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Bäumchen A, Balsters JM, Nenninger BS, Diebels S, Zimmermann H, Roland M, Gepp MM. Towards a Comprehensive Framework for Made-to-Measure Alginate Scaffolds for Tissue Engineering Using Numerical Simulation. Gels 2025; 11:185. [PMID: 40136890 PMCID: PMC11942394 DOI: 10.3390/gels11030185] [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: 12/19/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 03/27/2025] Open
Abstract
Alginate hydrogels are integral to many cell-based models in tissue engineering and regenerative medicine. As a natural biomaterial, the properties of alginates can vary and be widely adjusted through the gelation process, making them versatile additives or bulk materials for scaffolds, microcarriers or encapsulation matrices in tissue engineering and regenerative medicine. The requirements for alginates used in biomedical applications differ significantly from those for technical applications. Particularly, the generation of novel niches for stem cells requires reliable and predictable properties of the resulting hydrogel. Ultra-high viscosity (UHV) alginates possess alginates with special physicochemical properties, and thus far, numerical simulations for the gelation process are currently lacking but highly relevant for future designs of stem cell niches and cell-based models. In this article, the gelation of UHV alginates is studied using a microscopic approach for disc- and sphere-shaped hydrogels. Based on the collected data, a multiphase continuum model was implemented to describe the cross-linking process of UHV alginate polysaccharides. The model utilizes four coupled kinetic equations based on mixture theory, which are solved using finite element software. A good agreement between simulation results and experimental data was found, establishing a foundation for future refinements in the development of an interactive tool for cell biologists and material scientists.
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Affiliation(s)
- Alexander Bäumchen
- Applied Mechanics, Saarland University, Campus A4 2, 66123 Saarbruecken, Germany; (A.B.); (S.D.)
| | - Johnn Majd Balsters
- Fraunhofer Institute for Biomedical Engineering (IBMT), Joseph-von-Fraunhofer-Weg 1, 66280 Sulzbach, Germany; (J.M.B.); (B.-S.N.); (H.Z.); (M.M.G.)
- Molecular and Cellular Biotechnology/Nanotechnology, Saarland University, Campus Saarbruecken, 66123 Saarbruecken, Germany
| | - Beate-Sophie Nenninger
- Fraunhofer Institute for Biomedical Engineering (IBMT), Joseph-von-Fraunhofer-Weg 1, 66280 Sulzbach, Germany; (J.M.B.); (B.-S.N.); (H.Z.); (M.M.G.)
- Molecular and Cellular Biotechnology/Nanotechnology, Saarland University, Campus Saarbruecken, 66123 Saarbruecken, Germany
| | - Stefan Diebels
- Applied Mechanics, Saarland University, Campus A4 2, 66123 Saarbruecken, Germany; (A.B.); (S.D.)
| | - Heiko Zimmermann
- Fraunhofer Institute for Biomedical Engineering (IBMT), Joseph-von-Fraunhofer-Weg 1, 66280 Sulzbach, Germany; (J.M.B.); (B.-S.N.); (H.Z.); (M.M.G.)
- Molecular and Cellular Biotechnology/Nanotechnology, Saarland University, Campus Saarbruecken, 66123 Saarbruecken, Germany
- Faculty of Marine Science, Universidad Católica del Norte, Larrondo 1281, Coquimbo 1780000, Chile
| | - Michael Roland
- Applied Mechanics, Saarland University, Campus A4 2, 66123 Saarbruecken, Germany; (A.B.); (S.D.)
| | - Michael M. Gepp
- Fraunhofer Institute for Biomedical Engineering (IBMT), Joseph-von-Fraunhofer-Weg 1, 66280 Sulzbach, Germany; (J.M.B.); (B.-S.N.); (H.Z.); (M.M.G.)
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Nosrati H, Fallah Tafti M, Aghamollaei H, Bonakdar S, Moosazadeh Moghaddam M. Directed Differentiation of Adipose-Derived Stem Cells Using Imprinted Cell-Like Topographies as a Growth Factor-Free Approach. Stem Cell Rev Rep 2024; 20:1752-1781. [PMID: 39066936 DOI: 10.1007/s12015-024-10767-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2024] [Indexed: 07/30/2024]
Abstract
The influence of surface topography on stem cell behavior and differentiation has garnered significant attention in regenerative medicine and tissue engineering. The cell-imprinting method has been introduced as a promising approach to mimic the geometry and topography of cells. The cell-imprinted substrates are designed to replicate the topographies and dimensions of target cells, enabling tailored interactions that promote the differentiation of stem cells towards desired specialized cell types. In fact, by replicating the size and shape of cells, biomimetic substrates provide physical cues that profoundly impact stem cell differentiation. These cues play a pivotal role in directing cell morphology, cytoskeletal organization, and gene expression, ultimately influencing lineage commitment. The biomimetic substrates' ability to emulate the native cellular microenvironment supports the creation of platforms capable of steering stem cell fate with high precision. This review discusses the role of mechanical factors that impact stem cell fate. It also provides an overview of the design and fabrication principles of cell-imprinted substrates. Furthermore, the paper delves into the use of cell-imprinted polydimethylsiloxane (PDMS) substrates to direct adipose-derived stem cells (ADSCs) differentiation into a variety of specialized cells for tissue engineering and regenerative medicine applications. Additionally, the review discusses the limitations of cell-imprinted PDMS substrates and highlights the efforts made to overcome these limitations.
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Affiliation(s)
- Hamed Nosrati
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahsa Fallah Tafti
- Vision Health Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Hossein Aghamollaei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Shahin Bonakdar
- National Cell Bank Department, Pasteur Institute of Iran, Tehran, Iran
| | - Mehrdad Moosazadeh Moghaddam
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran.
- Tissue Engineering and Regenerative Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Lin Q, Yang Z, Xu H, Niu Y, Meng Q, Xing D. Advances in Shear Stress Stimulation of Stem Cells: A Review of the Last Three Decades. Biomedicines 2024; 12:1963. [PMID: 39335477 PMCID: PMC11429308 DOI: 10.3390/biomedicines12091963] [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: 07/22/2024] [Revised: 08/14/2024] [Accepted: 08/17/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are widely used in scientific research because of their ability to self-renew and differentiate into a variety of specialized cell types needed for body functions. However, the self-renewal and differentiation of stem cells are regulated by various stimuli, with mechanical stimulation being particularly notable due to its ability to mimic the physical environment in the body. This study systematically collected 2638 research papers published between 1994 and 2024, employing tools such as VOSviewer, CiteSpace, and GraphPad Prism to uncover research hotspots, publication trends, and collaboration networks. The results indicate a yearly increase in global research on the shear stress stimulation of stem cells, with significant contributions from the United States and China in terms of research investment and output. Future research directions include a deeper understanding of the mechanisms underlying mechanical stimulation's effects on stem cell differentiation, the development of new materials and scaffold designs to better replicate the natural cellular environment, and advancements in regenerative medicine. Despite considerable progress, challenges remain in translating basic research findings into clinical applications.
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Affiliation(s)
- Qiyuan Lin
- Arthritis Clinical and Research Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Zhen Yang
- Arthritis Clinical and Research Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Hao Xu
- Arthritis Clinical and Research Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Yudi Niu
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Qingchen Meng
- Arthritis Clinical and Research Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Dan Xing
- Arthritis Clinical and Research Center, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
- Arthritis Institute, Peking University, Beijing 100044, China
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Dong G, Wang J, Chen Z, Wang F, Xia B, Chen G. Regulatory effects of stress release from decellularized periosteum on proliferation, migration, and osteogenic differentiation of periosteum-derived cells. Biomater Sci 2024; 12:3360-3373. [PMID: 38771565 DOI: 10.1039/d4bm00358f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Bone injury is often associated with tears in the periosteum and changes in the internal stress microenvironment of the periosteum. In this study, we investigated the biological effects of periosteal prestress release on periosteum-derived cells (PDCs) and the potential mechanisms of endogenous stem cell recruitment. Decellularized periosteum with natural extracellular matrix (ECM) components was obtained by a combination of physical, chemical, and enzymatic decellularization. The decellularized periosteum removed immunogenicity while retaining the natural network structure and composition of the ECM. The Young's modulus has no significant difference between the periosteum before and after decellularization. The extracted PDCs were further composited with the decellularized periosteum and subjected to 20% stress release. It was found that the proliferative capacity of PDCs seeded on decellularized periosteum was significantly enhanced 6 h after stress release of the periosteum. The cell culture supernatant obtained after periosteal prestress release was able to significantly promote the migration ability of PDCs within 24 h. Enzyme-linked immunosorbnent assay (ELISA) experiments showed that the expression of stroma-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF) in the supernatant increased significantly after 3 h and 12 h of stress release, respectively. Furthermore, periosteal stress release promoted the high expression of osteogenic markers osteocalcin (OCN), osteopontin (OPN), and collagen type I of PDCs. The change in stress environment caused by the release of periosteal prestress was sensed by integrin β1, a mechanoreceptor on the membrane of PDCs, which further stimulated the expression of YAP in the nucleus. These investigations provided a novel method to evaluate the importance of mechanical stimulation in periosteum, which is also of great significance for the design and fabrication of artificial periosteum with mechanical regulation function.
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Affiliation(s)
- Gangli Dong
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. China.
| | - Jinsong Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. China.
| | - Zhongmin Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. China.
| | - Fuping Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. China.
| | - Bin Xia
- Engineering Research Center for Waste Oil Recovery Technology and Equipment, Ministry of Education, Chongqing Technology and Business University, Chongqing 400067, P. R. China.
| | - Guobao Chen
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P. R. China.
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Kiratitanaporn W, Guan J, Berry DB, Lao A, Chen S. Multimodal Three-Dimensional Printing for Micro-Modulation of Scaffold Stiffness Through Machine Learning. Tissue Eng Part A 2024; 30:280-292. [PMID: 37747804 DOI: 10.1089/ten.tea.2023.0193] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023] Open
Abstract
The ability to precisely control a scaffold's microstructure and geometry with light-based three-dimensional (3D) printing has been widely demonstrated. However, the modulation of scaffold's mechanical properties through prescribed printing parameters is still underexplored. This study demonstrates a novel 3D-printing workflow to create a complex, elastomeric scaffold with precision-engineered stiffness control by utilizing machine learning. Various printing parameters, including the exposure time, light intensity, printing infill, laser pump current, and printing speed were modulated to print poly (glycerol sebacate) acrylate (PGSA) scaffolds with mechanical properties ranging from 49.3 ± 3.3 kPa to 2.8 ± 0.3 MPa. This enables flexibility in spatial stiffness modulation in addition to high-resolution scaffold fabrication. Then, a neural network-based machine learning model was developed and validated to optimize printing parameters to yield scaffolds with user-defined stiffness modulation for two different vat photopolymerization methods: a digital light processing (DLP)-based 3D printer was utilized to rapidly fabricate stiffness-modulated scaffolds with features on the hundreds of micron scale and a two-photon polymerization (2PP) 3D printer was utilized to print fine structures on the submicron scale. A novel 3D-printing workflow was designed to utilize both DLP-based and 2PP 3D printers to create multiscale scaffolds with precision-tuned stiffness control over both gross and fine geometric features. The described workflow can be used to fabricate scaffolds for a variety of tissue engineering applications, specifically for interfacial tissue engineering for which adjacent tissues possess heterogeneous mechanical properties (e.g., muscle-tendon).
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Affiliation(s)
- Wisarut Kiratitanaporn
- Department of Bioengineering, University of California San Diego, La Jolla, California, USA
| | - Jiaao Guan
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, California, USA
| | - David B Berry
- Department of Orthopedic Surgery, University of California San Diego, La Jolla, California, USA
| | - Alison Lao
- Department of NanoEngineering, University of California San Diego, La Jolla, California, USA
| | - Shaochen Chen
- Department of Bioengineering, University of California San Diego, La Jolla, California, USA
- Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, California, USA
- Department of NanoEngineering, University of California San Diego, La Jolla, California, USA
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Huang Y, Lee S, Liu W, Takayama S, Jia S. OctoShaker: A versatile robotic biomechanical agitator for cellular and organoid research. THE REVIEW OF SCIENTIFIC INSTRUMENTS 2023; 94:124104. [PMID: 38126811 PMCID: PMC10746356 DOI: 10.1063/5.0174526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Abstract
Mechanical forces have increasingly been recognized as a key regulator in the fate of cellular development and functionality. Different mechanical transduction methods, such as substrate stiffness and magnetic bead vibration, have been experimented with to understand the interaction between the biophysical cues and cellular outcome. In the exploration and utilization of the intrinsic cellular mechanism, bio-shakers, traditionally invented for stirring liquid, have garnered more interest as a tool to provide precise mechanical stimuli to aid in this study. Nonetheless, despite the usefulness of current bio-shaking technology, each type of shaker often offers a single mode of motion, insufficient for generating complex force dynamics needed to resemble the actual physical condition that occurs inside living organisms. In this study, we present OctoShaker, a robotic instrument capable of creating a multitude of motions that could be sequenced or programmed to mimic sophisticated hemodynamics in vivo. We demonstrated the programmed motion of circular convection and investigated its influence on micro-particle distribution in 96-well culture microplates. Biological samples, including HeLa cells and organoids, were tested, and unique resultant patterns were observed. We anticipate the open-source dissemination of OctoShaker in diverse biological applications, encompassing biomechanical studies for cellular and organoid research, as well as other disciplines that demand dynamic mechanical force generation.
