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Kulkarni S, Tebar F, Rentero C, Zhao M, Sáez P. Competing signaling pathways controls electrotaxis. iScience 2025; 28:112329. [PMID: 40292314 PMCID: PMC12032939 DOI: 10.1016/j.isci.2025.112329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/01/2024] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Understanding how cells follow exogenous cues is a key question for biology, medicine, and bioengineering. Growing evidence shows that electric fields represent a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane proteins and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell is still poorly understood. Here, we develop a mechanistic model that explains electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that the simultaneous and asymmetric distribution of these membrane receptors establish multiple cooperative and competing stimuli for directing the anodal and cathodal migration of the cell. Using electric fields, we enhance, cancel, or switch directed cell migration, with clear implications in promoting tissue regeneration or arresting tumor progression.
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Affiliation(s)
- S. Kulkarni
- Laboratori de Càlcul Numèric (LaCàN), ETS de Ingeniería de Caminos, Canales y Puertos, Universitat Politècnica de Catalunya, Barcelona, Spain
| | - F. Tebar
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Cell Compartments and Signaling Group, Fundació de Recerca Clínic Barcelona - Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 08036 Barcelona, Spain
| | - C. Rentero
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Cell Compartments and Signaling Group, Fundació de Recerca Clínic Barcelona - Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 08036 Barcelona, Spain
| | - M. Zhao
- Department of Ophthalmology & Vision Science, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - P. Sáez
- Laboratori de Càlcul Numèric (LaCàN), ETS de Ingeniería de Caminos, Canales y Puertos, Universitat Politècnica de Catalunya, Barcelona, Spain
- IMTech (Institute of Mathematics), Universitat Politècnica de Catalunya-BarcelonaTech., 08034 Barcelona, Spain
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2
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Shi K, Peng X, Xu T, Lin Z, Sun M, Li Y, Xian Q, Xiao T, Chen S, Xie Y, Zhang R, Zeng J, Xu B. Precise Electromagnetic Modulation of the Cell Cycle and Its Applications in Cancer Therapy. Int J Mol Sci 2025; 26:4445. [PMID: 40362682 PMCID: PMC12072891 DOI: 10.3390/ijms26094445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/17/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Precise modulation of the cell cycle via electromagnetic (EM) control presents a groundbreaking approach for cancer therapy, especially in the development of personalized treatment strategies. EM fields can precisely regulate key cellular homeostatic mechanisms such as proliferation, apoptosis, and repair by finely tuning parameters like frequency, intensity, and duration. This review summarizes the mechanisms through which EM fields influence cancer cell dynamics, highlighting recent developments in high-throughput electromagnetic modulation platforms that facilitate precise cell cycle regulation. Additionally, the integration of electromagnetic modulation with emerging technologies such as artificial intelligence, immunotherapy, and nanotechnology is explored, collectively enhancing targeting precision, immune activation, and therapeutic efficacy. A systematic analysis of existing clinical studies indicates that EM modulation technology significantly overcomes key challenges such as tumor heterogeneity, microenvironment complexity, and treatment-related adverse effects. This review summarizes the prospects of electromagnetic modulation in clinical translation and future research directions, emphasizing its critical potential as a core element in individualized and multimodal cancer treatment strategies.
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Affiliation(s)
- Keni Shi
- School of Biomedical Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China; (K.S.)
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Xiqing Peng
- School of Biomedical Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China; (K.S.)
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Ting Xu
- School of Biomedical Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China; (K.S.)
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Ziqi Lin
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Mingyu Sun
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Yiran Li
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Qingyi Xian
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Tingting Xiao
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Siyuan Chen
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Ying Xie
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Ruihan Zhang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Medical University, Dongguan 523808, China
- Xinghai Institute of Cell, Dongguan 523808, China
| | - Bingzhe Xu
- School of Biomedical Engineering, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, China; (K.S.)
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Shenzhen 518107, China
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3
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Sun Q, Li CH, Liu QS, Zhang YB, Hu BS, Feng Q, Lang Y. Research status of biomaterials based on physical signals for bone injury repair. Regen Ther 2025; 28:544-557. [PMID: 40027992 PMCID: PMC11872413 DOI: 10.1016/j.reth.2025.01.025] [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: 10/08/2024] [Revised: 01/02/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Bone defects repair continues to be a significant challenge facing the world. Biological scaffolds, bioactive molecules, and cells are the three major elements of bone tissue engineering, which have been widely used in bone regeneration therapy, especially with the rise of bioactive molecules in recent years. According to their physical properties, they can be divided into force, magnetic field (MF), electric field (EF), ultrasonic wave, light, heat, etc. However, the transmission of bioactive molecules has obvious shortcomings that hinder the development of the tissue-rearing process. This paper reviews the mechanism of physical signal induction in bone tissue engineering in recent years. It summarizes the application strategies of physical signal in bone tissue engineering, including biomaterial designs, physical signal loading strategies and related pathways. Finally, the ongoing challenges and prospects for the future are discussed.
