-MSCs. The isolated hUC-MSCs showed self-renewal potential and MSCs' characteristics. In the in vitro two-dimensional culture microenvironment, OMD or OMD with rhBMP-7 significantly enhanced hUC-MSCs' osteocalcin immunofluorescence staining, alkaline phosphatase, and Alizarin red staining; OMD with rhBMP-7 exhibited the highest ALP secretion and mineralized matrix formation. In the in vitro three-dimensional culture microenvironment, nHAC/PLA supported hUC-MSCs' adhesion, proliferation, and differentiation; the microenvironment containing OMD or OMD and rhBMP-7 shortened cell proliferation progression and made osteogenic differentiation progression advance; rhBMP-7 significantly attenuated the inhibiting effect of OMD on hUC-MSCs' proliferation and significantly enhanced the promoting effect of OMD on gene expression and protein secretion of osteogenic differentiation markers, calcium and phosphorous concentration, and mineralized matrix formation. The in vitro three-dimensional culture microenvironment containing OMD and rhBMP-7 induced hUC-MSCs to form the most new bones in ectopic or orthotopic microenvironment as proved by microcomputed tomography and hematoxylin and eosin staining, but bone formation in orthotopic microenvironment was significantly higher than that in ectopic microenvironment. The results indicated that the combination of in vitro hUC-MSCs+nHAC/PLA+OMD+rhBMP-7 microenvironment and in vivo orthotopic microenvironment provided a more optimized niche for bone regeneration of hUC-MSCs. This study elucidates that hUC-MSCs and their local microenvironment, or niche, play an important role in hUC-MSC-based bone regeneration. The endogenously produced BMP may serve an important regulatory role in the process.
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25
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Liu J, Peng D, You J, Zhou O, Qiu H, Hao C, Chen H, Fu Z, Zou L. Type 2 Alveolar Epithelial Cells Differentiated from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Mouse Pulmonary Fibrosis Through β-Catenin-Regulated Cell Apoptosis. Stem Cells Dev 2021; 30:660-670. [PMID: 33899513 DOI: 10.1089/scd.2020.0208] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Pulmonary fibrosis (PF) is a chronic, progressive, and lethal disease with little response to available therapies. One of the major mechanisms of PF is the repeated injury and inadequate regeneration of the alveolar epithelium. In this study, we induced human umbilical cord mesenchymal stem cells (hUC-MSCs) to differentiate into type 2 alveolar epithelial cells (AEC2s), and we provided evidence that intratracheal transplantation of hUC-MSC-derived AEC2s (MSC-AEC2s) could improve mortality and alleviate fibrosis in bleomycin-induced PF mice. Transplantation of MSC-AEC2s could increase the AEC2 cell count in these mice, and the results of the cell tracing experiment exhibited that the increased AEC2s originated from the self-renewal of mouse alveolar epithelium. The AEC2 survival was controlled by the apoptosis of AEC2s via the expression of β-catenin in PF mice. In in vitro experiments, MSC-AEC2s could alleviate the apoptosis of MLE-12 cells induced by transforming growth factor beta (TGF-β1), which could be eliminated by using PRI-724, a β-catenin inhibitor, suggesting β-catenin signaling involved in the protection against apoptosis provided by MSC-AEC2s. Our study demonstrated that MSC-AEC2s could protect PF mice through regulating apoptosis mediated by β-catenin, which provided a viable strategy for the treatment of PF.
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Affiliation(s)
- Jiang Liu
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Danyi Peng
- Department of Respiratory, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jingyi You
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China.,Department of Respiratory, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ou Zhou
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Huijun Qiu
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Chang Hao
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Chen
- Department of Pediatric, the First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Haerbin, China
| | - Zhou Fu
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China.,Department of Respiratory, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Zou
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy; Children's Hospital of Chongqing Medical University, Chongqing, China.,Center of Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.,Clinical Research Unit, Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
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26
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Zhao L, Hu C, Han F, Chen D, Ma Y, Cai F, Chen J. Combination of mesenchymal stromal cells and machine perfusion is a novel strategy for organ preservation in solid organ transplantation. Cell Tissue Res 2021; 384:13-23. [PMID: 33439348 PMCID: PMC8016762 DOI: 10.1007/s00441-020-03406-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/15/2020] [Indexed: 12/22/2022]
Abstract
Organ preservation is a prerequisite for an urgent increase in the availability of organs for solid organ transplantation (SOT). An increasing amount of expanded criteria donor (ECD) organs are used clinically. Currently, the paradigm of organ preservation is shifting from simple reduction of cellular metabolic activity to maximal simulation of an ex vivo physiological microenvironment. An ideal organ preservation technique should not only preserve isolated organs but also offer the possibility of rehabilitation and evaluation of organ function prior to transplantation. Based on the fact that mesenchymal stromal cells (MSCs) possess strong regeneration properties, the combination of MSCs with machine perfusion (MP) is expected to be superior to conventional preservation methods. In recent years, several studies have attempted to use this strategy for SOT showing promising outcomes. With better organ function during ex vivo preservation and the potential of utilization of organs previously deemed untransplantable, this strategy is meaningful for patients with organ failure to help overcome organ shortage in the field of SOT.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Fei Han
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Dajin Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Yanhong Ma
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Fanghao Cai
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang Province People’s Republic of China
- Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
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27
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Xia Y, Ling X, Hu G, Zhu Q, Zhang J, Li Q, Zhao B, Wang Y, Deng Z. Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke. Stem Cell Res Ther 2020; 11:313. [PMID: 32698909 PMCID: PMC7374834 DOI: 10.1186/s13287-020-01834-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/21/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Background Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions. Methods Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro. Results We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro. Conclusions Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.
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Affiliation(s)
- Yuguo Xia
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Xiaozheng Ling
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Guowen Hu
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Qingwei Zhu
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Juntao Zhang
- Institute of Microsurgery and Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Qing Li
- Institute of Microsurgery and Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Bizeng Zhao
- Institute of Microsurgery and Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Yang Wang
- Institute of Microsurgery and Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
| | - Zhifeng Deng
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
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28
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Liu J, Wang H, Ren W, Zhou Y, Ye Z, Tan WS. β-mercaptoethanol promotes osteogenesis of human mesenchymal stem cells via sirt1-ERK pathway. Cytotechnology 2020; 72:695-706. [PMID: 32691200 DOI: 10.1007/s10616-020-00412-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (hUMSCs) hold strong self-renewal capacity and low immunogenicity, which have attracted attention as potential candidates for bone repair and regeneration. However, insufficient osteogenic differentiation markedly hinders the clinical applications of hUMSCs. In the present study, the effect of β-mercaptoethanol (BME), a small molecule antioxidant which has been identified to regulate cell proliferation and differentiation, on osteogenic differentiation of hUMSCs and underlying signaling mechanism were investigated. The results indicated that under osteogenic induction conditions, BME treatment increased the alkaline phosphatase (ALP) activity and promoted calcium mineralization in hUMSCs. The gene and protein expression of osteogenesis-related markers such as ALP, osteopontin (OPN), osteocalcin (OCN) and collagen type I (COLI) were also significantly up-regulated. Besides, BME promoted the protein expression of silent information regulator type 1 (sirt1) and stimulated the activation of extracellular signal-related kinase (ERK), contributing to increased Runx2 expression. Furthermore, blocking the expression of sirt1 attenuated BME-enhanced ERK phosphorylation and osteogenic differentiation of hUMSCs. These results indicated that BME accelerated osteogenic differentiation of hUMSCs by activating the sirt1-ERK signaling pathway, thereby providing insights into the development of MSCs-based bone regeneration strategies.