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Affiliation(s)
- Yan Huang
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA
| | - Soojung Lee
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA
| | - Wenhao Liu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA
| | | | - Shu Jia
- Author to whom correspondence should be addressed:
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Tian JQ, Wei TF, Wei YR, Xiao FJ, He XS, Lin K, Lu S, He XM, He W, Wei QS, Xiang XW, He MC. Effect of whole body vibration therapy in the rat model of steroid-induced osteonecrosis of the femoral head. Front Cell Dev Biol 2023; 11:1251634. [PMID: 37876552 PMCID: PMC10590907 DOI: 10.3389/fcell.2023.1251634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/25/2023] [Indexed: 10/26/2023] Open
Abstract
Background: Steroid-induced Osteonecrosis of the Femoral Head (SIONFH) is a skeletal disease with a high incidence and a poor prognosis. Whole body vibration therapy (WBVT), a new type of physical training, is known to promote bone formation. However, it remains unclear whether WBVT has a therapeutic effect on SIONFH. Materials and methods: Thirty adult male and female Sprague-Dawley (SD) rats were selected and randomly assigned to three experimental groups: the control group, the model group, and the mechanical vibration group, respectively. SIONFH induction was achieved through the combined administration of lipopolysaccharides (LPS) and methylprednisolone sodium succinate for injection (MPS). The femoral head samples underwent hematoxylin and eosin (H&E) staining to visualize tissue structures. Structural parameters of the region of interest (ROI) were compared using Micro-CT analysis. Immunohistochemistry was employed to assess the expression levels of Piezo1, BMP2, RUNX2, HIF-1, VEGF, CD31, while immunofluorescence was used to examine CD31 and Emcn expression levels. Results: The H&E staining results revealed a notable improvement in the ratio of empty lacuna in various groups following WBVT intervention. Immunohistochemical analysis showed that the expression levels of Piezo1, BMP2, RUNX2, HIF-1, VEGF, and CD31 in the WBVT group exhibited significant differences when compared to the Model group (p < 0.05). Additionally, immunofluorescence analysis demonstrated statistically significant differences in CD31 and Emcn expression levels between the WBVT group and the Model group (p < 0.05). Conclusion: WBVT upregulates Piezo1 to promote osteogenic differentiation, potentially by enhancing the HIF-1α/VEGF axis and regulating H-vessel angiogenesis through the activation of the Piezo1 ion channel. This mechanism may lead to improved blood flow supply and enhanced osteogenic differentiation within the femoral head.
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Affiliation(s)
- Jia-Qing Tian
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Teng-Fei Wei
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yu-Rou Wei
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Fang-Jun Xiao
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xian-Shun He
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Kun Lin
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shun Lu
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiao-Ming He
- The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei He
- The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, Guangdong, China
| | - Qiu-Shi Wei
- The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiao-Wei Xiang
- Shenzhen Luohu Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
| | - Min-Cong He
- The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, Guangdong, China
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Komsa-Penkova R, Yordanova A, Tonchev P, Kyurkchiev S, Todinova S, Strijkova V, Iliev M, Dimitrov B, Altankov G. Altered Mesenchymal Stem Cells Mechanotransduction from Oxidized Collagen: Morphological and Biophysical Observations. Int J Mol Sci 2023; 24:3635. [PMID: 36835046 PMCID: PMC9961414 DOI: 10.3390/ijms24043635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/05/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Extracellular matrix (ECM) provides various mechanical cues that are able to affect the self-renewal and differentiation of mesenchymal stem cells (MSC). Little is known, however, how these cues work in a pathological environment, such as acute oxidative stress. To better understand the behavior of human adipose tissue-derived MSC (ADMSC) in such conditions, we provide morphological and quantitative evidence for significantly altered early steps of mechanotransduction when adhering to oxidized collagen (Col-Oxi). These affect both focal adhesion (FA) formation and YAP/TAZ signaling events. Representative morphological images show that ADMSCs spread better within 2 h of adhesion on native collagen (Col), while they tended to round up on Col-Oxi. It also correlates with the lesser development of the actin cytoskeleton and FA formation, confirmed quantitatively by morphometric analysis using ImageJ. As shown by immunofluorescence analysis, oxidation also affected the ratio of cytosolic-to-nuclear YAP/TAZ activity, concentrating in the nucleus for Col while remaining in the cytosol for Col-Oxi, suggesting abrogated signal transduction. Comparative Atomic Force Microscopy (AFM) studies show that native collagen forms relatively coarse aggregates, much thinner with Col-Oxi, possibly reflecting its altered ability to aggregate. On the other hand, the corresponding Young's moduli were only slightly changed, so viscoelastic properties cannot explain the observed biological differences. However, the roughness of the protein layer decreased dramatically, from RRMS equal to 27.95 ± 5.1 nm for Col to 5.51 ± 0.8 nm for Col-Oxi (p < 0.05), which dictates our conclusion that it is the most altered parameter in oxidation. Thus, it appears to be a predominantly topographic response that affects the mechanotransduction of ADMSCs by oxidized collagen.
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Affiliation(s)
| | | | - Pencho Tonchev
- Department of Surgery, Medical University Pleven, 5800 Pleven, Bulgaria
| | | | - Svetla Todinova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Velichka Strijkova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
- Institute of Optical Materials and Technologies, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Mario Iliev
- Faculty of Physics, Sofia University, St. Clément Ohnishi, 1164 Sofia, Bulgaria
| | - Borislav Dimitrov
- Department of Biochemistry, Medical University Pleven, 5800 Pleven, Bulgaria
| | - George Altankov
- Research Institute, Medical University Pleven, 5800 Pleven, Bulgaria
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9
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Nanotechnology in tissue engineering and regenerative medicine. KOREAN J CHEM ENG 2023. [DOI: 10.1007/s11814-022-1363-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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10
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Kiratitanaporn W, Berry DB, Mudla A, Fried T, Lao A, Yu C, Hao N, Ward SR, Chen S. 3D printing a biocompatible elastomer for modeling muscle regeneration after volumetric muscle loss. BIOMATERIALS ADVANCES 2022; 142:213171. [PMID: 36341746 PMCID: PMC12045644 DOI: 10.1016/j.bioadv.2022.213171] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 09/21/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022]
Abstract
Volumetric muscle loss (VML) injuries due to trauma, tumor ablation, or other degenerative muscle diseases are debilitating and currently have limited options for self-repair. Advancements in 3D printing allow for the rapid fabrication of biocompatible scaffolds with designer patterns. However, the materials chosen are often stiff or brittle, which is not optimal for muscle tissue engineering. This study utilized a photopolymerizable biocompatible elastomer - poly (glycerol sebacate) acrylate (PGSA) - to develop an in vitro model of muscle regeneration and proliferation into an acellular scaffold after VML injury. Mechanical properties of the scaffold were tuned by controlling light intensity during the 3D printing process to match the specific tension of skeletal muscle. The effect of both geometric (channel sizes between 300 and 600 μm) and biologic (decellularized muscle extracellular matrix (dECM)) cues on muscle progenitor cell infiltration, proliferation, organization, and maturation was evaluated in vitro using a near-infrared fluorescent protein (iRFP) transfected cell line to assess cells in the 3D scaffold. Larger channel sizes and dECM coating were found to enhance cell proliferation and maturation, while no discernable effect on cell alignment was observed. In addition, a pilot experiment was carried out to evaluate the regenerative capacity of this scaffold in vivo after a VML injury. Overall, this platform demonstrates a simple model to study muscle progenitor recruitment and differentiation into acellular scaffolds after VML repair.
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Affiliation(s)
- Wisarut Kiratitanaporn
- Department of Bioengineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - David B Berry
- Department of NanoEngineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA; Department of Orthopaedic Surgery, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - Anusorn Mudla
- Department of Section of Molecular Biology, Division of Biological Sciences, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA, 92093, USA.
| | - Trevor Fried
- Department of Bioengineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - Alison Lao
- Department of NanoEngineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - Claire Yu
- Department of NanoEngineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - Nan Hao
- Department of Section of Molecular Biology, Division of Biological Sciences, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA, 92093, USA.
| | - Samuel R Ward
- Department of Bioengineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA; Department of Orthopaedic Surgery, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA; Department of Radiology, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
| | - Shaochen Chen
- Department of Bioengineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA; Department of NanoEngineering, University of California, 9500 Gilman Dr. San Diego, La Jolla, CA 92093, USA.
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Lim JH, Kim HY, Kang HG, Jeong HJ, Kim HM. RANKL down-regulates the mast cell proliferation through inducing senescence. Cytokine 2022; 159:156018. [DOI: 10.1016/j.cyto.2022.156018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022]
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12
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Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis. Bioact Mater 2022; 22:423-452. [PMID: 36311050 PMCID: PMC9588998 DOI: 10.1016/j.bioactmat.2022.10.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.
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13
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Zhuang Y, Jiang S, Yuan C, Lin K. The potential therapeutic role of extracellular vesicles in osteoarthritis. Front Bioeng Biotechnol 2022; 10:1022368. [PMID: 36185451 PMCID: PMC9523151 DOI: 10.3389/fbioe.2022.1022368] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis (OA) is a worldwide and disabling disease, which cause severe pain and heavy socioeconomic burden. However, pharmacologic or surgical therapies cannot mitigate OA progression. Mesenchymal stem cells (MSCs) therapy has emerged as potential approach for OA treatment, while the immunogenicity and ethical audit of cell therapy are unavoidable. Compared with stem cell strategy, EVs induce less immunological rejection, and they are more stable for storage and in vivo application. MSC-EVs-based therapy possesses great potential in regulating inflammation and promoting cartilage matrix reconstruction in OA treatment. To enhance the therapeutic effect, delivery efficiency, tissue specificity and safety, EVs can be engineered via different modification strategies. Here, the application of MSC-EVs in OA treatment and the potential underlying mechanism were summarized. Moreover, EV modification strategies including indirect MSC modification and direct EV modification were reviewed.
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Affiliation(s)
- Yu Zhuang
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China
| | - Shengjie Jiang
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China
| | - Changyong Yuan
- School of Stomatology, Xuzhou Medical University, Shanghai, China
- Department of Dental Implant, The Affiliated Stomatological Hospital of Xuzhou Medical University, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People’s Hospital, Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Changyong Yuan, ; Kaili Lin,
| | - Kaili Lin
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China
- *Correspondence: Changyong Yuan, ; Kaili Lin,
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14
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Lim R, Banerjee A, Biswas R, Chari AN, Raghavan S. Mechanotransduction through adhesion molecules: Emerging roles in regulating the stem cell niche. Front Cell Dev Biol 2022; 10:966662. [PMID: 36172276 PMCID: PMC9511051 DOI: 10.3389/fcell.2022.966662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/18/2022] [Indexed: 11/23/2022] Open
Abstract
Stem cells have been shown to play an important role in regenerative medicine due to their proliferative and differentiation potential. The challenge, however, lies in regulating and controlling their potential for this purpose. Stem cells are regulated by growth factors as well as an array of biochemical and mechanical signals. While the role of biochemical signals and growth factors in regulating stem cell homeostasis is well explored, the role of mechanical signals has only just started to be investigated. Stem cells interact with their niche or to other stem cells via adhesion molecules that eventually transduce mechanical cues to maintain their homeostatic function. Here, we present a comprehensive review on our current understanding of the influence of the forces perceived by cell adhesion molecules on the regulation of stem cells. Additionally, we provide insights on how this deeper understanding of mechanobiology of stem cells has translated toward therapeutics.