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Affiliation(s)
- Qi Sun
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
| | - Chao-Hua Li
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
| | - Qi-Shun Liu
- Department of Orthopedics, Zhejiang Medical & Health Group Hangzhou Hospital, Hangzhou, 310015, China
| | - Yuan-Bin Zhang
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
| | - Bai-Song Hu
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
| | - Qi Feng
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
| | - Yong Lang
- Department of Orthopedics, Hangzhou Fuyang Hospital of Orthopedics of Traditional Chinese Medicine, Hangzhou, 311499, China
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Artamonov MY, Pyatakovich FA, Minenko IA. Influence of Super-Low-Intensity Microwave Radiation on Mesenchymal Stem Cells. Int J Mol Sci 2025; 26:1705. [PMID: 40004170 PMCID: PMC11855362 DOI: 10.3390/ijms26041705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/11/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising tool for regenerative medicine due to their multipotency and immunomodulatory properties. According to recent research, exposing MSCs to super-low-intensity microwave radiation can have a significant impact on how they behave and operate. This review provides an overview of the most recent studies on the effects of microwave radiation on MSCs with power densities that are much below thermal values. Studies repeatedly show that non-thermal mechanisms affecting calcium signaling, membrane transport, mitochondrial activity, along ion channel activation may increase MSC proliferation, differentiation along mesodermal lineages, paracrine factor secretion, and immunomodulatory capabilities during brief, regulated microwave exposures. These bioeffects greatly enhance MSC regeneration capability in preclinical models of myocardial infarction, osteoarthritis, brain damage, and other diseases. Additional study to understand microwave treatment settings, biological processes, and safety assessments will aid in the translation of this unique, non-invasive strategy of activating MSCs with microwave radiation to improve cell engraftment, survival, and tissue healing results. Microwave-enhanced MSC treatment, if shown safe and successful, might have broad relevance as a novel cell-based approach for a variety of regenerative medicine applications.
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Affiliation(s)
| | - Felix A. Pyatakovich
- Department of Internal Medicine, Belgorod State University, Belgorod 308015, Russia;
| | - Inessa A. Minenko
- Department of Rehabilitation, Sechenov Medical University, Moscow 119991, Russia;
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Wang S, Yu L, Guo H, Zuo W, Guo Y, Liu H, Wang J, Wang J, Li X, Hou W, Wang M. Gastrodin Ameliorates Post-Stroke Depressive-Like Behaviors Through Cannabinoid-1 Receptor-Dependent PKA/RhoA Signaling Pathway. Mol Neurobiol 2025; 62:366-385. [PMID: 38856794 DOI: 10.1007/s12035-024-04267-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 05/26/2024] [Indexed: 06/11/2024]
Abstract
Post-stroke depression (PSD) is a significant complication in stroke patients, increases long-term mortality, and exaggerates ischemia-induced brain injury. However, the underlying molecular mechanisms and effective therapeutic targets related to PSD have remained elusive. Here, we employed an animal behavioral model of PSD by combining the use of middle cerebral artery occlusion (MCAO) followed by spatial restraint stress to study the molecular underpinnings and potential therapies of PSD. Interestingly, we found that sub-chronic application of gastrodin (Gas), a traditional Chinese medicinal herb Gastrodia elata extraction, relieved depression-related behavioral deficits, increased the impaired expression of synaptic transmission-associated proteins, and restored the altered spine density in hippocampal CA1 of PSD animals. Furthermore, our results indicated that the anti-PSD effect of Gas was dependent on membrane cannabinoid-1 receptor (CB1R) expression. The contents of phosphorated protein kinase A (p-PKA) and phosphorated Ras homolog gene family member A (p(ser188)-RhoA) were decreased in the hippocampus of PSD-mice, which was reversed by Gas treatment, and CB1R depletion caused a diminished efficacy of Gas on p-PKA and p-RhoA expression. In addition, the anti-PSD effect of Gas was partially blocked by PKA inhibition or RhoA activation, indicating that the anti-PSD effect of Gas is associated with the CB1R-mediated PKA/RhoA signaling pathway. Together, our findings revealed that Gas treatment possesses protective effects against the post-stroke depressive-like state; the CB1R-involved PKA/RhoA signaling pathway is critical in mediating Gas's anti-PSD potency, suggesting that Gas application may be beneficial in the prevention and adjunctive treatment of PSD.
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Affiliation(s)
- Shiquan Wang
- College of Life Sciences, Northwest University, Xi'an, 710127, Shaanxi, China
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Liang Yu
- Department of Information, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Haiyun Guo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wenqiang Zuo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yaru Guo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Huiqing Liu
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jiajia Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jin Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xia Li
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Wugang Hou
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Minghui Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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6
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Ryu Y, Wague A, Liu X, Feeley BT, Ferguson AR, Morioka K. Cellular signaling pathways in the nervous system activated by various mechanical and electromagnetic stimuli. Front Mol Neurosci 2024; 17:1427070. [PMID: 39430293 PMCID: PMC11486767 DOI: 10.3389/fnmol.2024.1427070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/25/2024] [Indexed: 10/22/2024] Open
Abstract
Mechanical stimuli, such as stretch, shear stress, or compression, activate a range of biomolecular responses through cellular mechanotransduction. In the nervous system, studies on mechanical stress have highlighted key pathophysiological mechanisms underlying traumatic injury and neurodegenerative diseases. However, the biomolecular pathways triggered by mechanical stimuli in the nervous system has not been fully explored, especially compared to other body systems. This gap in knowledge may be due to the wide variety of methods and definitions used in research. Additionally, as mechanical stimulation techniques such as ultrasound and electromagnetic stimulation are increasingly utilized in psychological and neurorehabilitation treatments, it is vital to understand the underlying biological mechanisms in order to develop accurate pathophysiological models and enhance therapeutic interventions. This review aims to summarize the cellular signaling pathways activated by various mechanical and electromagnetic stimuli with a particular focus on the mammalian nervous system. Furthermore, we briefly discuss potential cellular mechanosensors involved in these processes.