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Affiliation(s)
- Jiaxing Liu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China
| | - Hui Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China
| | - Wenxia Ren
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China
| | - Yan Zhou
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China.
| | - Zhaoyang Ye
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China
| | - Wen-Song Tan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Mei-Long Road, P. O. Box 309#, Shanghai, 200237, People's Republic of China
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29
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Zheng JH, Zhang JK, Kong DS, Song YB, Zhao SD, Qi WB, Li YN, Zhang ML, Huang XH. Quantification of the CM-Dil-labeled human umbilical cord mesenchymal stem cells migrated to the dual injured uterus in SD rat. Stem Cell Res Ther 2020; 11:280. [PMID: 32660551 PMCID: PMC7359016 DOI: 10.1186/s13287-020-01806-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 05/29/2020] [Accepted: 07/01/2020] [Indexed: 12/23/2022] Open
Abstract
Background Human umbilical cord mesenchymal stem cell (hUC-MSC) therapy is considered as a promising approach in the treatment of intrauterine adhesions (IUAs). Considerable researches have already detected hUC-MSCs by diverse methods. This paper aims at exploring the quantitative distribution of CM-Dil-labeled hUC-MSCs in different regions of the uterus tissue of the dual injury-induced IUAs in rats and the underlying mechanism of restoration of fertility after implantation of hUC-MSCs in the IUA model. Methods In this study, we investigated the quantification of the CM-Dil-labeled hUC-MSCs migrated to the dual injured uterus in Sprague Dawley rats. Additionally, we investigated the differentiation of CM-Dil-labeled hUC-MSCs. The differentiation potential of epithelial cells, vascular endothelial cells, and estrogen receptor (ER) cells were assessed by an immunofluorescence method using CK7, CD31, and ERα. The therapeutic impact of hUC-MSCs in the IUA model was assessed by hematoxylin and eosin, Masson, immunohistochemistry staining, and reproductive function test. Finally, the expression of TGF-β1/Smad3 pathway in uterine tissues was determined by qRT-PCR and Western blotting. Results The CM-Dil-labeled cells in the stroma region were significantly higher than those in the superficial myometrium (SM) (71.67 ± 7.98 vs. 60.92 ± 3.96, p = 0.005), in the seroma (71.67 ± 7.98 vs. 23.67 ± 8.08, p = 0.000) and in the epithelium (71.67 ± 7.98 vs. 4.17 ± 1.19, p = 0.000). From the 2nd week of treatment, hUC-MSCs began to differentiate into epithelial cells, vascular endothelial cells, and ER cells. The therapeutic group treated with hUC-MSCs exhibited a significant decrease in fibrosis (TGF-β1/Smad3) as well as a significant increase in vascularization (CD31) compared with the untreated rats. Conclusion Our findings suggested that the distribution of the migrated hUC-MSCs in different regions of the uterine tissue was unequal. Most cells were in the stroma and less were in the epithelium of endometrium and gland. Injected hUC-MSCs had a capacity to differentiate into epithelial cells, vascular endothelial cells, and ER cells; increase blood supply; inhibit fibration; and then restore the fertility of the IUA model.
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Affiliation(s)
- Jia-Hua Zheng
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jing-Kun Zhang
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - De-Sheng Kong
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yan-Biao Song
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shuang-Dan Zhao
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wen-Bo Qi
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ya-Nan Li
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ming-le Zhang
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiang-Hua Huang
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
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30
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Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AA, Yousefi M, Talebi M, Shamsasenjan K. Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J Cell Physiol 2020; 235:9230-9240. [PMID: 32557631 DOI: 10.1002/jcp.29810] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022]
Abstract
Umbilical cord Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have recently gained considerable attention in the field of regenerative medicine. Their high proliferation rate, differentiation ability into various cell lineages, easy collection procedure, immuno-privileged status, nontumorigenic properties along with minor ethical issues make them an ideal approach for tissue repair. Besides, the number of WJ-MSCs in the umbilical cord samples is high as compared to other sources. Because of these properties, WJ-MSCs have rapidly advanced into clinical trials for the treatment of a wide range of disorders. Therefore, this paper summarized the current preclinical and clinical studies performed to investigate the regenerative potential of WJ-MSCs in neural, myocardial, skin, liver, kidney, cartilage, bone, muscle, and other tissue injuries.
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Affiliation(s)
- Hossein Abbaszadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Ghorbani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Derakhshani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Barre A, Naudot M, Colin F, Sevestre H, Collet L, Devauchelle B, Lack S, Marolleau JP, Le Ricousse S. An Alginate-Based Hydrogel with a High Angiogenic Capacity and a High Osteogenic Potential. Biores Open Access 2020; 9:174-182. [PMID: 32642332 PMCID: PMC7337169 DOI: 10.1089/biores.2020.0010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2020] [Indexed: 12/22/2022] Open
Abstract
In bone tissue engineering, autologous cells are combined with osteoconductive scaffolds and implanted into bone defects. The major challenge is the lack of post-implantation vascular growth into biomaterial. The objective of the present study was to develop a new alginate-based hydrogel that enhances the regeneration of bone defects after surgery. The viability of human bone marrow-derived mesenchymal stem cells (BM-MSCs) or human endothelial cells (ECs) cultured alone or together on the hydrogel was analyzed for 24 and 96 h. After seeding, the cells self-assembled and aggregated to form clusters. For functional validation, empty or cellularized hydrogel matrices were implanted ectopically at subcutaneous sites in nude mice. After 2 months, the matrices were explanted. Transplanted human cells were present, and we observed vessels expressing human von Willebrand factor (resulting from the incorporation of transplanted ECs into neovessels and/or the differentiation of BM-MSCs into ECs). The addition of BM-MSCs improved host vascularization and neovessel formation from human cells, relative to ECs alone. Although we did not observe bone formation, the transplanted BM-MSCs were able to differentiate into osteoblasts. This new biomaterial provided an appropriate three-dimensional environment for transplanted cells and has a high angiogenic capacity and an osteogenic potential.