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Affiliation(s)
- Ryan Lim
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Avinanda Banerjee
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Ritusree Biswas
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Campus, Bangalore, India
- Sastra University, Thanjavur, TN, India
| | - Anana Nandakumar Chari
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Srikala Raghavan
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Campus, Bangalore, India
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15
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Protick F, Amit SK, Amar K, Nath SD, Akand R, Davis VA, Nilufar S, Chowdhury F. Additive Manufacturing of Viscoelastic Polyacrylamide Substrates for Mechanosensing Studies. ACS OMEGA 2022; 7:24384-24395. [PMID: 35874232 PMCID: PMC9301700 DOI: 10.1021/acsomega.2c01817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Polymerized polyacrylamide (PAA) substrates are linearly elastic hydrogels that are widely used in mechanosensing studies due to their biocompatibility, wide range of functionalization capability, and tunable mechanical properties. However, such cellular response on purely elastic substrates, which do not mimic the viscoelastic living tissues, may not be physiologically relevant. Because the cellular response on 2D viscoelastic PAA substrates remains largely unknown, we used stereolithography (SLA)-based additive manufacturing technique to create viscoelastic PAA substrates with tunable mechanical properties that allow us to identify physiologically relevant cellular behaviors. Three PAA substrates of different complex moduli were fabricated by SLA. By embedding fluorescent markers during the additive manufacturing of the substrates, we show a homogeneous and uniform composition throughout, which conventional manufacturing techniques cannot produce. Rheological investigation of the additively manufactured PAA substrates shows a viscoelastic behavior with a 5-10% loss moduli compared to their elastic moduli, mimicking the living tissues. To understand the cell mechanosensing on the dissipative PAA substrates, single live cells were seeded on PAA substrates to establish the basic relationships between cell traction, cytoskeletal prestress, and cell spreading. With the increasing substrate moduli, we observed a concomitant increase in cellular traction and prestress, but not cell spreading, suggesting that cell spreading can be decoupled from traction and intracellular prestress in physiologically relevant environments. Together, additively manufactured PAA substrates fill the void of lacking real tissue like viscoelastic materials that can be used in a variety of mechanosensing studies with superior reproducibility.
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Affiliation(s)
- Fardeen
Kabir Protick
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
| | - Sadat Kamal Amit
- Samuel
Ginn Department of Chemical Engineering, Auburn University, Auburn, Alabama 36849, United States
| | - Kshitij Amar
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
| | - Shukantu Dev Nath
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
| | - Rafee Akand
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
| | - Virginia A. Davis
- Samuel
Ginn Department of Chemical Engineering, Auburn University, Auburn, Alabama 36849, United States
| | - Sabrina Nilufar
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
| | - Farhan Chowdhury
- School
of Mechanical, Aerospace, and Materials Engineering, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States
- Biomedical
Engineering Program, School of Electrical, Computer, and Biomedical
Engineering, Southern Illinois University
Carbondale, Carbondale, Illinois 62901, United
States
- Materials
Technology Center, Southern Illinois University
Carbondale, Carbondale, Illinois 62901, United
States
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16
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Lee PS, Heinemann C, Zheng K, Appali R, Alt F, Krieghoff J, Bernhardt A, Boccaccini AR, van Rienen U, Hintze V. The interplay of collagen/bioactive glass nanoparticle coatings and electrical stimulation regimes distinctly enhanced osteogenic differentiation of human mesenchymal stem cells. Acta Biomater 2022; 149:373-386. [PMID: 35817340 DOI: 10.1016/j.actbio.2022.06.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/24/2022] [Accepted: 06/30/2022] [Indexed: 12/25/2022]
Abstract
Increasing research has incorporated bioactive glass nanoparticles (BGN) and electric field (EF) stimulation for bone tissue engineering and regeneration applications. However, their interplay and the effects of different EF stimulation regimes on osteogenic differentiation of human mesenchymal stem cells (hMSC) are less investigated. In this study, we introduced EF with negligible magnetic field strength through a well-characterized transformer-like coupling (TLC) system, and applied EF disrupted (4/4) or consecutive (12/12) regime on type I collagen (Col) coatings with/without BGN over 28 days. Additionally, dexamethasone was excluded to enable an accurate interpretation of BGN and EF in supporting osteogenic differentiation. Here, we demonstrated the influences of BGN and EF on collagen topography and maintaining coating stability. Coupled with the release profile of Si ions from the BGN, cell proliferation and calcium deposition were enhanced in the Col-BGN samples after 28 days. Further, osteogenic differentiation was initiated as early as d 7, and each EF regime was shown to activate distinct pathways. The disrupted (4/4) regime was associated with the BMP/Smad4 pathways that up-regulate Runx2/OCN gene expression on d 7, with a lesser effect on ALP activity. In contrast, the canonical Wnt/β-Catenin signaling pathway activated through mechanotransduction cues is associated with the consecutive (12/12) regime, with significantly elevated ALP activity and Sp7 gene expression reported on d 7. In summary, our results illustrated the synergistic effects of BGN and EF in different stimulation regimes on osteogenic differentiation that can be further exploited to enhance current bone tissue engineering and regeneration approaches. STATEMENT OF SIGNIFICANCE: The unique release mechanisms of silica from bioactive glass nanoparticles (BGN) were coupled with pulsatile electric field (EF) stimulation to support hMSC osteogenic differentiation, in the absence of dexamethasone. Furthermore, the interplay with consecutive (12/12) and disrupted (4/4) stimulation regimes was investigated. The reported physical, mechanical and topographical effects of BGN and EF on the collagen coating, hMSC and the distinct progression of osteogenic differentiation (canonical Wnt/β-Catenin and BMP/Smad) triggered by respective stimulation regime were not explicitly reported previously. These results provide the fundamentals for further exploitations on BGN composites with metal ions and rotation of EF regimes to enhance osteogenic differentiation. The goal is sustaining continual osteogenic differentiation and achieving a more physiologically-relevant state and bone constructs in vitro.
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Affiliation(s)
- Poh Soo Lee
- Institute of General Electrical Engineering, Faculty of Computer Science and Electrical Engineering, University of Rostock, Albert-Einstein-Straße 2, Rostock 18059, Germany; Max Bergmann Centre of Biomaterials, Institute of Materials Science, Faculty of Mechanical Science and Engineering, Technische Universität Dresden, Budapesterstraße 27, Dresden, Saxony 01069, Germany.
| | - Christiane Heinemann
- Max Bergmann Centre of Biomaterials, Institute of Materials Science, Faculty of Mechanical Science and Engineering, Technische Universität Dresden, Budapesterstraße 27, Dresden, Saxony 01069, Germany
| | - Kai Zheng
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Material Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremburg, Cauerstraße 6, Erlangen 91058, Germany
| | - Revathi Appali
- Institute of General Electrical Engineering, Faculty of Computer Science and Electrical Engineering, University of Rostock, Albert-Einstein-Straße 2, Rostock 18059, Germany; Department of Ageing of Individuals and Society, Interdisciplinary Faculty, University of Rostock, Albert-Einstein-Straße 21, Rostock 18059, Germany
| | - Franziska Alt
- Max Bergmann Centre of Biomaterials, Institute of Materials Science, Faculty of Mechanical Science and Engineering, Technische Universität Dresden, Budapesterstraße 27, Dresden, Saxony 01069, Germany
| | - Jan Krieghoff
- Institute of Pharmacy, Pharmaceutical Technology, Faculty of Medicine, University Leipzig. Eilenburgerstraße 15a, Leipzig 04317, Germany
| | - Anne Bernhardt
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany
| | - Aldo R Boccaccini
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Material Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremburg, Cauerstraße 6, Erlangen 91058, Germany
| | - Ursula van Rienen
- Institute of General Electrical Engineering, Faculty of Computer Science and Electrical Engineering, University of Rostock, Albert-Einstein-Straße 2, Rostock 18059, Germany; Department of Ageing of Individuals and Society, Interdisciplinary Faculty, University of Rostock, Albert-Einstein-Straße 21, Rostock 18059, Germany; Department of Life, Light and Matter, Interdisciplinary Faculty, University of Rostock, Albert-Einstein-Straße 25, Rostock 18059, Germany
| | - Vera Hintze
- Max Bergmann Centre of Biomaterials, Institute of Materials Science, Faculty of Mechanical Science and Engineering, Technische Universität Dresden, Budapesterstraße 27, Dresden, Saxony 01069, Germany.
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17
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Song X, Zhao M, Cao Q, Wang S, Li R, Zhang X, Zhang L, Shi K. Transcriptome provides insights into bovine mammary regulatory mechanisms during the lactation cycle. JOURNAL OF APPLIED ANIMAL RESEARCH 2022. [DOI: 10.1080/09712119.2022.2064865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Xuyang Song
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Meng Zhao
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Qiaoqiao Cao
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Shengxuan Wang
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Ranran Li
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Xuan Zhang
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Letian Zhang
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
| | - Kerong Shi
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural University, Tai’an, People’s Republic of China
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18
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Impact of Treadmill Interval Running on the Appearance of Zinc Finger Protein FHL2 in Bone Marrow Cells in a Rat Model: A Pilot Study. Life (Basel) 2022; 12:life12040528. [PMID: 35455019 PMCID: PMC9029125 DOI: 10.3390/life12040528] [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: 02/18/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 11/17/2022] Open
Abstract
Although the benefits of physical exercise to preserve bone quality are now widely recognized, the intimate mechanisms leading to the underlying cell responses still require further investigations. Interval training running, for instance, appears as a generator of impacts on the skeleton, and particularly on the progenitor cells located in the bone marrow. Therefore, if this kind of stimulus initiates bone cell proliferation and differentiation, the activation of a devoted signaling pathway by mechano-transduction seems likely. This study aimed at investigating the effects of an interval running program on the appearance of the zinc finger protein FHL2 in bone cells and their anatomical location. Twelve 5-week-old male Wistar rats were randomly allocated to one of the following groups (n = 6 per group): sedentary control (SED) or high-intensity interval running (EX, 8 consecutive weeks). FHL2 identification in bone cells was performed by immuno-histochemistry on serial sections of radii. We hypothesized that impacts generated by running could activate, in vivo, a specific signaling pathway, through an integrin-mediated mechano-transductive process, leading to the synthesis of FHL2 in bone marrow cells. Our data demonstrated the systematic appearance of FHL2 (% labeled cells: 7.5%, p < 0.001) in bone marrow obtained from EX rats, whereas no FHL2 was revealed in SED rats. These results suggest that the mechanical impacts generated during high-intensity interval running activate a signaling pathway involving nuclear FHL2, such as that also observed with dexamethasone administration. Consequently, interval running could be proposed as a non-pharmacological strategy to contribute to bone marrow cell osteogenic differentiation.
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19
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Zhang C, Lü D, Zhang F, Wu Y, Zheng L, Zhang X, Li Z, Sun S, Long M. Gravity-Vector Induces Mechanical Remodeling of rMSCs via Combined Substrate Stiffness and Orientation. Front Bioeng Biotechnol 2022; 9:724101. [PMID: 35198547 PMCID: PMC8859489 DOI: 10.3389/fbioe.2021.724101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/30/2021] [Indexed: 11/23/2022] Open
Abstract
Distinct physical factors originating from the cellular microenvironment are crucial to the biological homeostasis of stem cells. While substrate stiffness and orientation are known to regulate the mechanical remodeling and fate decision of mesenchymal stem cells (MSCs) separately, it remains unclear how the two factors are combined to manipulate their mechanical stability under gravity vector. Here we quantified these combined effects by placing rat MSCs onto stiffness-varied poly-dimethylsiloxane (PDMS) substrates in upward (180°), downward (0°), or edge-on (90°) orientation. Compared with those values onto glass coverslip, the nuclear longitudinal translocation, due to the density difference between the nucleus and the cytosol, was found to be lower at 0° for 24 h and higher at 90° for 24 and 72 h onto 2.5 MPa PDMS substrate. At 0°, the cell was mechanically supported by remarkably reduced actin and dramatically enhanced vimentin expression. At 90°, both enhanced actin and vimentin expression worked cooperatively to maintain cell stability. Specifically, perinuclear actin stress fibers with a large number, low anisotropy, and visible perinuclear vimentin cords were formed onto 2.5 MPa PDMS at 90° for 72 h, supporting the orientation difference in nuclear translocation and global cytoskeleton expression. This orientation dependence tended to disappear onto softer PDMS, presenting distinctive features in nuclear translocation and cytoskeletal structures. Moreover, cellular morphology and focal adhesion were mainly affected by substrate stiffness, yielding a time course of increased spreading area at 24 h but decreased area at 72 h with a decrease of stiffness. Mechanistically, the cell tended to be stabilized onto these PDMS substrates via β1 integrin–focal adhesion complexes–actin mechanosensitive axis. These results provided an insight in understanding the combination of substrate stiffness and orientation in defining the mechanical stability of rMSCs.