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Affiliation(s)
- Youngjae Ryu
- Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Aboubacar Wague
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Xuhui Liu
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Brian T. Feeley
- Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Adam R. Ferguson
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
- Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, United States
- San Francisco Veterans Affairs Healthcare System, San Francisco, CA, United States
| | - Kazuhito Morioka
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, United States
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
- Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, United States
- Zuckerberg San Francisco General Hospital and Trauma CenterOrthopaedic Trauma Institute, , San Francisco, CA, United States
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Chen J, Su Y, Wu J, Zhang C, Liu N, Zhang Y, Lin K, Zhang S. A coaxial electrospun mat coupled with piezoelectric stimulation and atorvastatin for rapid vascularized bone regeneration. J Mater Chem B 2024; 12:9656-9674. [PMID: 39175374 DOI: 10.1039/d4tb00173g] [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: 08/24/2024]
Abstract
The repair of critical bone defects caused by various clinical conditions needs to be addressed urgently, and the regeneration of large bone defects depends on early vascularization. Therefore, enhanced vascularization of artificial bone grafts may be a promising strategy for the regeneration of critical-sized bone defects. Taking into account the importance of rapid angiogenesis during bone repair and the potential of piezoelectric stimulation in promoting bone regeneration, novel coaxial electrospun mats coupled with piezoelectric materials and angiogenic drugs were fabricated in this study using coaxial electrospinning technology, with a shell layer loaded with atorvastatin (AVT) and a core layer loaded with zinc oxide (ZnO). AVT was used as an angiogenesis inducer, and piezoelectric stimulation generated by the zinc oxide was used as an osteogenesis enhancer. The multifunctional mats were characterized in terms of morphology, core-shell structure, piezoelectric properties, drug release, and mechanical properties, and their osteogenic and angiogenic capabilities were validated in vivo and ex vivo. The results revealed that the coaxial electrospun mats exhibit a porous surface morphology and nanofibers with a core-shell structure, and the piezoelectricity of the mats improved with increasing ZnO content. Excellent biocompatibility, hydrophilicity and cell adhesion were observed in the multifunctional mats. Early and rapid release of AVT in the fibrous shell layer of the mat promoted angiogenesis in human umbilical vascular endothelial cells (HUVECs), whereas ZnO in the fibrous core layer harvested bioenergy and converted it into electrical energy to enhance osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs), and both modalities synergistically promoted osteogenesis and angiogenesis. Furthermore, optimal bone regeneration was achieved in a model of critical bone defects in the rat mandible. This osteogenesis-promoting effect was induced by electrical stimulation via activation of the calcium signaling pathway. This multifunctional mat coupling piezoelectric stimulation and atorvastatin promotes angiogenesis and bone regeneration, and shows great potential in the treatment of large bone defects.
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Affiliation(s)
- Jiangping Chen
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Yang Su
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Jinyang Wu
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Chuxi Zhang
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Nian Liu
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Yong Zhang
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Kaili Lin
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
| | - Shilei Zhang
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
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Fang X, Liu C, Wei K, Shu Z, Zou Y, Zhang Z, Ding Q, Jing S, Li W, Wang T, Li H, Wu H, Liu C, Ma T. Low frequency sinusoidal electromagnetic fields promote the osteogenic differentiation of rat bone marrow mesenchymal stem cells by modulating miR-34b-5p/STAC2. Commun Biol 2024; 7:1156. [PMID: 39284881 PMCID: PMC11405519 DOI: 10.1038/s42003-024-06866-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 09/09/2024] [Indexed: 09/20/2024] Open
Abstract
Electromagnetic fields (EMFs) have emerged as an effective treatment for osteoporosis. However, the specific mechanism underlying their therapeutic efficacy remains controversial. Herein, we confirm the pro-osteogenic effects of 15 Hz and 0.4-1 mT low-frequency sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs). Subsequent miRNA sequencing reveal that miR-34b-5p is downregulated in both the 0.4 mT and 1 mT SEMFs-stimulated groups. To clarify the role of miR-34b-5p in osteogenesis, BMSCs are transfected separately with miR-34b-5p mimic and inhibitor. The results indicate that miR-34b-5p mimic transfection suppress osteogenic differentiation, whereas inhibition of miR-34b-5p promote osteogenic differentiation of BMSCs. In vivo assessments using microcomputed tomography, H&E staining, and Masson staining show that miR-34b-5p inhibitor injections alleviate bone mass loss and trabecular microstructure deterioration in ovariectomy (OVX) rats. Further validation demonstrates that miR-34b-5p exerts its effects by regulating STAC2 expression. Modulating the miR-34b-5p/STAC2 axis attenuate the pro-osteogenic effects of low-frequency SEMFs on BMSCs. These studies indicate that the pro-osteogenic effect of SEMFs is partly due to the regulation of the miR-34b-5p/STAC2 pathway, which provides a potential therapeutic candidate for osteoporosis.
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Affiliation(s)
- Xuan Fang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changyu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kang Wei
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixing Shu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihao Zhang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Ding
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoze Jing
- Department of Orthopedics, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, China
| | - Weigang Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianqi Wang
- Departments of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hao Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoxu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Tian Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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9
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Jiang Z, Chen L, Huang L, Yu S, Lin J, Li M, Gao Y, Yang L. Bioactive Materials That Promote the Homing of Endogenous Mesenchymal Stem Cells to Improve Wound Healing. Int J Nanomedicine 2024; 19:7751-7773. [PMID: 39099796 PMCID: PMC11297574 DOI: 10.2147/ijn.s455469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/23/2024] [Indexed: 08/06/2024] Open
Abstract
Endogenous stem cell homing refers to the transport of endogenous mesenchymal stem cells (MSCs) to damaged tissue. The paradigm of using well-designed biomaterials to induce resident stem cells to home in to the injured site while coordinating their behavior and function to promote tissue regeneration is known as endogenous regenerative medicine (ERM). ERM is a promising new avenue in regenerative therapy research, and it involves the mobilizing of endogenous stem cells for homing as the principal means through which to achieve it. Comprehending how mesenchymal stem cells home in and grasp the influencing factors of mesenchymal stem cell homing is essential for the understanding and design of tissue engineering. This review summarizes the process of MSC homing, the factors influencing the homing process, analyses endogenous stem cell homing studies of interest in the field of skin tissue repair, explores the integration of endogenous homing promotion strategies with cellular therapies and details tissue engineering strategies that can be used to modulate endogenous homing of stem cells. In addition to providing more systematic theories and ideas for improved materials for endogenous tissue repair, this review provides new perspectives to explore the complex process of tissue remodeling to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.