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Affiliation(s)
- Anaïs Barre
- EA7516, CHIMERE, Jules Verne University of Picardie, Amiens, France
| | - Marie Naudot
- EA7516, CHIMERE, Jules Verne University of Picardie, Amiens, France
| | | | - Henri Sevestre
- Department of Pathology and Anatomy, Amiens University Medical Center, Amiens, France
| | - Louison Collet
- EA4666 HEMATIM, Jules Verne University of Picardie, Amiens, France
| | - Bernard Devauchelle
- EA7516, CHIMERE, Jules Verne University of Picardie, Amiens, France.,Department of Maxillofacial Surgery, Amiens University Medical Center, Amiens, France.,Facing Faces Institute, Amiens, France
| | | | - Jean-Pierre Marolleau
- EA4666 HEMATIM, Jules Verne University of Picardie, Amiens, France.,Facing Faces Institute, Amiens, France.,Department of Hematology, Amiens University Medical Center, Amiens, France
| | - Sophie Le Ricousse
- EA7516, CHIMERE, Jules Verne University of Picardie, Amiens, France.,Facing Faces Institute, Amiens, France
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32
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Mehdipour A, Ebrahimi A, Shiri-Shahsavar MR, Soleimani-Rad J, Roshangar L, Samiei M, Ebrahimi-Kalan A. The potentials of umbilical cord-derived mesenchymal stem cells in the treatment of multiple sclerosis. Rev Neurosci 2020; 30:857-868. [PMID: 31026226 DOI: 10.1515/revneuro-2018-0057] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 02/15/2019] [Indexed: 12/12/2022]
Abstract
Stem cell therapy has indicated a promising treatment capacity for tissue regeneration. Multiple sclerosis is an autoimmune-based chronic disease, in which the myelin sheath of the central nervous system is destructed. Scientists have not discovered any cure for multiple sclerosis, and most of the treatments are rather palliative. The pursuit of a versatile treatment option, therefore, seems essential. The immunoregulatory and non-chronic rejection characteristics of mesenchymal stem cells, as well as their homing properties, recommend them as a prospective treatment option for multiple sclerosis. Different sources of mesenchymal stem cells have distinct characteristics and functional properties; in this regard, choosing the most suitable cell therapy approach seems to be challenging. In this review, we will discuss umbilical cord/blood-derived mesenchymal stem cells, their identified exclusive properties compared to another adult mesenchymal stem cells, and the expectations of their potential roles in the treatment of multiple sclerosis.
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Affiliation(s)
- Ahmad Mehdipour
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayyub Ebrahimi
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Haliç University, Istanbul, Turkey
| | | | - Jafar Soleimani-Rad
- Department of Anatomical Sciences, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Department of Anatomical Sciences, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Samiei
- Endodontics Department of Dental Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Radiology, School of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran,
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33
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Xu GP, Zhang XF, Sun L, Chen EM. Current and future uses of skeletal stem cells for bone regeneration. World J Stem Cells 2020; 12:339-350. [PMID: 32547682 PMCID: PMC7280866 DOI: 10.4252/wjsc.v12.i5.339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/07/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
The postnatal skeleton undergoes growth, modeling, and remodeling. The human skeleton is a composite of diverse tissue types, including bone, cartilage, fat, fibroblasts, nerves, blood vessels, and hematopoietic cells. Fracture nonunion and bone defects are among the most challenging clinical problems in orthopedic trauma. The incidence of nonunion or bone defects following fractures is increasing. Stem and progenitor cells mediate homeostasis and regeneration in postnatal tissue, including bone tissue. As multipotent stem cells, skeletal stem cells (SSCs) have a strong effect on the growth, differentiation, and repair of bone regeneration. In recent years, a number of important studies have characterized the hierarchy, differential potential, and bone formation of SSCs. Here, we describe studies on and applications of SSCs and/or mesenchymal stem cells for bone regeneration.
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Affiliation(s)
- Guo-Ping Xu
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiang-Feng Zhang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Lu Sun
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, United States
| | - Er-Man Chen
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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34
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Liu Y, Fang J, Zhang Q, Zhang X, Cao Y, Chen W, Shao Z, Yang S, Wu D, Hung M, Zhang Y, Tong W, Tian H. Wnt10b-overexpressing umbilical cord mesenchymal stem cells promote critical size rat calvarial defect healing by enhanced osteogenesis and VEGF-mediated angiogenesis. J Orthop Translat 2020; 23:29-37. [PMID: 32477867 PMCID: PMC7248289 DOI: 10.1016/j.jot.2020.02.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/08/2020] [Accepted: 02/13/2020] [Indexed: 01/04/2023] Open
Abstract
Background/objectives Accelerating the process of bone regeneration is of great interest for surgeons and basic scientists alike. Recently, umbilical cord mesenchymal stem cells (UCMSCs) are considered clinically applicable for tissue regeneration due to their noninvasive harvesting and better viability. Nonetheless, the bone regenerative ability of human UCMSCs (HUCMSCs) is largely unknown. This study aimed to investigate whether Wnt10b-overexpressing HUCMSCs have enhanced bone regeneration ability in a rat model. Method A rat calvarial defect was performed on 8-week old male Sprague Dawley rats. Commercially purchased HUCMSCsEmp in hydrogel, HUCMSCsWnt10b in hydrogel and HUCMSCsWnt10b with IWR-1 were placed in the calvarial bone defect right after surgery on rats (N = 8 rats for each group). Calvaria were harvested for micro-CT analysis and histology four weeks after surgery. CFU-F and multi-differentiation assay by oil red staining, alizarin red staining and RT-PCR (real-time polymerase chain reaction) were performed on HUCMSCsEmp and HUCMSCsWnt10bin vitro. Conditioned media from HUCMSCsEmp and HUCMSCsWnt10b were collected and used to treat human umbilical cord vein endothelial cells in Matrigel to access vessel formation capacity by tube formation assay. Results Alizarin red staining, oil red staining and RT-PCR results showed robust osteogenic differentiation but poor adipogenic differentiation ability of HUCMSCsWnt10b. Furthermore, HUCMSCsWnt10b could accelerate bone defect healing, which was likely due to enhanced angiogenesis after the HUCMSCsWnt10b treatment, because more CD31+ vessels and increased vascular endothelial growth factor-A (VEGF-A) expression were observed, compared with the HUCMSCsEmp treatment. Conditioned media from HUCMSCsWnt10b also induced endothelial cells to form vessel tubes in a tube formation assay, which could be abolished by SU5416, an angiogenesis inhibitor. Conclusion To our knowledge, this is the first study providing empirical evidence that HUCMSCsWnt10b can enhance their ability to heal calvarial bone defects via VEGF-mediated angiogenesis. The translational potential of this article HUCMSCsWnt10b can accelerate critical size calvaria and are a new promising therapeutic cell source for fracture nonunion healing.
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Affiliation(s)
- Yong Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Jiarui Fang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Quan Zhang
- Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, Hubei, 430075, China
| | - Xiaoguang Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Yulin Cao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Wei Chen
- The Third Hospital of Hebei Medical University, 139, Ziqiang Road, Shi Jiazhuang, Hebei, 050051, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Shuhua Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Dongcheng Wu
- Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, Hubei, 430075, China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, China
| | - Man Hung
- College of Dental Medicine, Roseman University of Health Sciences, 10984 S River Front Pkwy, South Jordan, UT, 84095, USA
| | - Yingze Zhang
- The Third Hospital of Hebei Medical University, 139, Ziqiang Road, Shi Jiazhuang, Hebei, 050051, China
| | - Wei Tong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
| | - Hongtao Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277, Jiefang Avenue, Wuhan, Hubei, 430022, China
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Yang S, Zhu B, Yin P, Zhao L, Wang Y, Fu Z, Dang R, Xu J, Zhang J, Wen N. Integration of Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomes with Hydroxyapatite-Embedded Hyaluronic Acid-Alginate Hydrogel for Bone Regeneration. ACS Biomater Sci Eng 2020; 6:1590-1602. [PMID: 33455380 DOI: 10.1021/acsbiomaterials.9b01363] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The treatment of bone defects has plagued clinicians. Exosomes, the naturally secreted nanovesicles by cells, exhibit great potential in bone defect regeneration to realize cell-free therapy. In this work, we successfully revealed that human umbilical cord mesenchymal stem cells-derived exosomes could effectively promote the proliferation, migration, and osteogenic differentiation of a murine calvariae preosteoblast cell line in vitro. Considering the long period of bone regeneration, to effectively exert the reparative effect of exosomes, we synthesized an injectable hydroxyapatite (HAP)-embedded in situ cross-linked hyaluronic acid-alginate (HA-ALG) hydrogel system to durably retain exosomes at the defect sites. Then, we combined the exosomes with the HAP-embedded in situ cross-linked HA-ALG hydrogel system to repair bone defects in rats in vivo. The results showed that the combination of exosomes and composite hydrogel could significantly enhance bone regeneration. Our experiment provides a new strategy for exosome-based therapy, which shows great potential in future tissue and organ repair.