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Affiliation(s)
- Chen Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Dongyuan Lü
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Fan Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Yi Wu
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Lu Zheng
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyu Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Zhan Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Shujin Sun
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
| | - Mian Long
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
- School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Mian Long,
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20
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Ambattu LA, Gelmi A, Yeo LY. Short-Duration High Frequency MegaHertz-Order Nanomechanostimulation Drives Early and Persistent Osteogenic Differentiation in Mesenchymal Stem Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2106823. [PMID: 35023629 DOI: 10.1002/smll.202106823] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/12/2021] [Indexed: 06/14/2023]
Abstract
Stem cell fate can be directed through the application of various external physical stimuli, enabling a controlled approach to targeted differentiation. Studies involving the use of dynamic mechanical cues driven by vibrational excitation to date have, however, been limited to low frequency (Hz to kHz) forcing over extended durations (typically continuous treatment for >7 days). Contrary to previous assertions that there is little benefit in applying frequencies beyond 1 kHz, we show here that high frequency MHz-order mechanostimulation in the form of nanoscale amplitude surface reflected bulk waves are capable of triggering differentiation of human mesenchymal stem cells from various donor sources toward an osteoblast lineage, with early, short time stimuli inducing long-term osteogenic commitment. More specifically, rapid treatments (10 min daily over 5 days) of the high frequency (10 MHz) mechanostimulation are shown to trigger significant upregulation in early osteogenic markers (RUNX2, COL1A1) and sustained increase in late markers (osteocalcin, osteopontin) through a mechanistic pathway involving piezo channel activation and Rho-associated protein kinase signaling. Given the miniaturizability and low cost of the devices, the possibility for upscaling the platform toward practical bioreactors, to address a pressing need for more efficient stem cell differentiation technologies in the pursuit of translatable regenerative medicine strategies, is ensivaged.
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Affiliation(s)
- Lizebona August Ambattu
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne, Victoria, 3000, Australia
| | - Amy Gelmi
- School of Science, RMIT University, Melbourne, Victoria, 3000, Australia
| | - Leslie Y Yeo
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne, Victoria, 3000, Australia
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21
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Moghimi N, Peng K, Voloshin A. Biomechanical characterization and modeling of human mesenchymal stem cells under compression. Comput Methods Biomech Biomed Engin 2022; 25:1608-1617. [PMID: 35062850 DOI: 10.1080/10255842.2022.2028777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The application of microelectromechanical systems (MEMS) in biomedical devices has expanded vastly over the last few decades, with MEMS devices being developed to measure different characteristics of cells. The study of cell mechanics offers valuable understanding of cell viability and functionality. Cell biomechanics approaches also facilitate the characterization of important cell and tissue behaviors. In particular, understanding of the biological response of cells to their biomechanical environment would enhance the knowledge of how cellular responses correlate to tissue level characteristics and how some diseases, such as cancer, grow in the body. This study focuses on viscoelastic modeling of the behavior of a single suspended human mesenchymal stem cell (hMSC). Mechanical properties of hMSC cells are particularly important in tissue engineering and research for the treatment of cardiovascular diseases. We evaluated the elastic and viscoelastic properties of hMSC cells using a miniaturized custom-made BioMEMS device. Our results were compared to the elastic and viscoelastic properties measured by other methods such as atomic force microscopy (AFM) and micropipette aspiration. Different approaches were applied to model the experimentally obtained force data, including elastic and Standard Linear Solid (SLS) constitutive models, and the corresponding constants were derived. These values were compared to the ones in literature that were based on micropipette aspiration and AFM methods. We then utilized a tensegrity approach to model major parts of the internal structure of the cell and treat the cell as a network of viscoelastic microtubules and microfilaments, as opposed to a simple spherical blob. The results predicted from the tensegrity model were similar to the recorded experimental data.
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Affiliation(s)
- Negar Moghimi
- Electrical and Computer Engineering Department, Lehigh University, Bethlehem, PA, USA
| | - Kaiyuan Peng
- Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA, USA
| | - Arkady Voloshin
- Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA, USA.,Department of Bioengineering, Lehigh University, Bethlehem, PA, USA
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22
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Jin R, Cui Y, Chen H, Zhang Z, Weng T, Xia S, Yu M, Zhang W, Shao J, Yang M, Han C, Wang X. Three-dimensional bioprinting of a full-thickness functional skin model using acellular dermal matrix and gelatin methacrylamide bioink. Acta Biomater 2021; 131:248-261. [PMID: 34265473 DOI: 10.1016/j.actbio.2021.07.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/27/2021] [Accepted: 07/04/2021] [Indexed: 11/29/2022]
Abstract
Treatment of full-thickness skin defects still presents a significant challenge in clinical practice. Three-dimensional (3D) bioprinting technique offers a promising approach for fabricating skin substitutes. However, it is necessary to identify bioinks that have both sufficient mechanical properties and desirable biocompatibilities. In this study, we successfully fabricated acellular dermal matrix (ADM) and gelatin methacrylamide (GelMA) bioinks. The results demonstrated that ADM preserved the main extracellular matrix (ECM) components of the skin and GelMA had tunable mechanical properties. Both bioinks with shear-thinning properties were suitable for 3D bioprinting and GelMA bioink exhibited high printability. Additionally, the results revealed that 20% GelMA with sufficient mechanical properties was suitable to engineer epidermis, 1.5% ADM and 10% GelMA displayed relatively good cytocompatibilities. Here, we proposed a new 3D structure to simulate natural full-thickness skin, which included 20% GelMA with HaCaTs as an epidermal layer, 1.5% ADM with fibroblasts as the dermis, and 10% GelMA mesh with human umbilical vein endothelial cells (HUVECs) as the vascular network and framework. We demonstrated that this 3D bioprinting functional skin model (FSM) could not only promote cell viability and proliferation, but also support epidermis reconstruction in vitro. When transplanted in vivo, the FSM could maintain cell viability for at least 1 week. Furthermore, the FSM promoted wound healing and re-epithelization, stimulated dermal ECM secretion and angiogenesis, and improved wound healing quality. The FSM may provide viable functional skin substitutes for future clinical applications. STATEMENT OF SIGNIFICANCE: We propose a new 3D structure to simulate natural full-thickness skin, which included 20% GelMA with HaCaTs as an epidermal layer, 1.5% ADM with fibroblasts as the dermis, and 10% GelMA mesh with HUVECs as the vascular network. It could not only maintain a moist microenvironment and barrier function, but also recreate the natural skin microenvironment to promote cell viability and proliferation. This may provide viable functional skin substitutes for future clinical applications.
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Affiliation(s)
- Ronghua Jin
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Yuecheng Cui
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Haojiao Chen
- Department of Burns, Shaoxing Second Hospital, Shaoxing, China
| | - Zhenzhen Zhang
- First People's Hospital of Hangzhou Xiaoshan District, Hangzhou, China
| | - Tingting Weng
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Sizhan Xia
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Meirong Yu
- Clinical Research Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China
| | - Wei Zhang
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Jiaming Shao
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Min Yang
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Chunmao Han
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China
| | - Xingang Wang
- Department of Burns & Wound Care Center, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou 310009, China.
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23
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Maheden K, Bashth OS, Shakiba N. Evening the playing field: microenvironmental control over stem cell competition during fate programming. Curr Opin Genet Dev 2021; 70:66-75. [PMID: 34153929 DOI: 10.1016/j.gde.2021.05.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/26/2022]
Abstract
Recent advancements in cellular engineering, including reprogramming of somatic cells into pluripotent stem cells, have opened the door to a new era of regenerative medicine. Given that cellular decisions are guided by microenvironmental cues, such as secreted factors and interactions with neighbouring cells, reproducible cell manufacturing requires robust control over cell-cell interactions. Cell competition has recently emerged as a previously unknown interaction that plays a significant role in shaping the growth and death dynamics of multicellular stem cell populations, both in vivo and in vitro. Although recent studies have largely focused on exploring how the differential expression of key genes mediate the competitive elimination of some cells, little is known about the impact of the microenvironment on cell competition, despite its critical role in shaping cell fate outcomes. Here, we explore recent findings that have brought cell competition into the spotlight, while dissecting the role of microenvironmental factors for controlling competition in cell fate programming applications.
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Affiliation(s)
- Kieran Maheden
- School of Biomedical Engineering, Faculty of Applied Science and Faculty of Medicine, University of British Columbia, Biomedical Research Centre, 2222 Health Sciences Mall, V6T 1Z3, Vancouver, Canada
| | - Omar S Bashth
- School of Biomedical Engineering, Faculty of Applied Science and Faculty of Medicine, University of British Columbia, Biomedical Research Centre, 2222 Health Sciences Mall, V6T 1Z3, Vancouver, Canada
| | - Nika Shakiba
- School of Biomedical Engineering, Faculty of Applied Science and Faculty of Medicine, University of British Columbia, Biomedical Research Centre, 2222 Health Sciences Mall, V6T 1Z3, Vancouver, Canada.
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24
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Liao Q, Li BJ, Li Y, Xiao Y, Zeng H, Liu JM, Yuan LX, Liu G. Low-intensity pulsed ultrasound promotes osteoarthritic cartilage regeneration by BMSC-derived exosomes via modulating the NF-κB signaling pathway. Int Immunopharmacol 2021; 97:107824. [PMID: 34102487 DOI: 10.1016/j.intimp.2021.107824] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022]
Abstract
Osteoarthritis is the most common disabling joint disease throughout the world, and the effect of therapy on its course is still unsatisfactory in clinical practice. Recent studies have shown that mesenchymal stem cell (MSC)-derived exosomes can promote cartilage repair and regeneration in osteoarthritis, indicating that these exosomes could be a novel and promising strategy for treating osteoarthritis. This study investigated whether low-intensity pulsed ultrasound (LIPUS) enhances the effects of bone marrow MSC (BMSC)-derived exosomes on cartilage regeneration in osteoarthritis and examined the underlying mechanism. Our results revealed that BMSC-derived exosomes display the typical morphological features of exosomes. LIPUS-mediated BMSC-derived exosomes promoted cartilage regeneration, increased chondrocyte proliferation and extracellular matrix synthesis, suppressed inflammation, and inhibited the interleukin (IL)-1β-induced activation of the nuclear factor kappa B (NF-κB) pathway. In brief, LIPUS enhances the promoting effects of BMSC-derived exosomes on osteoarthritic cartilage regeneration, mainly by strengthening the inhibition of inflammation and further enhancing chondrocyte proliferation and cartilage matrix synthesis. The underlying mechanism could be related to the inhibition of the IL-1β-induced activation of the NF-κB pathway.
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Affiliation(s)
- Qing Liao
- Department of Rehabilitation Medicine, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China; Department of Rehabilitation Medicine, Shunde Hospital of Southern Medical University, Foshan 528000, China
| | - Bao Jian Li
- Department of Rehabilitation Medicine, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China
| | - Yang Li
- Department of Rehabilitation Medicine, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China
| | - Yu Xiao
- Department of Rehabilitation Medicine, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China
| | - Hui Zeng
- Department of Rehabilitation Medicine, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China
| | - Jie Mei Liu
- Department of Rehabilitation Medicine, Shunde Hospital of Southern Medical University, Foshan 528000, China
| | - Li Xia Yuan
- Southern Medical University, Guangzhou 510000, China.
| | - Gang Liu
- Department of Rehabilitation Medicine, Shunde Hospital of Southern Medical University, Foshan 528000, China; Department of Rehabilitation Medicine, Nanfang Hospital of Southern Medical University, Guangzhou 510000, China.
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25
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Rezalotfi A, Vrynas AV, Dehghanian M, Rezaei N. Lessons from the Embryo: an Unrejected Transplant and a Benign Tumor. Stem Cell Rev Rep 2021; 17:850-861. [PMID: 33225425 DOI: 10.1007/s12015-020-10088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 10/22/2022]
Abstract
Embryogenesis is regarded the 'miracle of life', yet numerous aspects of this process are not fully understood. As the embryo grows in the mother's womb, immune components, stem cells and microenvironmental cues cooperate among others to promote embryonic development. Evidently, these key players are frequently associated with transplantation failure and tumor growth. While the fields of transplantation and cancer biology do not overlap, both can be viewed from the perspective of an embryo. As an 'unrejected transplant' and a 'benign tumor', lessons from embryonic development may reveal features of transplants and tumors that have been overlooked. Therefore, eavesdropping at these natural complex events during pregnancy may inspire more durable approaches to arrest transplant rejection or cancer progression.