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Affiliation(s)
- Ziwei Jiang
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Lianglong Chen
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Lei Huang
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shengxiang Yu
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jiabao Lin
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Mengyao Li
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yanbin Gao
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Lei Yang
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
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10
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Jeung SY, An JH, Kim SS, Youn HY. Safety of Gonadal Tissue-Derived Mesenchymal Stem Cell Therapy in Geriatric Dogs with Chronic Disease. Animals (Basel) 2024; 14:2134. [PMID: 39061596 PMCID: PMC11273526 DOI: 10.3390/ani14142134] [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: 05/12/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Ensuring the safety of mesenchymal stem cell (MSC) therapy is a fundamental requirement in clinical practice. This study aimed to assess the safety of using gonadal tissue-derived MSCs (n = 10) compared to the commonly utilized adipose tissue-derived MSCs (n = 9) in geriatric dogs with chronic diseases. All participants received allogeneic MSC therapy, and no allergic reactions due to allogeneic cell immunogenicity were noted. Both groups showed no adverse changes in physical exams or hematological parameters before and after therapy. Importantly, there were no instances of tumor formation or growth post-treatment in either group. The findings demonstrated that dogs treated with gonadal tissue-derived MSCs experienced no clinical adverse effects. However, clinical adverse effects were reported in one case of adipose tissue-derived MSC therapy. Despite limitations in monitoring beyond one year and constraints due to a small and diverse patient group, this pioneering study validates the safe use of gonadal tissue-derived MSCs in aged companion animals. It underscores the potential of utilizing tissues from neutering procedures to advance regenerative medicine and expand cell banks and therapy options for companion animals.
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Affiliation(s)
- So-Young Jeung
- VIP Animal Medical Center, Seoul 02830, Republic of Korea; (S.-Y.J.); (S.-S.K.)
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Ju-Hyun An
- Laboratory of Veterinary Emergency and Critical Care, Department of Veterinary Clinical Science, College of Veterinary Medicine, Kangwon National University, Chuncheon-si 24341, Republic of Korea;
| | - Sung-Soo Kim
- VIP Animal Medical Center, Seoul 02830, Republic of Korea; (S.-Y.J.); (S.-S.K.)
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Hwa-Young Youn
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
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11
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Luo S, Zhang C, Xiong W, Song Y, Wang Q, Zhang H, Guo S, Yang S, Liu H. Advances in electroactive biomaterials: Through the lens of electrical stimulation promoting bone regeneration strategy. J Orthop Translat 2024; 47:191-206. [PMID: 39040489 PMCID: PMC11261049 DOI: 10.1016/j.jot.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/16/2024] [Accepted: 06/07/2024] [Indexed: 07/24/2024] Open
Abstract
The regenerative capacity of bone is indispensable for growth, given that accidental injury is almost inevitable. Bone regenerative capacity is relevant for the aging population globally and for the repair of large bone defects after osteotomy (e.g., following removal of malignant bone tumours). Among the many therapeutic modalities proposed to bone regeneration, electrical stimulation has attracted significant attention owing to its economic convenience and exceptional curative effects, and various electroactive biomaterials have emerged. This review summarizes the current knowledge and progress regarding electrical stimulation strategies for improving bone repair. Such strategies range from traditional methods of delivering electrical stimulation via electroconductive materials using external power sources to self-powered biomaterials, such as piezoelectric materials and nanogenerators. Electrical stimulation and osteogenesis are related via bone piezoelectricity. This review examines cell behaviour and the potential mechanisms of electrostimulation via electroactive biomaterials in bone healing, aiming to provide new insights regarding the mechanisms of bone regeneration using electroactive biomaterials. The translational potential of this article This review examines the roles of electroactive biomaterials in rehabilitating the electrical microenvironment to facilitate bone regeneration, addressing current progress in electrical biomaterials and the mechanisms whereby electrical cues mediate bone regeneration. Interactions between osteogenesis-related cells and electroactive biomaterials are summarized, leading to proposals regarding the use of electrical stimulation-based therapies to accelerate bone healing.
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Affiliation(s)
- Songyang Luo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, 110001, China
| | - Chengshuo Zhang
- Hepatobiliary Surgery Department, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Wei Xiong
- Department of Plastic Surgery, The First Hospital of Shihezi Medical University, Shihezi, 832000, China
| | - Yiping Song
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Qiang Wang
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, 110001, China
| | - Hangzhou Zhang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang Sports Medicine Clinical Medical Research Center, Shenyang, 110001, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shude Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, 110001, China
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, 110001, China
| | - Huanye Liu
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, 110001, China
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12
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Rajalekshmi R, Agrawal DK. Energizing Healing with Electromagnetic Field Therapy in Musculoskeletal Disorders. JOURNAL OF ORTHOPAEDICS AND SPORTS MEDICINE 2024; 6:89-106. [PMID: 39036742 PMCID: PMC11258965 DOI: 10.26502/josm.511500147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
There is mounting evidence to suggest that exogenous electromagnetic fields (EMF) may play a significant role in various biological processes that are crucial to therapeutic interventions. EMFs have been identified as a non-invasive, safe, and effective therapy that appears to have no apparent side effects. Numerous studies have demonstrated that pulsed EMFs (PEMFs) have the potential to become a stand-alone or adjunctive treatment modality for managing musculoskeletal disorders. However, several questions remain unresolved. Before their widespread clinical application, further research from well-designed, high-quality studies is required to standardize treatment parameters and determine the optimal protocol for healthcare decision-making. This article provides a comprehensive overview of the impact of musculoskeletal diseases on overall well-being, the limitations of conventional treatments, and the need to explore alternative therapeutic modalities such as electromagnetic field (EMF) therapy. EMF therapy uses low-frequency electromagnetic waves to stimulate tissue repair, reduce inflammation, and modulate pain signals, making it a safe and convenient alternative to conventional treatments. The article also discusses the historical perspective of EMF therapy in medicine. The article highlights the potential of EMF therapy as a personalized and comprehensive care option for musculoskeletal diseases, either alone or in conjunction with other therapies. It emphasizes the imperative for further research in this field and presents a compelling case for the use of EMF therapy in managing musculoskeletal diseases. Overall, the available findings on the underlying cellular and molecular biology support the use of EMF therapy as a viable option for the management of musculoskeletal disorders and stresses the need for continued research in this area.