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Affiliation(s)
- Shuo Yang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Biao Zhu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Peng Yin
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Lisheng Zhao
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yizhu Wang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhiguang Fu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Ruijie Dang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Juan Xu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Jianjun Zhang
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Ning Wen
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
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36
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Hu Y, Zhang Y, Ni CY, Chen CY, Rao SS, Yin H, Huang J, Tan YJ, Wang ZX, Cao J, Liu ZZ, Xie PL, Wu B, Luo J, Xie H. Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism. Am J Cancer Res 2020; 10:2293-2308. [PMID: 32089743 PMCID: PMC7019162 DOI: 10.7150/thno.39238] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/30/2019] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis and osteoporotic fractures severely compromise quality of life in elderly people and lead to early death. Human umbilical cord mesenchymal stromal cell (MSC)-derived extracellular vesicles (hucMSC-EVs) possess considerable therapeutic effects in tissue repair and regeneration. Thus, in the present study, we investigated the effects of hucMSC-EVs on primary and secondary osteoporosis and explored the underlying mechanisms. Methods: hucMSCs were isolated and cultured. EVs were obtained from the conditioned medium of hucMSCs and determined by using transmission electron microscopy, dynamic light scattering and Western Blot analyses. The effects of hucMSC-EVs on ovariectomy-induced postmenopausal osteoporosis and tail suspension-induced hindlimb disuse osteoporosis in mouse models were assessed by using microcomputed tomography, biomechanical, histochemical and immunohistochemical, as well as histomorphometric analyses. Proteomic analysis was applied between hucMSC-EVs and hucMSCs to screen the candidate proteins that mediate hucMSC-EVs function. The effects of hucMSC-EVs on osteogenic and adipogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs), and osteoclastogenesis of the macrophage cell line RAW264.7 in vitro were determined by using cytochemical staining and quantitative real-time PCR analysis. Subsequently, the roles of the key protein in hucMSC-EVs-induced regulation on BMSCs and RAW264.7 cells were evaluated. Results: hucMSCs were able to differentiate into osteoblasts, adipocytes or chondrocytes and positively expressed CD29, CD44, CD73 and CD90, but negatively expressed CD34 and CD45. The morphological assessment revealed the typical cup- or sphere-shaped morphology of hucMSC-EVs with diameters predominantly ranging from 60 nm to 150 nm and expressed CD9, CD63, CD81 and TSG101. The systemic administration of hucMSC-EVs prevented bone loss and maintained bone strength in osteoporotic mice by enhancing bone formation, reducing marrow fat accumulation and decreasing bone resorption. Proteomic analysis showed that the potently pro-osteogenic protein, CLEC11A (C-type lectin domain family 11, member A) was very highly enriched in hucMSC-EVs. In addition, hucMSC-EVs enhanced the shift from adipogenic to osteogenic differentiation of BMSCs via delivering CLEC11A in vitro. Moreover, CLEC11A was required for the inhibitory effects of hucMSC-EVs on osteoclast formation. Conclusion: Our results suggest that hucMSC-EVs serve as a critical regulator of bone metabolism by transferring CLEC11A and may represent a potential agent for prevention and treatment of osteoporosis.
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Naudot M, Barre A, Caula A, Sevestre H, Dakpé S, Mueller AA, Devauchelle B, Testelin S, Marolleau JP, Le Ricousse S. Co-transplantation of Wharton's jelly mesenchymal stem cell-derived osteoblasts with differentiated endothelial cells does not stimulate blood vessel and osteoid formation in nude mice models. J Tissue Eng Regen Med 2020; 14:257-271. [PMID: 31713308 DOI: 10.1002/term.2989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 09/23/2019] [Accepted: 10/11/2019] [Indexed: 12/30/2022]
Abstract
A major challenge in bone tissue engineering is the lack of post-implantation vascular growth into biomaterials. In the skeletal system, blood vessel growth appears to be coupled to osteogenesis-suggesting the existence of molecular crosstalk between endothelial cells (ECs) and osteoblastic cells. The present study (performed in two murine ectopic models) was designed to determine whether co-transplantation of human Wharton's jelly mesenchymal stem cell-derived osteoblasts (WJMSC-OBs) and human differentiated ECs enhances bone regeneration and stimulates angiogenesis, relative to the seeding of WJMSC-OBs alone. Human WJMSC-OBs and human ECs were loaded into a silicate-substituted calcium phosphate (SiCaP) scaffold and then ectopically implanted at subcutaneous or intramuscular sites in nude mice. At both subcutaneous and intramuscular implantation sites, we observed ectopic bone formation and osteoids composed of host cells when WJMSC-OBs were seeded into the scaffold. However, the addition of ECs was associated with a lower level of osteogenesis, and we did not observe stimulation of blood vessel ingrowth. in vitro studies demonstrated that WJMSC-OBs lost their ability to secrete vascular endothelial growth factor and stromal cell-derived factor 1-including when ECs were present. In these two murine ectopic models, our cell-matrix environment combination did not seem to be optimal for inducing vascularized bone reconstruction.