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Affiliation(s)
- Alaleh Rezalotfi
- Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Maryam Dehghanian
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
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26
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Li Y, Wang J, Zhong W. Regulation and mechanism of YAP/TAZ in the mechanical microenvironment of stem cells (Review). Mol Med Rep 2021; 24:506. [PMID: 33982785 PMCID: PMC8134874 DOI: 10.3892/mmr.2021.12145] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 02/02/2021] [Indexed: 12/31/2022] Open
Abstract
Stem cells receive cues from their physical and mechanical microenvironment via mechanosensing and mechanotransduction. These cues affect proliferation, self‑renewal and differentiation into specific cell fates. A growing body of evidence suggests that yes‑associated protein (YAP) and transcriptional coactivator with PDZ‑binding motif (TAZ) mechanotransduction is key for driving stem cell behavior and regeneration via the Hippo and other signaling pathways. YAP/TAZ receive a range of physical cues, including extracellular matrix stiffness, cell geometry, flow shear stress and mechanical forces in the cytoskeleton, and translate them into cell‑specific transcriptional programs. However, the mechanism by which mechanical signals regulate YAP/TAZ activity in stem cells is not fully understand. The present review summarizes the current knowledge of the mechanisms involved in YAP/TAZ regulation on the physical and mechanical microenvironment, as well as its potential effects on stem cell differentiation.
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Affiliation(s)
- Ying Li
- Department of Orthopaedics Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Jinming Wang
- Department of Orthopaedics Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Weiliang Zhong
- Department of Orthopaedics Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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27
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Sharifi S, Islam MM, Sharifi H, Islam R, Koza D, Reyes-Ortega F, Alba-Molina D, Nilsson PH, Dohlman CH, Mollnes TE, Chodosh J, Gonzalez-Andrades M. Tuning gelatin-based hydrogel towards bioadhesive ocular tissue engineering applications. Bioact Mater 2021; 6:3947-3961. [PMID: 33937594 PMCID: PMC8080056 DOI: 10.1016/j.bioactmat.2021.03.042] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/26/2021] [Accepted: 03/26/2021] [Indexed: 12/27/2022] Open
Abstract
Gelatin based adhesives have been used in the last decades in different biomedical applications due to the excellent biocompatibility, easy processability, transparency, non-toxicity, and reasonable mechanical properties to mimic the extracellular matrix (ECM). Gelatin adhesives can be easily tuned to gain different viscoelastic and mechanical properties that facilitate its ocular application. We herein grafted glycidyl methacrylate on the gelatin backbone with a simple chemical modification of the precursor, utilizing epoxide ring-opening reactions and visible light-crosslinking. This chemical modification allows the obtaining of an elastic protein-based hydrogel (GELGYM) with excellent biomimetic properties, approaching those of the native tissue. GELGYM can be modulated to be stretched up to 4 times its initial length and withstand high tensile stresses up to 1.95 MPa with compressive strains as high as 80% compared to Gelatin-methacryloyl (GeIMA), the most studied derivative of gelatin used as a bioadhesive. GELGYM is also highly biocompatible and supports cellular adhesion, proliferation, and migration in both 2 and 3-dimensional cell-cultures. These characteristics along with its super adhesion to biological tissues such as cornea, aorta, heart, muscle, kidney, liver, and spleen suggest widespread applications of this hydrogel in many biomedical areas such as transplantation, tissue adhesive, wound dressing, bioprinting, and drug and cell delivery.
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Affiliation(s)
- Sina Sharifi
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Mohammad Mirazul Islam
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Hannah Sharifi
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Rakibul Islam
- Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway
| | - Darrell Koza
- Department of Physical Sciences, Eastern Connecticut State University, Willimantic, CT, USA
| | - Felisa Reyes-Ortega
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Ophthalmology, Reina Sofia University Hospital and University of Cordoba, Cordoba, Spain
| | - David Alba-Molina
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Ophthalmology, Reina Sofia University Hospital and University of Cordoba, Cordoba, Spain
| | - Per H Nilsson
- Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.,Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Claes H Dohlman
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Tom Eirik Mollnes
- Department of Immunology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway.,Research Laboratory, Nordland Hospital, Bodø, Norway.,Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.,Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Norway
| | - James Chodosh
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Miguel Gonzalez-Andrades
- Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Ophthalmology, Reina Sofia University Hospital and University of Cordoba, Cordoba, Spain
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28
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van de Vyver M, Powrie YSL, Smith C. Targeting Stem Cells in Chronic Inflammatory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:163-181. [PMID: 33725353 DOI: 10.1007/978-3-030-55035-6_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cell (MSC) dysfunction is a serious complication in ageing and age-related inflammatory diseases such as type 2 diabetes mellitus. Inflammation and oxidative stress-induced cellular senescence alter the immunomodulatory ability of MSCs and hamper their pro-regenerative function, which in turn leads to an increase in disease severity, maladaptive tissue damage and the development of comorbidities. Targeting stem/progenitor cells to restore their function and/or protect them against impairment could thus improve healing outcomes and significantly enhance the quality of life for diabetic patients. This review discusses the dysregulation of MSCs' immunomodulatory capacity in the context of diabetes mellitus and focuses on intervention strategies aimed at MSC rejuvenation. Research pertaining to the potential therapeutic use of either pharmacological agents (NFкB antagonists), natural products (phytomedicine) or biological agents (exosomes, probiotics) to improve MSC function is discussed and an overview of the most pertinent methodological considerations given. Based on in vitro studies, numerous anti-inflammatory agents, antioxidants and biological agents show tremendous potential to revitalise MSCs. An integrated systems approach and a thorough understanding of complete disease pathology are however required to identify feasible candidates for in vivo targeting of MSCs.
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Affiliation(s)
- Mari van de Vyver
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Yigael S L Powrie
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.,Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
| | - Carine Smith
- Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
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29
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Carthew J, Abdelmaksoud HH, Hodgson‐Garms M, Aslanoglou S, Ghavamian S, Elnathan R, Spatz JP, Brugger J, Thissen H, Voelcker NH, Cadarso VJ, Frith JE. Precision Surface Microtopography Regulates Cell Fate via Changes to Actomyosin Contractility and Nuclear Architecture. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003186. [PMID: 33747730 PMCID: PMC7967085 DOI: 10.1002/advs.202003186] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/12/2020] [Indexed: 05/06/2023]
Abstract
Cells are able to perceive complex mechanical cues from their microenvironment, which in turn influences their development. Although the understanding of these intricate mechanotransductive signals is evolving, the precise roles of substrate microtopography in directing cell fate is still poorly understood. Here, UV nanoimprint lithography is used to generate micropillar arrays ranging from 1 to 10 µm in height, width, and spacing to investigate the impact of microtopography on mechanotransduction. Using mesenchymal stem cells (MSCs) as a model, stark pattern-specific changes in nuclear architecture, lamin A/C accumulation, chromatin positioning, and DNA methyltransferase expression, are demonstrated. MSC osteogenesis is also enhanced specifically on micropillars with 5 µm width/spacing and 5 µm height. Intriguingly, the highest degree of osteogenesis correlates with patterns that stimulated maximal nuclear deformation which is shown to be dependent on myosin-II-generated tension. The outcomes determine new insights into nuclear mechanotransduction by demonstrating that force transmission across the nuclear envelope can be modulated by substrate topography, and that this can alter chromatin organisation and impact upon cell fate. These findings have potential to inform the development of microstructured cell culture substrates that can direct cell mechanotransduction and fate for therapeutic applications in both research and clinical sectors.
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Affiliation(s)
- James Carthew
- Department of Materials Science and EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
- Centre to Impact Antimicrobial Resistance – Sustainable SolutionsMonash UniversityClaytonVictoria3800Australia
| | - Hazem H. Abdelmaksoud
- Department of Mechanical and Aerospace EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
- Melbourne Centre for NanofabricationVictorian Node of the Australian National Fabrication FacilityClaytonVictoria3168Australia
| | - Margeaux Hodgson‐Garms
- Department of Materials Science and EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
| | - Stella Aslanoglou
- Melbourne Centre for NanofabricationVictorian Node of the Australian National Fabrication FacilityClaytonVictoria3168Australia
- Monash Institute of Pharmaceutical SciencesMonash University381 Royal ParadeParkvilleVictoria3052Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO)ClaytonVictoria3168Australia
| | - Sara Ghavamian
- Centre to Impact Antimicrobial Resistance – Sustainable SolutionsMonash UniversityClaytonVictoria3800Australia
- Department of Mechanical and Aerospace EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
| | - Roey Elnathan
- Department of Materials Science and EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
- Melbourne Centre for NanofabricationVictorian Node of the Australian National Fabrication FacilityClaytonVictoria3168Australia
- Monash Institute of Pharmaceutical SciencesMonash University381 Royal ParadeParkvilleVictoria3052Australia
| | - Joachim P. Spatz
- Department of Cellular BiophysicsMax Planck Institute for Medical ResearchJahnstraßeHeidelbergD‐69120Germany
- Heidelberg UniversityInstitute for Molecular Systems Engineering (IMSE)HeidelbergD‐69120Germany
- Max Planck School Matter to LifeGermany
| | - Juergen Brugger
- Microsystems LaboratoryÉcole Polytechnique Fédérale de Lausanne (EPFL)Lausanne1015Switzerland
| | - Helmut Thissen
- Commonwealth Scientific and Industrial Research Organisation (CSIRO)ClaytonVictoria3168Australia
| | - Nicolas H. Voelcker
- Department of Materials Science and EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
- Melbourne Centre for NanofabricationVictorian Node of the Australian National Fabrication FacilityClaytonVictoria3168Australia
- Monash Institute of Pharmaceutical SciencesMonash University381 Royal ParadeParkvilleVictoria3052Australia
- Commonwealth Scientific and Industrial Research Organisation (CSIRO)ClaytonVictoria3168Australia
| | - Victor J. Cadarso
- Centre to Impact Antimicrobial Resistance – Sustainable SolutionsMonash UniversityClaytonVictoria3800Australia
- Department of Mechanical and Aerospace EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
- Melbourne Centre for NanofabricationVictorian Node of the Australian National Fabrication FacilityClaytonVictoria3168Australia
| | - Jessica E. Frith
- Department of Materials Science and EngineeringMonash UniversityWellington RoadClaytonVictoria3800Australia
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30
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Backes EH, Fernandes EM, Diogo GS, Marques CF, Silva TH, Costa LC, Passador FR, Reis RL, Pessan LA. Engineering 3D printed bioactive composite scaffolds based on the combination of aliphatic polyester and calcium phosphates for bone tissue regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 122:111928. [PMID: 33641921 DOI: 10.1016/j.msec.2021.111928] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/21/2020] [Accepted: 01/28/2021] [Indexed: 12/01/2022]
Abstract
In this study, polylactic acid (PLA) filled with hydroxyapatite (HA) or beta-tricalcium phosphate (TCP) in 5 wt% and 10 wt% of concentration were produced employing twin-screw extrusion followed by fused filament fabrication in two different architectures, varying the orientation of fibers of adjacent layers. The extruded 3D filaments presented suitable rheological and thermal properties to manufacture of 3D scaffolds envisaging bone tissue engineering. The produced scaffolds exhibited a high level of printing accuracy related to the 3D model; confirmed by micro-CT and electron microscopy analysis. The developed architectures presented mechanical properties compatible with human bone replacement. The addition of HA and TCP made the filaments bioactive, and the deposition of new calcium phosphates was observed upon 7 days of incubation in simulated body fluid, exemplifying a microenvironment suitable for cell attachment and proliferation. After 7 days of cell culture, the constructs with a higher percentage of HA and TCP demonstrated a significantly superior amount of DNA when compared to neat PLA, indicating that higher concentrations of HA and TCP could guide a good cellular response and increasing cell cytocompatibility. Differentiation tests were performed, and the biocomposites of PLA/HA and PLA/TCP exhibited earlier markers of cell differentiation as confirmed by alkaline phosphatase and alizarin red assays. The 3D printed composite scaffolds, manufactured with bioactive materials and adequate porous size, supported cell attachment, proliferation, and differentiation, which together with their scalability, promise a high potential for bone tissue engineering applications.