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Affiliation(s)
- Resmi Rajalekshmi
- Department of Translational Research, College of the Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California USA
| | - Devendra K Agrawal
- Department of Translational Research, College of the Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California USA
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13
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Sendera A, Adamczyk-Grochala J, Pikuła B, Cholewa M, Banaś-Ząbczyk A. Electromagnetic field (50 Hz) enhance metabolic potential and induce adaptive/reprogramming response mediated by the increase of N6-methyladenosine RNA methylation in adipose-derived mesenchymal stem cells in vitro. Toxicol In Vitro 2024; 95:105743. [PMID: 38040129 DOI: 10.1016/j.tiv.2023.105743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 11/08/2023] [Accepted: 11/24/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND Electromagnetic fields (EMF) have an impact on numerous cellular processes. It can positively and negatively affect adipose-derived stem cells (ASCs) thus their fate through the influence of specific factors and protein secretion. EMF can be a great factor for preconditioning ASCs for regenerative medicine purposes, however, understanding the cell's biological response to its effects in vitro is essential. METHODS ASCs were exposed to the EMF (50 Hz; 1.5 mT) for 24 and 48 h, and then cell biological response was analyzed. RESULTS 24 h exposure of ASCs to EMF, significantly increased N6-methyladenosine (m6A) RNA methylation, indicating epitranscriptomic changes as an important factor in ASCs preconditioning. Furthermore, the expression of stem cell markers such as Nanog, Oct-4, Sox-2, CD44, and CD105 increased after 24 h of EMF exposure. Besides, western blot analysis showed upregulation of p21 and DNMT2/TRDMT1 protein levels compared to control cells with no differences in the p53 profile. Moreover, after 24 h of exposure to EMF, cell membrane flexibility, the metabolic potential of cells as well as the distribution, morphology, and metabolism of mitochondria were altered. CONCLUSION ASCs undergo a process of mobilization and adaptation under the EMF influence through the increased m6A RNA modifications. These conditions may "force" ASCs to redefine their stem cell fate mediated by RNA-modifying enzymes and alter their reprogramming decision of as differentiation begins.
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Affiliation(s)
- Anna Sendera
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Jagoda Adamczyk-Grochala
- Department of Biotechnology, Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Barbara Pikuła
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Marian Cholewa
- Institute of Physics, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Agnieszka Banaś-Ząbczyk
- Department of Biology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland.
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14
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Vecheck AM, McNamee CM, Reijo Pera R, Usselman RJ. Magnetic Field Intervention Enhances Cellular Migration Rates in Biological Scaffolds. Bioengineering (Basel) 2023; 11:9. [PMID: 38247887 PMCID: PMC10813414 DOI: 10.3390/bioengineering11010009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/15/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
The impact of magnetic fields on cellular function is diverse but can be described at least in part by the radical pair mechanism (RPM), where magnetic field intervention alters reactive oxygen species (ROS) populations and downstream cellular signaling. Here, cellular migration within three-dimensional scaffolds was monitored in an applied oscillating 1.4 MHz radiofrequency (RF) magnetic field with an amplitude of 10 µT and a static 50 µT magnetic field. Given that cellular bioenergetics can be altered based on applied RF magnetic fields, this study focused on a magnetic field configuration that increased cellular respiration. Results suggest that RF accelerated cell clustering and elongation after 1 day, with increased levels of clustering and cellular linkage after 7 days. Cell distribution analysis within the scaffolds revealed that the clustering rate during the first day was increased nearly five times in the RF environment. Electron microscopy provided additional topological information and verified the development of fibrous networks, with a cell-derived matrix (CDM) visualized after 7 days in samples maintained in RF. This work demonstrates time-dependent cellular migration that may be influenced by quantum biology (QB) processes and downstream oxidative signaling, enhancing cellular migration behavior.