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Affiliation(s)
- Marie Naudot
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France
| | - Anaïs Barre
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France
| | - Alexandre Caula
- Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France
| | - Henri Sevestre
- Service d'anatomie et de cytology pathologique, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France
| | - Stéphanie Dakpé
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Andreas Albert Mueller
- Department of Cranio-Maxillofacial Surgery, University and University Hospital Basel, Basel, Switzerland.,Department of Biomedical Engineering, Regenerative Medicine and Oral Health Technologies, University of Basel, Allschwil, Switzerland
| | - Bernard Devauchelle
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Sylvie Testelin
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Service de chirurgie maxillo-faciale, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,Institut Faire Faces, Amiens, France
| | - Jean Pierre Marolleau
- Service d'Hématologie Clinique, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.,EA 4666, HEMATIM, University of Picardie Jules Verne, Amiens, France
| | - Sophie Le Ricousse
- EA 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France.,Institut Faire Faces, Amiens, France
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38
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Efficient One-Step Induction of Human Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) Produces MSC-Derived Neurospheres (MSC-NS) with Unique Transcriptional Profile and Enhanced Neurogenic and Angiogenic Secretomes. Stem Cells Int 2019; 2019:9208173. [PMID: 31933651 PMCID: PMC6942888 DOI: 10.1155/2019/9208173] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 10/23/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023] Open
Abstract
Cell therapy has emerged as a promising strategy for treating neurological diseases such as stroke, spinal cord injury, and various neurodegenerative diseases, but both embryonic neural stem cells and human induced Pluripotent Stem Cell- (iPSC-) derived neural stem cells have major limitations which restrict their broad use in these diseases. We want to find a one-step induction method to transdifferentiate the more easily accessible Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) into neural stem/progenitor cells suitable for cell therapy purposes. In this study, UC-MSCs were induced to form neurospheres under a serum-free suspension culture with Epidermal Growth Factor- (EGF-) and basic Fibroblast Growth Factor- (bFGF-) containing medium within 12 hours. These MSC-derived neurospheres can self-renew to form secondary neurospheres and can be readily induced to become neurons and glial cells. Real-time PCR showed significantly upregulated expression of multiple stemness and neurogenic genes after induction. RNA transcriptional profiling study showed that UC-MSC-derived neurospheres had a unique transcriptional profile of their own, with features of both UC-MSCs and neural stem cells. RayBio human growth factor cytokine array analysis showed significantly upregulated expression levels of multiple neurogenic and angiogenic growth factors, skewing toward a neural stem cell phenotype. Thus, we believe that these UC-MSC-derived neurospheres have amenable features of both MSCs and neural stem/progenitor cells and have great potential in future stem cell transplantation clinical trials targeting neurological disorders.
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39
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Westhauser F, Widholz B, Nawaz Q, Tsitlakidis S, Hagmann S, Moghaddam A, Boccaccini AR. Favorable angiogenic properties of the borosilicate bioactive glass 0106-B1 result in enhanced in vivo osteoid formation compared to 45S5 Bioglass. Biomater Sci 2019; 7:5161-5176. [PMID: 31584047 DOI: 10.1039/c9bm01220f] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The 45S5-bioactive glass (BG) composition is the most commonly investigated amongst BG-based bone substitutes. By changing BG compositions and by addition of therapeutically active ions such as boron, the biological features of BGs can be tailored towards specific needs and possible drawbacks can be overcome. The borosilicate glass 0106-B1 (composition in wt%: 37.5 SiO2, 22.6 CaO, 5.9 Na2O, 4.0 P2O5, 12.0 K2O, 5.5 MgO, 12.5 B2O3) has demonstrated pro-angiogenic properties. However, the osteogenic performance of the 0106-B1-BG and its influence on cell viability and proliferation in vitro as well as its osteogenic and angiogenic properties in vivo have not been investigated. Therefore, in this study, the impact of 0106-B1-BG and 45S5-BG on osteogenic differentiation, viability and proliferation on human mesenchymal stromal cells (MSCs) was assessed in vitro. Furthermore, MSC-seeded scaffolds made from both BG types were implanted subcutaneously in immunodeficient mice for 10 weeks. Osteoid formation was quantified by histomorphometry, vascularization was visualized by immunohistological staining. Additionally, the in vivo expression patterns of genes correlating with osteogenesis and angiogenesis were analyzed. In vitro, the impact of 45S5-BG and 0106-B1-BG on the proliferation, viability and osteogenic differentiation of MSCs was comparable. In vivo, scaffolds made from 0106-B1-BG significantly outperformed the 45S5-BG-based scaffolds regarding the amount and maturation of the osteoid. Furthermore, 0106-B1-BG-based scaffolds showed significantly increased angiogenic gene expression patterns. In conclusion, the beneficial angiogenic properties of 0106-B1-BG result in improved osteogenic properties in vivo, making the 0106-B1-BG a promising candidate for further investigation, e.g. in a bone defect model.
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Affiliation(s)
- F Westhauser
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - B Widholz
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - Q Nawaz
- Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstr. 6, 91058 Erlangen, Germany.
| | - S Tsitlakidis
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - S Hagmann
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - A Moghaddam
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany. and ATORG - Aschaffenburg Trauma and Orthopedic Research Group, Center for Trauma Surgery, Orthopedics, and Sports Medicine, Klinikum Aschaffenburg-Alzenau, Am Hasenkopf 1, 63739 Aschaffenburg, Germany
| | - A R Boccaccini
- Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstr. 6, 91058 Erlangen, Germany.
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40
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Cui Y, Xu B, Yin Y, Chen B, Zhao Y, Xiao Z, Yang B, Meng Q, Fang Y, Liang Q, Zhou L, Ma X, Dai J. Repair of lumbar vertebral bone defects by bone particles combined with hUC-MSCs in weaned rabbit. Regen Med 2019; 14:915-923. [PMID: 31556342 DOI: 10.2217/rme-2018-0134] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Aim: The major symptom of many closed spinal dysraphism patients is that the laminas or arches of vertebra are not fused well. To date, the bone repair of spina bifida for young children is a significant challenge in clinical practice. Materials & methods: Bovine bone collagen particle (BBCP) scaffolds combined with human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were implanted in the defect area. X-ray analysis was performed after 3 months. Tissues were harvested for gross observation, and histological and immunohistochemical staining. Results: The BBCP supported hUC-MSCs adhesion and growth. Implanted BBCP combined with hUC-MSCs also promoted bone regeneration in the vertebral lamina and arch defect area. Conclusion: This method represents a new strategy for vertebral lamina and arch reconstruction in children.
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Affiliation(s)
- Yi Cui
- Reproductive & Genetic Center, National Research Institute for Family Planning, Beijing 100081, PR China
| | - Bai Xu
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Yanyun Yin
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Bing Chen
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Yannan Zhao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Zhifeng Xiao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Bin Yang
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Qingyuan Meng
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
| | - Yongxiang Fang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Ministry of Agriculture, Lanzhou Veterinary Research Institute, CAAS, Lanzhou 730046, PR China
| | - Qinghan Liang
- Department of Gynaecology, Beijing haidian maternal & child health hospital, Beijing 100089, PR China
| | - Ling Zhou
- Department of Gynaecology & Obstetrics, Strategic Support Force Medical Centre of PLA, Beijing 100101, PR China
| | - Xu Ma
- Reproductive & Genetic Center, National Research Institute for Family Planning, Beijing 100081, PR China
| | - Jianwu Dai
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100080, PR China
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Rauff A, LaBelle SA, Strobel HA, Hoying JB, Weiss JA. Imaging the Dynamic Interaction Between Sprouting Microvessels and the Extracellular Matrix. Front Physiol 2019; 10:1011. [PMID: 31507428 PMCID: PMC6713949 DOI: 10.3389/fphys.2019.01011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022] Open
Abstract
Thorough understanding of growth and evolution of tissue vasculature is fundamental to many fields of medicine including cancer therapy, wound healing, and tissue engineering. Angiogenesis, the growth of new vessels from existing ones, is dynamically influenced by a variety of environmental factors, including mechanical and biophysical factors, chemotactic factors, proteolysis, and interaction with stromal cells. Yet, dynamic interactions between neovessels and their environment are difficult to study with traditional fixed time imaging techniques. Advancements in imaging technologies permit time-series and volumetric imaging, affording the ability to visualize microvessel growth over 3D space and time. Time-lapse imaging has led to more informative investigations of angiogenesis. The environmental factors implicated in angiogenesis span a wide range of signals. Neovessels advance through stromal matrices by forming attachments and pulling and pushing on their microenvironment, reorganizing matrix fibers, and inducing large deformations of the surrounding stroma. Concurrently, neovessels secrete proteolytic enzymes to degrade their basement membrane, create space for new vessels to grow, and release matrix-bound cytokines. Growing neovessels also respond to a host of soluble and matrix-bound growth factors, and display preferential growth along a cytokine gradient. Lastly, stromal cells such as macrophages and mesenchymal stem cells (MSCs) interact directly with neovessels and their surrounding matrix to facilitate sprouting, vessel fusion, and tissue remodeling. This review highlights how time-lapse imaging techniques advanced our understanding of the interaction of blood vessels with their environment during sprouting angiogenesis. The technology provides means to characterize the evolution of microvessel behavior, providing new insights and holding great promise for further research on the process of angiogenesis.