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Affiliation(s)
- Eduardo H Backes
- Graduate Program in Materials Science and Engineering, Federal University of São Carlos, via Washington Luiz, Km 235, 13565-905 São Carlos, SP, Brazil; 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal.
| | - Emanuel M Fernandes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
| | - Gabriela S Diogo
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
| | - Catarina F Marques
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
| | - Tiago H Silva
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
| | - Lidiane C Costa
- Graduate Program in Materials Science and Engineering, Federal University of São Carlos, via Washington Luiz, Km 235, 13565-905 São Carlos, SP, Brazil.
| | - Fabio R Passador
- Science and Technology Institute, Federal University of São Paulo, Talim St. 330, 12231-280 São José dos Campos, SP, Brazil.
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
| | - Luiz A Pessan
- Graduate Program in Materials Science and Engineering, Federal University of São Carlos, via Washington Luiz, Km 235, 13565-905 São Carlos, SP, Brazil.
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31
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Lin LM, Huang GTJ, Sigurdsson A, Kahler B. Clinical cell-based versus cell-free regenerative endodontics: clarification of concept and term. Int Endod J 2021; 54:887-901. [PMID: 33389773 DOI: 10.1111/iej.13471] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 12/29/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022]
Abstract
There is no consensus on the true meaning of clinical regenerative endodontics, and there is confusion over the concept and the term. Commonly used terms include revitalization and revascularization. The clinical methods for endodontic revitalization procedures and the tissue engineering concept differ depending on whether there is exogenous delivery of cells - called cell therapy, or not. Here, in this review, the difference is clarified by emphasizing the correct terminology: cell-free versus cell-based regenerative endodontic therapy (CF-RET versus CB-RET). The revitalization procedures practised clinically do not fit into the modern tissue engineering concepts of pulp regeneration but can be categorized as CF-RET. The modern tissue engineering concept in pulp regeneration is a CB-RET, which so far is at the clinical trial stage. However, histological examination of teeth following regenerative endodontic treatments reveals healing with repair derived from stem cells that originate from the periodontal, bone and other tissues. The aim of regenerative endodontics is regeneration of the pulp-dentine complex. This review discusses why CF-RET is unlikely to regenerate a pulp-dentine complex with current protocols. The American Association of Endodontists and the European Society of Endodontology have not yet recommended autologous stem cell transplantation (CB-RERT) which aspires for regeneration. Therefore, an understanding of the concept, term, difficulties and differences in current protocols is important for the clinician. However, rather than being discouraged that ideal regeneration has not been achieved to date, repair can be an acceptable outcome in clinical regenerative endodontics as it has also been accepted in medicine. Repair should also be considered in the context that resolution of the clinical signs/symptoms of pulp necrosis/apical periodontitis is generally reliably obtained in clinical regenerative endodontics.
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Affiliation(s)
- L M Lin
- College of Dentistry, New York University, New York, NY, USA
| | - G T-J Huang
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN, USA
| | - A Sigurdsson
- College of Dentistry, New York University, New York, NY, USA
| | - B Kahler
- School of Dentistry, University of Queensland, Brisbane, Australia
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Zhang H, Huang W, Liu H, Zheng Y, Liao L. Mechanical stretching of pulmonary vein stimulates matrix metalloproteinase-9 and transforming growth factor-β1 through stretch-activated channel/MAPK pathways in pulmonary hypertension due to left heart disease model rats. PLoS One 2020; 15:e0235824. [PMID: 32881898 PMCID: PMC7470280 DOI: 10.1371/journal.pone.0235824] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 06/23/2020] [Indexed: 12/23/2022] Open
Abstract
Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-β1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-β1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-β1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.
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Affiliation(s)
- Hui Zhang
- Department of Cardiac Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
| | - Wenhui Huang
- Department of Cardiac Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
| | - Hongjin Liu
- Department of Cardiac Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
| | - Yihan Zheng
- Department of Cardiac Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
| | - Lianming Liao
- Department of Medical Laboratory, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, P.R. China
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Zona pellucida shear modulus, a possible novel non-invasive method to assist in embryo selection during in-vitro fertilization treatment. Sci Rep 2020; 10:14066. [PMID: 32826934 PMCID: PMC7443135 DOI: 10.1038/s41598-020-70739-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/22/2020] [Indexed: 11/14/2022] Open
Abstract
The present study investigated the association between oocyte zona pellucida shear modulus (ZPSM) and implantation rate (IR). Ninety-three oocytes collected from 38 in-vitro fertilization patients who underwent intracytoplasmic sperm injection were included in this case–control study. The ZP was modeled as an isotropic compressible hyperelastic material with parameter \documentclass[12pt]{minimal}
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\begin{document}$$C_{10}$$\end{document}C10, which represents the ZPSM. Computational methodology was used to calculate the mechanical parameters that govern ZP deformation. Fifty-one developed embryos were transferred and divided into two groups—implanted and not implanted. Multivariate logistic regression analysis was performed to identify the association between ZPSM and IR while controlling for confounders. Maternal age and number of embryos per transfer were significantly associated with implantation. The IR of embryos characterized by \documentclass[12pt]{minimal}
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\begin{document}$$C_{10}$$\end{document}C10 values in the range of 0.20–0.40 kPa was 66.75%, while outside this range it was 6.70%. This range was significantly associated with implantation (p < 0.001). Geometric properties were not associated with implantation. Multivariate logistic regression analysis that controlled for relevant confounders indicated that this range was independently associated with implantation (adjusted OR 38.03, 95% confidence interval 4.67–309.36, p = 0.001). The present study suggests that ZPSM may improve the classic embryo selection process with the aim of increasing IR.
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Xia S, Lim YB, Zhang Z, Wang Y, Zhang S, Lim CT, Yim EKF, Kanchanawong P. Nanoscale Architecture of the Cortical Actin Cytoskeleton in Embryonic Stem Cells. Cell Rep 2020; 28:1251-1267.e7. [PMID: 31365868 DOI: 10.1016/j.celrep.2019.06.089] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 04/24/2019] [Accepted: 06/25/2019] [Indexed: 12/15/2022] Open
Abstract
Mechanical cues influence pluripotent stem cell differentiation, but the underlying mechanisms are not well understood. Mouse embryonic stem cells (mESCs) exhibit unusual cytomechanical properties, including low cell stiffness and attenuated responses to substrate rigidity, but the underlying structural basis remains obscure. Using super-resolution microscopy to investigate the actin cytoskeleton in mESCs, we observed that the actin cortex consists of a distinctively sparse and isotropic network. Surprisingly, the architecture and mechanics of the mESC actin cortex appear to be largely myosin II-independent. The network density can be modulated by perturbing Arp2/3 and formin, whereas capping protein (CP) negatively regulates cell stiffness. Transient Arp2/3-containing aster-like structures are implicated in the organization and mechanical homeostasis of the cortical network. By generating a low-density network that physically excludes myosin II, the interplay between Arp2/3, formin, and CP governs the nanoscale architecture of the actin cortex and prescribes the cytomechanical properties of mESCs.
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Affiliation(s)
- Shumin Xia
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Ying Bena Lim
- Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore
| | - Zhen Zhang
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Yilin Wang
- Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China
| | - Shan Zhang
- Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore
| | - Chwee Teck Lim
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore; Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore 117599, Singapore
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Pakorn Kanchanawong
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore 117583, Singapore.
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Zhang M, Shi J, Xie M, Wen J, Niibe K, Zhang X, Luo J, Yan R, Zhang Z, Egusa H, Jiang X. Recapitulation of cartilage/bone formation using iPSCs via biomimetic 3D rotary culture approach for developmental engineering. Biomaterials 2020; 260:120334. [PMID: 32862124 DOI: 10.1016/j.biomaterials.2020.120334] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 07/13/2020] [Accepted: 08/15/2020] [Indexed: 12/21/2022]
Abstract
The recapitulation of cartilage/bone formation via guiding induced pluripotent stem cells (iPSCs) differentiation toward chondrogenic mesoderm lineage is an ideal approach to investigate cartilage/bone development and also for cartilage/bone regeneration. However, current induction protocols are time-consuming and complicated to follow. Here, we established a rapid and efficient approach that directly induce iPSCs differentiation toward chondrogenic mesoderm lineage by regulating the crucial Bmp-4 and FGF-2 signaling pathways using a 3D rotary suspension culture system. The mechanical stimulation from 3D rotary suspension accelerates iPSCs differentiation toward mesodermal and subsequent chondrogenic lineage via the Bmp-4-Smad1 and Tgf-β-Smad2/3 signaling pathways, respectively. The scaffold-free homogenous cartilaginous pellets or hypertrophic cartilaginous pellets derived from iPSCs within 28 days were capable of articular cartilage regeneration or vascularized bone regeneration via endochondral ossification in vivo, respectively. This biomimetic culture approach will contribute to research related to cartilage/bone development, regeneration, and hence to therapeutic applications in cartilage-/bone-related diseases.
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Affiliation(s)
- Maolin Zhang
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Junfeng Shi
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Ming Xie
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Jin Wen
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Kunimichi Niibe
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Xiangkai Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Jiaxin Luo
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Ran Yan
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Zhiyuan Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan.
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.
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Effect of the 3D Artificial Nichoid on the Morphology and Mechanobiological Response of Mesenchymal Stem Cells Cultured In Vitro. Cells 2020; 9:cells9081873. [PMID: 32796521 PMCID: PMC7464958 DOI: 10.3390/cells9081873] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 02/07/2023] Open
Abstract
Stem cell fate and behavior are affected by the bidirectional communication of cells and their local microenvironment (the stem cell niche), which includes biochemical cues, as well as physical and mechanical factors. Stem cells are normally cultured in conventional two-dimensional monolayer, with a mechanical environment very different from the physiological one. Here, we compare culture of rat mesenchymal stem cells on flat culture supports and in the "Nichoid", an innovative three-dimensional substrate micro-engineered to recapitulate the architecture of the physiological niche in vitro. Two versions of the culture substrates Nichoid (single-layered or "2D Nichoid" and multi-layered or "3D Nichoid") were fabricated via two-photon laser polymerization in a biocompatible hybrid organic-inorganic photoresist (SZ2080). Mesenchymal stem cells, isolated from rat bone marrow, were seeded on flat substrates and on 2D and 3D Nichoid substrates and maintained in culture up to 2 weeks. During cell culture, we evaluated cell morphology, proliferation, cell motility and the expression of a panel of 89 mesenchymal stem cells' specific genes, as well as intracellular structures organization. Our results show that mesenchymal stem cells adhered and grew in the 3D Nichoid with a comparable proliferation rate as compared to flat substrates. After seeding on flat substrates, cells displayed large and spread nucleus and cytoplasm, while cells cultured in the 3D Nichoid were spatially organized in three dimensions, with smaller and spherical nuclei. Gene expression analysis revealed the upregulation of genes related to stemness and to mesenchymal stem cells' features in Nichoid-cultured cells, as compared to flat substrates. The observed changes in cytoskeletal organization of cells cultured on 3D Nichoids were also responsible for a different localization of the mechanotransducer transcription factor YAP, with an increase of the cytoplasmic retention in cells cultured in the 3D Nichoid. This difference could be explained by alterations in the import of transcription factors inside the nucleus due to the observed decrease of mean nuclear pore diameter, by transmission electron microscopy. Our data show that 3D distribution of cell volume has a profound effect on mesenchymal stem cells structure and on their mechanobiological response, and highlight the potential use of the 3D Nichoid substrate to strengthen the potential effects of MSC in vitro and in vivo.
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Mu X, Tseng C, Hambright WS, Matre P, Lin C, Chanda P, Chen W, Gu J, Ravuri S, Cui Y, Zhong L, Cooke JP, Niedernhofer LJ, Robbins PD, Huard J. Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome. Aging Cell 2020; 19:e13152. [PMID: 32710480 PMCID: PMC7431831 DOI: 10.1111/acel.13152] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 03/10/2020] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle-derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24-/- (Z24-/- ) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin-induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F-actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei-induced cGAS-Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24-/- mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.