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Affiliation(s)
- Amy M. Vecheck
- Department of Biomedical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32901, USA
| | - Cameron M. McNamee
- Department of Mathematics, California Institute of Technology, Pasadena, CA 91125, USA
- McLaughlin Research Institute, Great Falls, MT 59405, USA
| | | | - Robert J. Usselman
- Department of Chemistry and Chemical Engineering, Florida Institute of Technology, Melbourne, FL 32901, USA
- Computational Research At Florida Tech (CRAFT), Florida Institute of Technology, Melbourne, FL 32901, USA
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15
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Huang Y, Liao J, Vlashi R, Chen G. Focal adhesion kinase (FAK): its structure, characteristics, and signaling in skeletal system. Cell Signal 2023; 111:110852. [PMID: 37586468 DOI: 10.1016/j.cellsig.2023.110852] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/29/2023] [Accepted: 08/13/2023] [Indexed: 08/18/2023]
Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and distributes important regulatory functions in skeletal system. Mesenchymal stem cell (MSC) possesses significant migration and differentiation capacity, is an important source of distinctive bone cells production and a prominent bone development pathway. MSC has a wide range of applications in tissue bioengineering and regenerative medicine, and is frequently employed for hematopoietic support, immunological regulation, and defect repair, although current research is insufficient. FAK has been identified to cross-link with many other keys signaling pathways in bone biology and is considered as a fundamental "crossroad" on the signal transduction pathway and a "node" in the signal network to mediate MSC lineage development in skeletal system. In this review, we summarized the structure, characteristics, cellular signaling, and the interactions of FAK with other signaling pathways in the skeletal system. The discovery of FAK and its mediated molecules will lead to a new knowledge of bone development and bone construction as well as considerable potential for therapeutic use in the treatment of bone-related disorders such as osteoporosis, osteoarthritis, and osteosarcoma.
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Affiliation(s)
- Yuping Huang
- College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Junguang Liao
- College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Rexhina Vlashi
- College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Guiqian Chen
- College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
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16
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Li D, Li X, Wang J, Li H, Shen H, Xu X, Chen G. Cleavage of semaphorin 4 C interferes with the neuroprotective effect of the semaphorin 4 C/Plexin B2 pathway on experimental intracerebral hemorrhage in rats. J Chem Neuroanat 2023; 132:102318. [PMID: 37482144 DOI: 10.1016/j.jchemneu.2023.102318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/13/2023] [Accepted: 07/20/2023] [Indexed: 07/25/2023]
Abstract
Semaphorin 4 C (SEMA4C) and its cognate receptor Plexin B2 are important regulators of axon guidance and are involved in many neurological diseases, in which SEMA4C acts not only as a ligand ("forward" mode) but also as a signaling receptor ("reverse" mode). However, the role of SEMA4C/Plexin B2 in intracerebral hemorrhage (ICH) remains unclear. In this study, ICH in adult male Sprague-Dawley rats was induced by autologous blood injection in the right basal ganglia. In vitro, cultured primary neurons were subjected to OxyHb to imitate ICH injury. Recombinant SEMA4C (rSEMA4C) and overexpressing lentiviruses encoding full-length SEMA4C or secretory SEMA4C (sSEMA4C) were administered to rats by intraventricular injection. First, we found that elevated levels of sSEMA4C in the cerebrospinal fluid (CSF) of clinical patients were associated with poor prognosis. Both SEMA4C and sSEMA4C were increased in brain tissue around the hematoma after ICH in rats. Overexpression of SEMA4C attenuated neuronal apoptosis, neurosis, and neurologic impairment after ICH. However, treatment with rSEMA4C or sSEMA4C overexpression exacerbated neuronal injury. In addition, when treated with SEMA4C overexpression, the forward mode downstream protein RhoA and the reverse mode downstream ID1/3 transcriptional factors of SEMA4C/Plexin B2 signaling were all activated. Nevertheless, when exposed to rSEMA4C or sSEMA4C overexpression, only the forward mode was activated. Thus, sSEMA4C may be a novel molecular biomarker to predict the prognosis of patients with ICH, and the prevention of SEMA4C cleavage is expected to be a promising therapeutic target.
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Affiliation(s)
- Dong Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China
| | - Jiahe Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China
| | - Xiang Xu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China.
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17
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Qin L, Sun K, Shi L, Xu Y, Zhang R. High-Fat Mouse Model to Explore the Relationship between Abnormal Lipid Metabolism and Enolase in Pancreatic Cancer. Mediators Inflamm 2023; 2023:4965223. [PMID: 37731842 PMCID: PMC10509005 DOI: 10.1155/2023/4965223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/27/2022] [Accepted: 03/21/2023] [Indexed: 09/22/2023] Open
Abstract
Malignant tumors have become a major social health problem that seriously threatens human health, among which pancreatic cancer has a high degree of malignancy, difficult diagnosis and treatment, short survival time, and high mortality. More and more attention has been paid to abnormal lipid metabolism as a momentous carcinogenesis mechanism. Here, we explored the relationship between abnormal lipid metabolism, enolase, and pancreatic cancer by clinical data analysis. A high-fat mouse model was constructed, and then, a subcutaneous tumorigenesis mouse model of carcinoma of pancreatic cells and a metastatic neoplasm mouse pattern of pancreatic carcinoma cells injected through the tail vein were constructed to explore whether abnormal lipid metabolism affects the progression of pancreatic cancer in mice. We constructed a high-lipid model of pancreatic carcinoma cell lines and knockdown and overexpressed enolase in pancreatic carcinoma cell lines and investigated whether high lipid regulates epithelial-mesenchymal transition (EMT) by upregulating enolase (ENO), thereby promoting the cells of pancreatic carcinoma to invade and migrate. Triglycerides, total cholesterol, free cholesterin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and neuron-specific enolase (NSE) from pancreatic cancer patients and nonpancreatic cancer patients were tested. The differences in blood lipids between patients with and without pancreatic carcinoma were compared, and the correlation between blood lipids and neuron-specific enolase was analyzed. We confirmed that the serum triglyceride level of pancreatic cancer patients at initial diagnosis is overtopping nonpancreatic cancer patients, and the neuron-specific enolase level of patients with pancreatic carcinoma is better than nonpancreatic carcinoma sufferers. Triglyceride level is positively correlated with neuron-specific enolase level, and serum triglyceride level has predictive value for pancreatic cancer. Hyperlipidemia can promote tumor growth and increase the expression levels of ENO1, ENO2, and ENO3 in subcutaneous tumor formation of pancreatic cancer in mice. Additional hyperlipidemia promoted pancreatic carcinoma metastasis in the lung in mice injected through the tail vein, which confirmed that hyperlipidemia accelerated the process of EMT by increasing the expression of ENO1, ENO2, and ENO3, therefore promoting the pancreatic cancer cell metastasis.