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Affiliation(s)
- Adam Rauff
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
| | - Steven A. LaBelle
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
| | - Hannah A. Strobel
- Innovations Laboratory, Advanced Solutions Life Sciences, Manchester, NH, United States
| | - James B. Hoying
- Innovations Laboratory, Advanced Solutions Life Sciences, Manchester, NH, United States
| | - Jeffrey A. Weiss
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States
- Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, UT, United States
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Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Int J Oral Sci 2019; 11:23. [PMID: 31423011 PMCID: PMC6802669 DOI: 10.1038/s41368-019-0060-3] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/28/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
In modern medicine, bone and dental loss and defects are common and widespread morbidities, for which regenerative therapy has shown great promise. Mesenchymal stem cells, obtained from various sources and playing an essential role in organ development and postnatal repair, have exhibited enormous potential for regenerating bone and dental tissue. Currently, mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled, especially in diseased microenvironments. Specifically, the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs, both as donors and recipients. Accordingly, approaches targeting a diseased microenvironment have been established, including improving the diseased niche to restore endogenous MSCs, enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies. Moreover, the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy. In this review, we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment, emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.
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Mesenchymal Stem Cell Therapy Facilitates Donor Lung Preservation by Reducing Oxidative Damage during Ischemia. Stem Cells Int 2019; 2019:8089215. [PMID: 31481974 PMCID: PMC6701419 DOI: 10.1155/2019/8089215] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/28/2019] [Accepted: 07/09/2019] [Indexed: 12/16/2022] Open
Abstract
Lung transplantation is a lifesaving therapy for people living with severe, life-threatening lung disease. The high mortality rate among patients awaiting transplantation is mainly due to the low percentage of lungs that are deemed acceptable for implantation. Thus, the current shortage of lung donors may be significantly reduced by implementing different therapeutic strategies which facilitate both organ preservation and recovery. Here, we studied whether the anti-inflammatory effect of human umbilical cord-derived mesenchymal stem cells (HUCPVCs) increases lung availability by improving organ preservation. We developed a lung preservation rat model that mimics the different stages by which donor organs must undergo before implantation. The therapeutic schema was as follows: cardiac arrest, warm ischemia (2 h at room temperature), cold ischemia (1.5 h at 4°C, with Perfadex), and normothermic lung perfusion with ventilation (Steen solution, 1 h). After 1 h of warm ischemia, HUCPVCs (1 × 106 cells) or vehicle was infused via the pulmonary artery. Physiologic data (pressure-volume curves) were acquired right after the cardiac arrest and at the end of the perfusion. Interestingly, although lung edema did not change among groups, lung compliance dropped to 34% in the HUCPVC-treated group, while the vehicle group showed a stronger reduction (69%, p < 0.0001). Histologic assessment demonstrated less overall inflammation in the HUCPVC-treated lungs. In addition, MPO activity, a neutrophil marker, was reduced by 41% compared with vehicle (p < 0.01). MSC therapy significantly decreased tissue oxidative damage by controlling reactive oxygen species production. Accordingly, catalase and superoxide dismutase enzyme activities remained at baseline levels. In conclusion, these results demonstrate that the anti-inflammatory effect of MSCs protects donor lungs against ischemic injury and postulates MSC therapy as a novel tool for organ preservation.
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Hu Y, Xu R, Chen CY, Rao SS, Xia K, Huang J, Yin H, Wang ZX, Cao J, Liu ZZ, Tan YJ, Luo J, Xie H. Extracellular vesicles from human umbilical cord blood ameliorate bone loss in senile osteoporotic mice. Metabolism 2019; 95:93-101. [PMID: 30668962 DOI: 10.1016/j.metabol.2019.01.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 01/14/2019] [Accepted: 01/17/2019] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Senile osteoporosis is one of the most common age-related diseases worldwide. Accumulating evidences have indicated that young blood can reverse age-related impairments. Extracellular vesicles (EVs) exert therapeutic effects in a variety of diseases by delivering bioactive molecules such as microRNAs (miRNAs). The aim of the study is to evaluate the therapeutic potential of EVs from human umbilical cord blood plasma (UCB-EVs) on senile osteoporosis and to preliminarily clarify the underlying mechanism. METHODS UCB-EVs were injected into the tail vein of aged (16 months old) male C57BL/6 mice. Microcomputed tomography was performed to evaluate bone mass and microarchitecture of mice. The osteogenic and osteoclastic activities were determined by quantitative real-time PCR (qRT-PCR), histological examination and western blot analysis. In vitro, qRT-PCR assay was undertaken to explore the enrichment levels of a number of miRNAs that have positive effects in reducing bone loss. The efficacy of UCB-EVs on osteoblastic differentiation of bone marrow mesenchymal stromal cells (BMSCs) and osteoclastogenesis of RAW264.7 cells were assessed by cytochemical staining. Gene and protein expression changes were detected by qRT-PCR and western blotting respectively. Meanwhile, the roles of the selected miRNA in the regulatory effects of UCB-EVs on BMSCs and RAW264.7 cells were evaluated by using specific miRNA inhibitor. RESULTS The intravenous injection of UCB-EVs for two months attenuated bone loss in old mice, as defined by increased trabecular and cortical bone mass, enhanced osteoblast formation and reduced osteoclast formation compared to the control mice. In vitro, UCB-EVs could promote the osteogenic differentiation of BMSCs and inhibit the osteoclastogenesis of RAW264.7 cells. Moreover, it was confirmed that miR-3960 was highly enriched in UCB-EVs and miR-3960 inhibitor reversed the stimulatory effect of UCB-EVs on osteoblastic differentiation of BMSCs. CONCLUSION Our findings indicate that UCB-EVs ameliorate age-related bone loss by stimulating bone formation and inhibiting bone resorption, and miR-3960 mediated the osteogenic effect of UCB-EVs on BMSCs. Thus, UCB-EVs may represent a promising agent for prevention of senile osteoporosis.