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Affiliation(s)
- Xiaodong Mu
- Department of Molecular Physiology and BiophysicsBaylor College of MedicineHoustonTexas
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
- Shandong First Medical University & Shandong Academy of Medical SciencesJi'nanChina
| | - Chieh Tseng
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
| | - William S. Hambright
- Center for Regenerative Sports MedicineSteadman Philippon Research InstituteVailColorado
| | - Polina Matre
- Department of Cardiovascular SciencesHouston Methodist Research InstituteHoustonTexas
| | - Chih‐Yi Lin
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
| | - Palas Chanda
- Department of Cardiovascular SciencesHouston Methodist Research InstituteHoustonTexas
| | - Wanqun Chen
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
- Shandong First Medical University & Shandong Academy of Medical SciencesJi'nanChina
| | - Jianhua Gu
- Electron Microscopy CoreHouston Methodist Research InstituteHoustonTexas
| | - Sudheer Ravuri
- Center for Regenerative Sports MedicineSteadman Philippon Research InstituteVailColorado
| | - Yan Cui
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
| | - Ling Zhong
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
| | - John P. Cooke
- Department of Cardiovascular SciencesHouston Methodist Research InstituteHoustonTexas
| | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and BiophysicsUniversity of MinnesotaMinneapolisMinnesota
| | - Paul D. Robbins
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and BiophysicsUniversity of MinnesotaMinneapolisMinnesota
| | - Johnny Huard
- Department of Orthopaedic SurgeryMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexas
- Center for Regenerative Sports MedicineSteadman Philippon Research InstituteVailColorado
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Yadav A, Seth B, Chaturvedi RK. Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders. Neuroscientist 2020; 27:388-426. [PMID: 32723210 DOI: 10.1177/1073858420943192] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Unravelling the complexity of the human brain is a challenging task. Nowadays, modern neurobiologists have developed 3D model systems called "brain organoids" to overcome the technical challenges in understanding human brain development and the limitations of animal models to study neurological diseases. Certainly like most model systems in neuroscience, brain organoids too have limitations, as these minuscule brains lack the complex neuronal circuitry required to begin the operational tasks of human brain. However, researchers are hopeful that future endeavors with these 3D brain tissues could provide mechanistic insights into the generation of circuit complexity as well as reproducible creation of different regions of the human brain. Herein, we have presented the contemporary state of brain organoids with special emphasis on their mode of generation and their utility in modelling neurological disorders, drug discovery, and clinical trials.
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Affiliation(s)
- Anuradha Yadav
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Brashket Seth
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rajnish Kumar Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Wu T, Yin F, Wang N, Ma X, Jiang C, Zhou L, Zong Y, Shan H, Xia W, Lin Y, Zhou Z, Yu X. Involvement of mechanosensitive ion channels in the effects of mechanical stretch induces osteogenic differentiation in mouse bone marrow mesenchymal stem cells. J Cell Physiol 2020; 236:284-293. [PMID: 32592173 DOI: 10.1002/jcp.29841] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/21/2020] [Accepted: 05/22/2020] [Indexed: 01/07/2023]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) can be induced to process osteogenic differentiation with appropriate mechanical and/or chemical stimuli. The present study described the successful culture of murine BMSCs under mechanical strain. BMSCs were subjected to 0%, 3%, 8%, 13%, and 18% cyclic tensile strain at 0.5 Hz for 8 hr/day for 3 days. The expression of osteogenic markers and mechanosensitive ion channels was evaluated with real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The expression of alkaline phosphatase (ALP) and matrix mineralization were evaluated with histochemical staining. To investigate the effects of mechanosensitive ion channel expression on cyclic tensile strain-induced osteogenic differentiation, the expression of osteogenic markers was evaluated with real-time RT-PCR in the cells without mechanosensitive ion channel expression. This study revealed a significant augment in osteogenic marker in BMSC strained at 8% compared to other treatments; therefore, an 8% strain was used for further investigations. The ALP expression and matrix mineralization were enhanced in osteogenic induced BMSCs subjected to 8% strain after 7 and 14 days, respectively. Under the same conditions, the osteogenic marker and mechanosensitive ion channel expression were significantly promoted. However, the loss function of mechanosensitive ion channels resulted in the inhibition of osteogenic marker expression. This study demonstrated that strain alone can successfully induce osteogenic differentiation in BMSCs and the expression of mechanosensitive ion channels was involved in the process. The current findings suggest that mechanical stretch could function as efficient stimuli to induce the osteogenic differentiation of BMSCs via the activation of mechanosensitive ion channels.
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Affiliation(s)
- Tianyi Wu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Fuli Yin
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Nan Wang
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xin Ma
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chaolai Jiang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Lihui Zhou
- Department of Orthopaedic Surgery, Xiangshan First People's Hospital, Ningbo, Zhejiang, China
| | - Yang Zong
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Haojie Shan
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wenyang Xia
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yiwei Lin
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zubin Zhou
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaowei Yu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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URDEITX PAU, FARZANEH SOLMAZ, MOUSAVI SJAMALEDDIN, DOWEIDAR MOHAMEDH. ROLE OF OXYGEN CONCENTRATION IN THE OSTEOBLASTS BEHAVIOR: A FINITE ELEMENT MODEL. J MECH MED BIOL 2020. [DOI: 10.1142/s0219519419500647] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Oxygen concentration plays a key role in cell survival and viability. Besides, it has important effects on essential cellular biological processes such as cell migration, differentiation, proliferation and apoptosis. Therefore, the prediction of the cellular response to the alterations of the oxygen concentration can help significantly in the advances of cell culture research. Here, we present a 3D computational mechanotactic model to simulate all the previously mentioned cell processes under different oxygen concentrations. With this model, three cases have been studied. Starting with mesenchymal stem cells within an extracellular matrix with mechanical properties suitable for its differentiation into osteoblasts, and under different oxygen conditions to evaluate their behavior under normoxia, hypoxia and anoxia. The obtained results, which are consistent with the experimental observations, indicate that cells tend to migrate toward zones with higher oxygen concentration where they accelerate their differentiation and proliferation. This technique can be employed to control cell migration toward fracture zones to accelerate the healing process. Besides, as expected, to avoid cell apoptosis under conditions of anoxia and to avoid the inhibition of the differentiation and proliferation processes under conditions of hypoxia, the state of normoxia should be maintained throughout the entire cell-culture process.
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Affiliation(s)
- PAU URDEITX
- Mechanical Engineering Department, School of Engineering and Architecture (EINA), University of Zaragoza, Zaragoza, Spain
- Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain
| | - SOLMAZ FARZANEH
- Mines Saint-Etienne, Univ Lyon, Univ Jean Monnet, INSERM, U 1059, Sainbiose, Centre CIS, F - 42023, Saint-Etienne, France
| | - S. JAMALEDDIN MOUSAVI
- Mines Saint-Etienne, Univ Lyon, Univ Jean Monnet, INSERM, U 1059, Sainbiose, Centre CIS, F - 42023, Saint-Etienne, France
| | - MOHAMED H. DOWEIDAR
- Mechanical Engineering Department, School of Engineering and Architecture (EINA), University of Zaragoza, Zaragoza, Spain
- Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain
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Zhang Q, Nettleship I, Schmelzer E, Gerlach J, Zhang X, Wang J, Liu C. Tissue Engineering and Regenerative Medicine Therapies for Cell Senescence in Bone and Cartilage. TISSUE ENGINEERING PART B-REVIEWS 2020; 26:64-78. [DOI: 10.1089/ten.teb.2019.0215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Qinghao Zhang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
- Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ian Nettleship
- Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eva Schmelzer
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jorg Gerlach
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xuewei Zhang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
| | - Jing Wang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
| | - Changsheng Liu
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
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Abstract
The tooth provides an excellent system for deciphering the molecular mechanisms of organogenesis, and has thus been of longstanding interest to developmental and stem cell biologists studying embryonic morphogenesis and adult tissue renewal. In recent years, analyses of molecular signaling networks, together with new insights into cellular heterogeneity, have greatly improved our knowledge of the dynamic epithelial-mesenchymal interactions that take place during tooth development and homeostasis. Here, we review recent progress in the field of mammalian tooth morphogenesis and also discuss the mechanisms regulating stem cell-based dental tissue homeostasis, regeneration and repair. These exciting findings help to lay a foundation that will ultimately enable the application of fundamental research discoveries toward therapies to improve oral health.
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Affiliation(s)
- Tingsheng Yu
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA 94143, USA
| | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA 94143, USA
- Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, CA 94143, USA
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Nasb M, Liangjiang H, Gong C, Hong C. Human adipose-derived Mesenchymal stem cells, low-intensity pulsed ultrasound, or their combination for the treatment of knee osteoarthritis: study protocol for a first-in-man randomized controlled trial. BMC Musculoskelet Disord 2020; 21:33. [PMID: 31941483 PMCID: PMC6964002 DOI: 10.1186/s12891-020-3056-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/08/2020] [Indexed: 01/22/2023] Open
Abstract
Background Human adipose-derived Mesenchymal stem cells (HADMSCs) have proven their efficacy in treating osteoarthritis (OA), in earlier preclinical and clinical studies. As the tissue repairers are under the control of mechanical and biochemical signals, improving regeneration outcomes using such signals has of late been the focus of attention. Among mechanical stimuli, low-intensity pulsed ultrasound (LIPUS) has recently shown promise both in vitro and in vivo. This study will investigate the potential of LIPUS in enhancing the regeneration process of an osteoarthritic knee joint. Methods This study involves a prospective, randomized, placebo-controlled, and single-blind trial based on the SPIRIT guidelines, and aims to recruit 96 patients initially diagnosed with knee osteoarthritis, following American College of Rheumatology criteria. Patients will be randomized in a 1:1:1 ratio to receive Intraarticular HADMSCs injection with LIPUS, Intraarticular HADMSCs injection with shame LIPUS, or Normal saline with LIPUS. The primary outcome is Western Ontario and McMaster Universities Index of OA (WOMAC) score, while the secondary outcomes will be other knee structural changes, and lower limb muscle strength such as the knee cartilage thickness measured by MRI. Blinded assessments will be performed at baseline (1 month prior to treatment), 1 month, 3 months, and 6 months following the interventions. Discussion This trial will be the first clinical study to comprehensively investigate the safety and efficacy of LIPUS on stem cell therapy in OA patients. The results may provide evidence of the effectiveness of LIPUS in improving stem cell therapy and deliver valuable information for the design of subsequent trials. Trial registration This study had been prospectively registered with the Chinese Clinical Trials Registry. registration number: ChiCTR1900025907 at September 14, 2019.
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Affiliation(s)
- Mohammad Nasb
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.,Department of Physical Therapy, Health science faculty, Albaath University, Homs, Syria
| | - Huang Liangjiang
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Chenzi Gong
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Chen Hong
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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Chen X, Du W, Cai Z, Ji S, Dwivedi M, Chen J, Zhao G, Chu J. Uniaxial Stretching of Cell-Laden Microfibers for Promoting C2C12 Myoblasts Alignment and Myofibers Formation. ACS APPLIED MATERIALS & INTERFACES 2020; 12:2162-2170. [PMID: 31856565 DOI: 10.1021/acsami.9b22103] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Fiber-shaped cellular constructs have attracted increasing attention in the regeneration of blood vessels, nerve networks, and skeletal myofibers. Nevertheless, the generation of functional fiber-shaped cellular constructs suffers from limited appropriate microfiber-based fabrication approaches and the maintenance of regenerated tissue functions. Herein, we demonstrate a silicone-tube-based coagulant bath free method to fabricate tens of centimeters long cell-laden microfibers using single UV exposure without pretreatment of nozzles or microchannels. By modulating the exposure time, the gelatin methacrylate microfibers with tissue-like microstructures and mechanical properties are obtained. Then, a culture system integrated with a pillar well-array based stretching device is used to apply uniaxial stretching with various strain ratios in situ to cell-laden microfibers in a 60 mm petri dish. Cells with improved spreading, elongation, and alignment are obtained under uniaxial stretching. Moreover, the promotional effects of uniaxial stretching on the differentiation of C2C12 myoblasts, the formation, and contractility of myofibers become more pronounced with increasing strain ratio and achieve saturation level as strain ratio up to ∼35%.