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Affiliation(s)
- Lin Qin
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650000, China
- School of Pharmaceutical Science, Kunming Medical University, Kunming, Yunnan 650500, China
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China
- Yunnan Province Clinical Research Center for Metabolic diseases, Kunming, Yunnan 650000, China
- Yunnan Clinical Medical Center for Endocrine and Metabolic Diseases, Kunming, Yunnan 650000, China
| | - Kai Sun
- Affiliated Hospital of Yunnan University, Qingnian Road, Kunming, Yunnan 650000, China
| | - Li Shi
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650000, China
- Yunnan Province Clinical Research Center for Metabolic diseases, Kunming, Yunnan 650000, China
- Yunnan Clinical Medical Center for Endocrine and Metabolic Diseases, Kunming, Yunnan 650000, China
| | - Yushan Xu
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650000, China
- Yunnan Province Clinical Research Center for Metabolic diseases, Kunming, Yunnan 650000, China
- Yunnan Clinical Medical Center for Endocrine and Metabolic Diseases, Kunming, Yunnan 650000, China
| | - Rongping Zhang
- School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China
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Ambattu LA, Yeo LY. Sonomechanobiology: Vibrational stimulation of cells and its therapeutic implications. BIOPHYSICS REVIEWS 2023; 4:021301. [PMID: 38504927 PMCID: PMC10903386 DOI: 10.1063/5.0127122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/27/2023] [Indexed: 03/21/2024]
Abstract
All cells possess an innate ability to respond to a range of mechanical stimuli through their complex internal machinery. This comprises various mechanosensory elements that detect these mechanical cues and diverse cytoskeletal structures that transmit the force to different parts of the cell, where they are transcribed into complex transcriptomic and signaling events that determine their response and fate. In contrast to static (or steady) mechanostimuli primarily involving constant-force loading such as compression, tension, and shear (or forces applied at very low oscillatory frequencies (≤ 1 Hz) that essentially render their effects quasi-static), dynamic mechanostimuli comprising more complex vibrational forms (e.g., time-dependent, i.e., periodic, forcing) at higher frequencies are less well understood in comparison. We review the mechanotransductive processes associated with such acoustic forcing, typically at ultrasonic frequencies (> 20 kHz), and discuss the various applications that arise from the cellular responses that are generated, particularly for regenerative therapeutics, such as exosome biogenesis, stem cell differentiation, and endothelial barrier modulation. Finally, we offer perspectives on the possible existence of a universal mechanism that is common across all forms of acoustically driven mechanostimuli that underscores the central role of the cell membrane as the key effector, and calcium as the dominant second messenger, in the mechanotransduction process.
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Affiliation(s)
- Lizebona August Ambattu
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne VIC 3000, Australia
| | - Leslie Y. Yeo
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne VIC 3000, Australia
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19
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Ma T, Ding Q, Liu C, Wu H. Electromagnetic fields regulate calcium-mediated cell fate of stem cells: osteogenesis, chondrogenesis and apoptosis. Stem Cell Res Ther 2023; 14:133. [PMID: 37194107 DOI: 10.1186/s13287-023-03303-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/28/2023] [Indexed: 05/18/2023] Open
Abstract
Electromagnetic fields (EMF) are increasing in popularity as a safe and non-invasive therapy. On the one hand, it is widely acknowledged that EMF can regulate the proliferation and differentiation of stem cells, promoting the undifferentiated cells capable of osteogenesis, angiogenesis, and chondroblast differentiation to achieve bone repair purpose. On the other hand, EMF can inhibit tumor stem cells proliferation and promote apoptosis to suppress tumor growth. As an essential second messenger, intracellular calcium plays a role in regulating cell cycle, such as proliferation, differentiation and apoptosis. There is increasing evidence that the modulation of intracellular calcium ion by EMF leads to differential outcomes in different stem cells. This review summarizes the regulation of channels, transporters, and ion pumps by EMF-induced calcium oscillations. It furtherly discusses the role of molecules and pathways activated by EMF-dependent calcium oscillations in promoting bone and cartilage repair and inhibiting tumor stem cells growth.
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Affiliation(s)
- Tian Ma
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Qing Ding
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Chaoxu Liu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Hua Wu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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20
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Lazzarini R, Eléxpuru-Zabaleta M, Piva F, Giulietti M, Fulgenzi G, Tartaglione MF, Zingaretti L, Tagliabracci A, Valentino M, Santarelli L, Bracci M. Effects of extremely low-frequency magnetic fields on human MDA-MB-231 breast cancer cells: proteomic characterization. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 253:114650. [PMID: 36805133 DOI: 10.1016/j.ecoenv.2023.114650] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/29/2023] [Accepted: 02/11/2023] [Indexed: 06/18/2023]
Abstract
Extremely low-frequency electromagnetic fields (ELF-MF) can modify the cell viability and regulatory processes of some cell types, including breast cancer cells. Breast cancer is a multifactorial disease where a role for ELF-MF cannot be excluded. ELF-MF may influence the biological properties of breast cells through molecular mechanisms and signaling pathways that are still unclear. This study analyzed the changes in the cell viability, cellular morphology, oxidative stress response and alteration of proteomic profile in breast cancer cells (MDA-MB-231) exposed to ELF-MF (50 Hz, 1 mT for 4 h). Non-tumorigenic human breast cells (MCF-10A) were used as control cells. Exposed MDA-MB-231 breast cancer cells increased their viability and live cell number and showed a higher density and length of filopodia compared with the unexposed cells. In addition, ELF-MF induced an increase of the mitochondrial ROS levels and an alteration of mitochondrial morphology. Proteomic data analysis showed that ELF-MF altered the expression of 328 proteins in MDA-MB-231 cells and of 242 proteins in MCF-10A cells. Gene Ontology term enrichment analysis demonstrated that in both cell lines ELF-MF exposure up-regulated the genes enriched in "focal adhesion" and "mitochondrion". The ELF-MF exposure decreased the adhesive properties of MDA-MB-231 cells and increased the migration and invasion cell abilities. At the same time, proteomic analysis, confirmed by Real Time PCR, revealed that transcription factors associated with cellular reprogramming were upregulated in MDA-MB-231 cells and downregulated in MCF-10A cells after ELF-MF exposure. MDA-MB-231 breast cancer cells exposed to 1 mT 50 Hz ELF-MF showed modifications in proteomic profile together with changes in cell viability, cellular morphology, oxidative stress response, adhesion, migration and invasion cell abilities. The main signaling pathways involved were relative to focal adhesion, mitochondrion and cellular reprogramming.