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Affiliation(s)
- Yin Hu
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Ran Xu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Chun-Yuan Chen
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shan-Shan Rao
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Xiangya Nursing School, Central South University, Changsha, Hunan 410013, China
| | - Kun Xia
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jie Huang
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Hao Yin
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhen-Xing Wang
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jia Cao
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zheng-Zhao Liu
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yi-Juan Tan
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Juan Luo
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Hui Xie
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China; Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
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Zhang Y, Hao Z, Wang P, Xia Y, Wu J, Xia D, Fang S, Xu S. Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Prolif 2019; 52:e12570. [PMID: 30663158 PMCID: PMC6496165 DOI: 10.1111/cpr.12570] [Citation(s) in RCA: 188] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/24/2018] [Accepted: 12/06/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Exosomes, as important players in intercellular communication due to their ability to transfer certain molecules to target cells, are believed to take similar effects in promoting bone regeneration with their derived stem cells. Studies have suggested that umbilical cord mesenchymal stem cells (uMSCs) could promote angiogenesis. This study investigated whether exosomes derived from uMSCs (uMSC-Exos) could enhance fracture healing as primary factors by promoting angiogenesis. MATERIALS AND METHODS uMSCs were obtained to isolate uMSC-Exos by ultrafiltration, with exosomes from human embryonic kidney 293 cells (HEK293) and phosphate-buffered saline (PBS) being used as control groups. NanoSight, laser light scattering spectrometer, transmission electron microscopy and Western blotting were used to identify exosomes. Next, uMSC-Exos combined with hydrogel were transplanted into the fracture site in a rat model of femoral fracture. Bone healing processes were monitored and evaluated by radiographic methods on days 7, 14, 21 and 31 after surgery; angiogenesis of the fracture sites was assessed by radiographic and histological strategies on post-operative day 14. In vitro, the expression levels of osteogenesis- or angiogenesis-related genes after being cultured with uMSC-Exos were identified by qRT-PCR. The internalization ability of exosomes was determined using the PKH67 assay. Cell cycle analysis, EdU incorporation and immunofluorescence staining, scratch wound assay and tube formation analysis were also used to determine the altered abilities of human umbilical vein endothelial cells (HUVECs) administered with uMSC-Exos in proliferation, migration and angiogenesis. Finally, to further explore the underlying molecular mechanisms, specific RNA inhibitors or siRNAs were used, and the subsequent effects were observed. RESULTS uMSC-Exos had a diameter of approximately 100 nm, were spherical, meanwhile expressing CD9, CD63 and CD81. Transplantation of uMSC-Exos markedly enhanced angiogenesis and bone healing processes in a rat model of femoral fracture. In vitro, other than enhancing osteogenic differentiation, uMSC-Exos increased the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α). uMSC-Exos were taken up by HUVECs and enhanced their proliferation, migration and tube formation. Finally, by using specific RNA inhibitors or siRNAs, it has been confirmed that HIF-1α played an important role in the uMSC-Exos-induced VEGF expression, pro-angiogenesis and enhanced fracture repair, which may be one of the underlying mechanisms. CONCLUSIONS These results revealed a novel role of exosomes in uMSC-mediated therapy and suggested that implanted uMSC-Exos may represent a crucial clinical strategy to accelerate fracture healing via the promotion of angiogenesis. HIF-1α played an important role in this process.
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Affiliation(s)
- Yuntong Zhang
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Zichen Hao
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
- Department of Orthopaedics and Rehabilitation, School of MedicineYale UniversityNew HavenConnecticut
| | - Panfeng Wang
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Yan Xia
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Jianghong Wu
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Demeng Xia
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Shuo Fang
- Department of Plastic and ReconstructionShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
| | - Shuogui Xu
- Department of Emergency and TraumaShanghai Changhai Hospital Affiliated to the Second Military Medical UniversityShanghaiChina
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Ishikawa K, Munar ML, Tsuru K, Miyamoto Y. Fabrication of carbonate apatite honeycomb and its tissue response. J Biomed Mater Res A 2019; 107:1014-1020. [PMID: 30706693 DOI: 10.1002/jbm.a.36640] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 01/24/2019] [Indexed: 01/01/2023]
Abstract
Carbonate apatite (CO3 Ap) block can be used as a bone substitute because it can be remodeled to new natural bone in a manner conforming with the bone remodeling process. Among the many porous structures available, honeycomb (HC) structure is advantageous for rapid replacement of CO3 Ap to bone. In this study, the feasibility to fabricate a CO3 Ap HC was studied, along with its initial tissue response in rabbit femur bone defect. First, a mixture of Ca(OH)2 and a wax-based binder was extruded from a HC mold. Then the fabricated HC was heated for binder removal and carbonation at 450°C in a mixed O2 -CO2 atmosphere, forming a CaCO3 HC. When the CaCO3 HC was immersed in 1 mol/L Na3 PO4 solution at 80°C for 7 days, its composition changed from CaCO3 to CO3 Ap, maintaining the structure of the original CaCO3 HC. Compressive strengths of the CaCO3 and CO3 Ap HCs were 65.2 ± 7.4 MPa and 88.7 ± 4.7 MPa, respectively. When the rabbit femur bone defect was reconstructed with the CO3 Ap HC, new bone penetrated the CO3 Ap HC completely. Osteoclasts and osteoblasts were found on the surface of the newly formed bone and osteocytes were also found in the newly formed bone, indicating ongoing bone remodeling. Furthermore, blood vessels were formed inside the pores of CO3 Ap HC. Therefore, CO3 Ap HC has good potential as an ideal bone substitute. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1014-1020, 2019.
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Affiliation(s)
- Kunio Ishikawa
- Department of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Melvin L Munar
- Department of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kanji Tsuru
- Department of Biomaterials, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Youji Miyamoto
- Department of Oral Surgery, Institute of Biomedical Sciences, Tokushima University, 3-18-15 Kuramotocho, Tokushima, 770-8504, Japan
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Lina IA, Ishida W, Liauw JA, Lo SFL, Elder BD, Perdomo-Pantoja A, Theodros D, Witham TF, Holmes C. A mouse model for the study of transplanted bone marrow mesenchymal stem cell survival and proliferation in lumbar spinal fusion. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2018; 28:710-718. [PMID: 30511246 DOI: 10.1007/s00586-018-5839-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 10/21/2018] [Accepted: 11/25/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE Bone marrow aspirate has been successfully used alongside a variety of grafting materials to clinically augment spinal fusion. However, little is known about the fate of these transplanted cells. Herein, we develop a novel murine model for the in vivo monitoring of implanted bone marrow cells (BMCs) following spinal fusion. METHODS A clinical-grade scaffold was implanted into immune-intact mice undergoing spinal fusion with or without freshly isolated BMCs from either transgenic mice which constitutively express the firefly luciferase gene or syngeneic controls. The in vivo survival, distribution and proliferation of these luciferase-expressing cells was monitored via bioluminescence imaging over a period of 8 weeks and confirmed via immunohistochemistry. MicroCT imaging was performed 8 weeks to assess fusion. RESULTS Bioluminescence imaging indicated transplanted cell survival and proliferation over the first 2 weeks, followed by a decrease in cell numbers, with transplanted cell survival still evident at the end of the study. New bone formation and increased fusion mass volume were observed in mice implanted with cell-seeded scaffolds. CONCLUSIONS By enabling the tracking of transplanted bone marrow-derived cells during spinal fusion in vivo, this mouse model will be integral to developing a deeper understanding of the biological processes underlying spinal fusion in future studies. These slides can be retrieved under Electronic Supplementary Material.