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Affiliation(s)
| | - Wenqiang Du
- Nationwide Children's Hospital , Columbus , Ohio 43205 , United States
- The Ohio State University College of Medicine , Columbus , Ohio 43205 , United States
| | | | | | | | - Jianfeng Chen
- Department of Mechanics Engineering , Nanchang University , Nanchang , Jiangxi 330031 , China
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Vainieri ML, Lolli A, Kops N, D'Atri D, Eglin D, Yayon A, Alini M, Grad S, Sivasubramaniyan K, van Osch GJVM. Evaluation of biomimetic hyaluronic-based hydrogels with enhanced endogenous cell recruitment and cartilage matrix formation. Acta Biomater 2020; 101:293-303. [PMID: 31726249 DOI: 10.1016/j.actbio.2019.11.015] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 01/17/2023]
Abstract
Biomaterials play a pivotal role in cell-free cartilage repair approaches, where cells must migrate through the scaffold, fill the defect, and then proliferate and differentiate facilitating tissue remodeling. Here we used multiple assays to test the influence of chemokines and growth factors on cell migration and cartilage repair in two different hyaluronan (HA)-based hydrogels. We first investigated bone marrow Mesenchymal Stromal Cells (BMSC) migration in vitro, in response to different concentrations of platelet-derived growth factor-BB (PDGF-BB), chemokine ligand 5 (CCL5/RANTES) and stromal cell-derived factor 1 (SDF-1), using a 3D spheroid-based assay. PDGF-BB was selected as most favourable chemotactic agent, and MSC migration was assessed in the context of physical impediment to cell recruitment by testing Fibrin-HA and HA-Tyramine hydrogels of different cross-linking densities. Supplementation of PDGF-BB stimulated progressive migration of MSC through the gels over time. We then investigated in situ cell migration into the hydrogels with and without PDGF-BB, using a cartilage-bone explant model implanted subcutaneously in athymic mice. In vivo studies show that when placed into an osteochondral defect, both hydrogels supported endogenous cell infiltration and provided an amenable microenvironment for cartilage production. These processes were best supported in Fibrin-HA hydrogel in the absence of PDGF-BB. This study used an advanced preclinical testing platform to select an appropriate microenvironment provided by implanted hydrogels, demonstrating that HA-based hydrogels can promote the initial and critical step of endogenous cell recruitment and circumvent some of the clinical challenges in cartilage tissue repair. STATEMENT OF SIGNIFICANCE: The challenge of articular cartilage repair arises from its complex structure and architecture, which confers the unique mechanical behavior of the extracellular matrix. The aim of our research is to identify biomaterials for implants that can support migration of endogenous stem and progenitor cell populations from cartilage and bone tissue, in order to permanently replace damaged cartilage with the original hyaline structure. Here, we present an in vitro 3D spheroid-based migration assay and an osteochondral defect model, which provide the opportunity to assess biomaterials and biomolecules, and to get stronger experimental evidence of the not well-characterized dynamic process of endogenous cells colonization in an osteochondral defect. Furthermore, the delicate step of early cell migration into biomaterials towards functional tissue engineering is reproduced. These tests can be used for pre-clinical testing of newly developed material designs in the field of scaffold engineering.
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Affiliation(s)
- M L Vainieri
- AO Research Institute Davos, Davos Platz, Switzerland; Department of Orthopeadics, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
| | - A Lolli
- Department of Orthopeadics, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
| | - N Kops
- Department of Orthopeadics, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
| | - D D'Atri
- Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel.
| | - D Eglin
- AO Research Institute Davos, Davos Platz, Switzerland.
| | - A Yayon
- ProCore Ltd., Weizmann Science Park, 7 Golda Meir St., Ness Ziona 70400, Israel.
| | - M Alini
- AO Research Institute Davos, Davos Platz, Switzerland.
| | - S Grad
- AO Research Institute Davos, Davos Platz, Switzerland.
| | - K Sivasubramaniyan
- Department of Orthopeadics, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
| | - G J V M van Osch
- Department of Orthopeadics, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands; Department of Otorhinolaryngology, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
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46
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Gonzalez-Fernandez T, Sikorski P, Leach JK. Bio-instructive materials for musculoskeletal regeneration. Acta Biomater 2019; 96:20-34. [PMID: 31302298 PMCID: PMC6717669 DOI: 10.1016/j.actbio.2019.07.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 06/26/2019] [Accepted: 07/09/2019] [Indexed: 02/06/2023]
Abstract
The prevalence and cost of disorders affecting the musculoskeletal system are predicted to rise significantly in the coming years due to the aging global population and the increase of associated risk factors. Despite being the second largest cause of disability, the clinical options for therapeutic intervention remain limited. The clinical translation of cell-based therapies for the treatment of musculoskeletal disorders faces many challenges including maintenance of cell survival in the harsh in vivo environment and the lack of control over regulating cell phenotype upon implantation. In order to address these challenges, the development of bio-instructive materials to modulate cell behavior has taken center stage as a strategy to increase the therapeutic potential of various cell populations. However, the determination of the necessary cues for a specific application and how these signals should be presented from a biomaterial remains elusive. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues. There is a particular emphasis on emerging efforts such as the engineering of immunomodulatory and antibacterial materials, as well as the incorporation of these strategies into biofabrication and organ-on-a-chip approaches. STATEMENT OF SIGNIFICANCE: Disorders affecting the musculoskeletal system affect individuals across the lifespan and have a profound effect on mobility and quality of life. While small defects in many tissues can heal successfully, larger defects are often unable to heal or instead heal with inferior quality fibrous tissue and require clinical intervention. Cell-based therapies are a promising option for clinical translation, yet challenges related to maintaining cell survival and instructing cell phenotype upon implantation have limited the success of this approach. Bio-instructive materials provide an exciting opportunity to modulate cell behavior and enhance the efficacy of cell-based approaches for musculoskeletal repair. However, the identification of critical instructive cues and how to present these stimuli is a focus of intense investigation. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues, while also considering exciting progress in the engineering of immunomodulatory and antibacterial materials.
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Affiliation(s)
| | - Pawel Sikorski
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA; Department of Physics, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - J Kent Leach
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA; Department of Orthopaedic Surgery, School of Medicine, UC Davis Health, Sacramento, CA, USA.
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47
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Svec KV, Patterson JB, Naim N, Howe AK. Single Cell Durotaxis Assay for Assessing Mechanical Control of Cellular Movement and Related Signaling Events. J Vis Exp 2019. [PMID: 31524855 DOI: 10.3791/59995] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Durotaxis is the process by which cells sense and respond to gradients of tension. In order to study this process in vitro, the stiffness of the substrate underlying a cell must be manipulated. While hydrogels with graded stiffness and long-term migration assays have proven useful in durotaxis studies, immediate, acute responses to local changes in substrate tension allow focused study of individual cell movements and subcellular signaling events. To repeatably test the ability of cells to sense and respond to the underlying substrate stiffness, a modified method for application of acute gradients of increased tension to individual cells cultured on deformable hydrogels is used which allows for real time manipulation of the strength and direction of stiffness gradients imparted upon cells in question. Additionally, by fine tuning the details and parameters of the assay, such as the shape and dimensions of the micropipette or the relative position, placement, and direction of the applied gradient, the assay can be optimized for the study of any mechanically sensitive cell type and system. These parameters can be altered to reliably change the applied stimulus and expand the functionality and versatility of the assay. This method allows examination of both long term durotactic movement as well as more immediate changes in cellular signaling and morphological dynamics in response to changing stiffness.
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Affiliation(s)
- Kathryn V Svec
- Department of Pharmacology, University of Vermont Larner College of Medicine; University of Vermont Cancer Center; Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine
| | - Johnathan B Patterson
- Department of Pharmacology, University of Vermont Larner College of Medicine; University of Vermont Cancer Center; Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine
| | - Nyla Naim
- Department of Pharmacology, University of Vermont Larner College of Medicine; University of Vermont Cancer Center; Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine
| | - Alan K Howe
- Department of Pharmacology, University of Vermont Larner College of Medicine; University of Vermont Cancer Center; Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine;
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Moosazadeh Moghaddam M, Bonakdar S, Shokrgozar MA, Zaminy A, Vali H, Faghihi S. Engineered substrates with imprinted cell-like topographies induce direct differentiation of adipose-derived mesenchymal stem cells into Schwann cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1022-1035. [PMID: 30942113 DOI: 10.1080/21691401.2019.1586718] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Differentiation of stem cells to Schwann is considered efficient way for nerve regeneration since the sources of human Schwann cells are limited for clinical application. It is demonstrated that mimicking micromechanical forces or micro/nanotopographical environments that stem cells are experienced in vivo could control their fate. Here, the potency of substrates with imprinted cell-like topographies for direct differentiation of adipose-derived mesenchymal stem cells (ADSCs) into Schwann cells (SCs) is reported. For the preparation of substrates with imprinted SC-Like topographies, SCs are isolated from the sciatic nerve, grown, fixed, and then SC morphologies are transferred to polydimethylsiloxane (PDMS) substrates by mold casting. Subsequently, mesenchymal stem cells (MSCs) are seeded on the SC-imprinted substrates and their differentiation to SCs is evaluated by immunocytochemistry, real-time PCR, and western blotting. Analysis of morphology and expression of SC-specific markers show that MSCs cultured on the imprinted substrates have the typical SC-like morphology and express SC-specific markers including S100b, p75NTR, and Sox10. It is believed that specific cell-like topographies and related micromechanical cues can be sufficient for direct differentiation of ADSCs into Schwann cells by cell-imprinting method as a physical technique.
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Affiliation(s)
- Mehrdad Moosazadeh Moghaddam
- a Stem Cell and Regenerative Medicine Group , National Institute of Genetic Engineering and Biotechnology (NIGEB) , Tehran , Iran
| | - Shahin Bonakdar
- b National Cell Bank , Pasteur Institute of Iran , Tehran , Iran
| | | | - Arash Zaminy
- c Neuroscience Research Center, Faculty of Medicine , Guilan University of Medical Sciences , Rasht , Iran
| | - Hojatollah Vali
- d Department of Anatomy and Cell Biology , McGill University , Montréal , QC , Canada.,e Facility for Electron Microscopy Research , McGill University , Montréal , QC , Canada
| | - Shahab Faghihi
- a Stem Cell and Regenerative Medicine Group , National Institute of Genetic Engineering and Biotechnology (NIGEB) , Tehran , Iran
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Alruwaili M, Lopez JA, McCarthy K, Reynaud EG, Rodriguez BJ. Liquid-phase 3D bioprinting of gelatin alginate hydrogels: influence of printing parameters on hydrogel line width and layer height. Biodes Manuf 2019. [DOI: 10.1007/s42242-019-00043-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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50
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Cucarián JD, Berrío JP, Rodrigues C, Zancan M, Wink MR, de Oliveira A. Physical exercise and human adipose-derived mesenchymal stem cells ameliorate motor disturbances in a male rat model of Parkinson's disease. J Neurosci Res 2019; 97:1095-1109. [PMID: 31119788 DOI: 10.1002/jnr.24442] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 01/20/2023]
Abstract
Parkinson's disease (PD) is a disabling and highly costly neurodegenerative condition with worldwide prevalence. Despite advances in treatments that slow progression and minimize locomotor impairments, its clinical management is still a challenge. Previous preclinical studies, using mesenchymal stem cell (MSC) transplantation and isolated physical exercise (EX), reported beneficial results for treatment of PD. Therefore, this experimental randomized study aimed to elucidate the therapeutic potential of combined therapy using adipose-derived human MSCs (ADSCs) grafted into the striatum in conjunction with aerobic treadmill training, specifically in terms of locomotor performance in a unilateral PD rat model induced by 6-hydroxydopamine (6-OHDA). Forty-one male Wistar rats were categorized into five groups in accordance with the type of treatment to which they were subjected (Sham, 6-OHDA - injury, 6-OHDA + exercise, 6-OHDA + cells, and 6-OHDA + combined). Subsequently, dopaminergic depletion was assessed by the methylphenidate challenge and the specified therapeutic intervention was conducted in each group. The foot fault task was performed at the end of the experiment to serve as an assessment of motor skills. The results showed that despite disturbances in motor balance and coordination, locomotor dysfunction was ameliorated in all treatment categories in comparison to the injury group (sign test, p < 0.001, effect size: 0.71). The exercise alone and combined groups were the categories that exhibited the best recovery in terms of movement performance (p < 0.001). Overall, this study confirms that exercise is a powerful option to improve motor function and a promising adjuvant intervention for stem cell transplantation in the treatment of PD motor symptoms. OPEN PRACTICES: This article has been awarded Open Data. All materials and data are publicly accessible at https://figshare.com/s/18a543c101a17a1d5560. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.
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Affiliation(s)
- Jaison D Cucarián
- Graduate Course in Rehabilitation Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Jenny P Berrío
- Graduate Course in Rehabilitation Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Cristiano Rodrigues
- Cell Biology Research Laboratory, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Mariana Zancan
- Graduate Course in Neuroscience, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Márcia R Wink
- Cell Biology Research Laboratory, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
| | - Alcyr de Oliveira
- Graduate Course in Rehabilitation Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.,Graduate Course in Psychology and Health, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
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