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Affiliation(s)
- Ioan A Lina
- Department of Otolaryngology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Jason A Liauw
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Sheng-Fu L Lo
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Benjamin D Elder
- Department of Neurological Surgery, Mayo Clinic School of Medicine, Rochester, MN, USA
| | - Alexander Perdomo-Pantoja
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Debebe Theodros
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA
| | - Christina Holmes
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1550 Orleans St, Rm 2M-51, Baltimore, MD, 21287, USA.
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Ansari AS, Yazid MD, Sainik NQAV, Razali RA, Saim AB, Idrus RBH. Osteogenic Induction of Wharton's Jelly-Derived Mesenchymal Stem Cell for Bone Regeneration: A Systematic Review. Stem Cells Int 2018; 2018:2406462. [PMID: 30534156 PMCID: PMC6252214 DOI: 10.1155/2018/2406462] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 07/27/2018] [Accepted: 09/03/2018] [Indexed: 12/13/2022] Open
Abstract
Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are emerging as a promising source for bone regeneration in the treatment of bone defects. Previous studies have reported the ability of WJ-MSCs to be induced into the osteogenic lineage. The purpose of this review was to systematically assess the potential of WJ-MSC differentiation into the osteogenic lineage. A comprehensive search was conducted in Medline via Ebscohost and Scopus, where relevant studies published between 1961 and 2018 were selected. The main inclusion criteria were that articles must be primary studies published in English evaluating osteogenic induction of WJ-MSCs. The literature search identified 92 related articles, but only 18 articles met the inclusion criteria. These include two animal studies, three articles containing both in vitro and in vivo assessments, and 13 articles on in vitro studies, all of which are discussed in this review. There were two types of osteogenic induction used in these studies, either chemical or physical. The studies demonstrate that WJ-MSCs are able to differentiate into osteogenic lineage and promote osteogenesis. In light of these observations, it is suggested that WJ-MSCs can be a potential source of stem cells for osteogenic induction, as an alternative to bone marrow-derived mesenchymal stem cells.
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Affiliation(s)
- Ayu Suraya Ansari
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Muhammad Dain Yazid
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Nur Qisya Afifah Veronica Sainik
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Rabiatul Adawiyah Razali
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
| | - Aminuddin Bin Saim
- Ear, Nose & Throat Consultant Clinic, Ampang Puteri Specialist Hospital, 68000 Ampang, Selangor, Malaysia
| | - Ruszymah Bt Hj Idrus
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
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Zhang Y, Grosfeld EC, Camargo WA, Tang H, Magri AMP, van den Beucken JJJP. Efficacy of intraoperatively prepared cell-based constructs for bone regeneration. Stem Cell Res Ther 2018; 9:283. [PMID: 30359312 PMCID: PMC6203202 DOI: 10.1186/s13287-018-1026-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/16/2018] [Accepted: 09/30/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Conventional cell-based bone regeneration suffers from the major disadvantage of limited cell supply, time-consuming in vitro expansion cultures, and limited patient-friendliness related to cell isolation and multiple visits to the clinic. Here, we utilized an alternative concept using "easy access cells" that can be obtained in an intraoperative manner to prepare cell-based constructs. METHODS We used stromal vascular fraction (SVF) from human adipose tissue and human monocytes for intraoperative preparation of bone constructs. Conventional constructs grafted with expanded human adipose tissue mesenchymal stem cells (ADMSCs) derived from the same donor were set as positive controls. Additionally, we combined both cell types either or not with monocytes. The cellular interaction of human SVF and ADMSCs with human monocytes was evaluated in vitro. The feasibility and bone-regenerative capacity of intraoperative constructs were determined histologically and histomorphometrically in a rat femoral condyle bone defect model. RESULTS SVF displayed equal in vitro osteogenic differentiation compared to donor-matched expanded ADMSCs, which for both was significantly enhanced upon co-culture with monocytes. Moreover, SVF and ADMSCs displayed different immunoregulatory effects on monocytes/macrophages. Upon implantation in rat femoral bone defects, SVF constructs demonstrated superior bone formation compared to ADMSC constructs and cell-free controls; no effects of monocyte addition were observed. CONCLUSION In conclusion, we here demonstrate the feasibility of intraoperative SVF construct preparation and superior bone-regenerative capacity thereof compared to donor-matched ADMSC constructs. The superiority of SVF constructs was found to be linked to the distinct differences between immunoregulatory effects of SVF and ADMSCs.
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Affiliation(s)
- Yang Zhang
- Department of Biomaterials, PO Box 9101, 6500HB Radboudumc, Nijmegen, the Netherlands
| | - Eline C Grosfeld
- Department of Biomaterials, PO Box 9101, 6500HB Radboudumc, Nijmegen, the Netherlands
| | - Winston A Camargo
- Department of Biomaterials, PO Box 9101, 6500HB Radboudumc, Nijmegen, the Netherlands
| | - Hongbo Tang
- Department of Biomaterials, PO Box 9101, 6500HB Radboudumc, Nijmegen, the Netherlands.,Department of Plastic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Angela M P Magri
- Department of Biomaterials, PO Box 9101, 6500HB Radboudumc, Nijmegen, the Netherlands.,Department of Biosciences, Federal University of São Paulo, Santos, São Paulo, Brazil
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Osteogenic Potential of Human Umbilical Cord Mesenchymal Stem Cells on Coralline Hydroxyapatite/Calcium Carbonate Microparticles. Stem Cells Int 2018; 2018:4258613. [PMID: 30254682 PMCID: PMC6145045 DOI: 10.1155/2018/4258613] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 05/16/2018] [Indexed: 01/15/2023] Open
Abstract
Coralline hydroxyapatite/calcium carbonate (CHACC) is a biodegradable and osteoconductive bone graft material with promising clinical performance. CHACC has been shown to support proliferation and osteogenic differentiation of human bone marrow mesenchymal stem cells (MSCs) in vitro and demonstrated to work as a functional scaffold for bone formation in vivo. Umbilical cord matrix is a more accessible and abundant tissue source of MSCs, but its osteogenic capacity in comparison to human bone marrow when cultured on CHACC has not yet been demonstrated. In this study, we assessed the osteogenic differentiation capacity of human MSCs, isolated from bone marrow and umbilical cord matrix and characterised by flow cytometry, when cultured on 200–300 μm CHACC granules. The 3D cultures were characterised by brightfield and scanning electron microscopy (SEM). Osteogenic potential was assessed by immunocytochemistry and qPCR for key markers of bone differentiation (alkaline phosphatase, runx2, type I collagen, and osteocalcin). By day 1, the MSCs had enveloped the surface of the CHACC granules to form organoids, and by day 7, cells had proliferated to bridge nearby organoids. Extracellular matrix deposition and osteogenic differentiation were demonstrated by MSCs from both tissue sources at day 21. However, MSCs from bone marrow demonstrated superior osteogenic differentiation capability compared to those from umbilical cord matrix. In conclusion, it is possible to culture and induce osteogenic differentiation of umbilical cord matrix MSCs on CHACC. Further research is required to optimise the osteogenicity of umbilical cord matrix MSCs to release their full potential as a readily available, accessible, and abundant tissue source for bone tissue engineering.
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