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Affiliation(s)
- Raffaella Lazzarini
- Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
| | - Maria Eléxpuru-Zabaleta
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, 39011 Santander, Spain.
| | - Francesco Piva
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Matteo Giulietti
- Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
| | - Gianluca Fulgenzi
- Experimental Pathology, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
| | - Maria Fiorella Tartaglione
- Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
| | - Laura Zingaretti
- Occupational Medicine Unit, Marche University Hospital, 60126 Ancona, Italy.
| | - Adriano Tagliabracci
- Department of Excellence of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.
| | - Matteo Valentino
- Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
| | - Lory Santarelli
- Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
| | - Massimo Bracci
- Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60126 Ancona, Italy.
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21
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Zhao H, Liu C, Liu Y, Ding Q, Wang T, Li H, Wu H, Ma T. Harnessing electromagnetic fields to assist bone tissue engineering. Stem Cell Res Ther 2023; 14:7. [PMID: 36631880 PMCID: PMC9835389 DOI: 10.1186/s13287-022-03217-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/08/2022] [Indexed: 01/13/2023] Open
Abstract
Bone tissue engineering (BTE) emerged as one of the exceptional means for bone defects owing to it providing mechanical supports to guide bone tissue regeneration. Great advances have been made to facilitate the success of BTE in regenerating bone within defects. The use of externally applied fields has been regarded as an alternative strategy for BTE. Electromagnetic fields (EMFs), known as a simple and non-invasive therapy, can remotely provide electric and magnetic stimulation to cells and biomaterials, thus applying EMFs to assist BTE would be a promising strategy for bone regeneration. When combined with BTE, EMFs improve cell adhesion to the material surface by promoting protein adsorption. Additionally, EMFs have positive effects on mesenchymal stem cells and show capabilities of pro-angiogenesis and macrophage polarization manipulation. These advantages of EMFs indicate that it is perfectly suitable for representing the adjuvant treatment of BTE. We also summarize studies concerning combinations of EMFs and diverse biomaterial types. The strategy of combining EMFs and BTE receives encouraging outcomes and holds a promising future for effectively treating bone defects.
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Affiliation(s)
- Hongqi Zhao
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Chaoxu Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Yang Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Qing Ding
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Tianqi Wang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Hao Li
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Tian Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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22
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Chen Y, Lu C, Shang X, Wu K, Chen K. Primary cilia: The central role in the electromagnetic field induced bone healing. Front Pharmacol 2022; 13:1062119. [DOI: 10.3389/fphar.2022.1062119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/07/2022] [Indexed: 12/03/2022] Open
Abstract
Primary cilia have emerged as the cellular “antenna” that can receive and transduce extracellular chemical/physical signals, thus playing an important role in regulating cellular activities. Although the electromagnetic field (EMF) is an effective treatment for bone fractures since 1978, however, the detailed mechanisms leading to such positive effects are still unclear. Primary cilia may play a central role in receiving EMF signals, translating physical signals into biochemical information, and initiating various signalingsignaling pathways to transduce signals into the nucleus. In this review, we elucidated the process of bone healing, the structure, and function of primary cilia, as well as the application and mechanism of EMF in treating fracture healing. To comprehensively understand the process of bone healing, we used bioinformatics to analyze the molecular change and associated the results with other studies. Moreover, this review summarizedsummarized some limitations in EMFs-related research and provides an outlook for ongoing studies. In conclusion, this review illustrated the primary cilia and related molecular mechanisms in the EMF-induced bone healing process, and it may shed light on future research.
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Sahm F, Freiin Grote V, Zimmermann J, Haack F, Uhrmacher AM, van Rienen U, Bader R, Detsch R, Jonitz-Heincke A. Long-term stimulation with alternating electric fields modulates the differentiation and mineralization of human pre-osteoblasts. Front Physiol 2022; 13:965181. [PMID: 36246121 PMCID: PMC9562827 DOI: 10.3389/fphys.2022.965181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Biophysical stimulation by electric fields can promote bone formation in bone defects of critical size. Even though, long-term effects of alternating electric fields on the differentiation of osteoblasts are not fully understood. Human pre-osteoblasts were stimulated over 31 days to gain more information about these cellular processes. An alternating electric field with 0.7 Vrms and 20 Hz at two distances was applied and viability, mineralization, gene expression, and protein release of differentiation factors were analyzed. The viability was enhanced during the first days of stimulation. A higher electric field resulted in upregulation of typical osteogenic markers like osteoprotegerin, osteopontin, and interleukin-6, but no significant changes in mineralization. Upregulation of the osteogenic markers could be detected with a lower electric field after the first days of stimulation. As a significant increase in the mineralized matrix was identified, an enhanced osteogenesis due to low alternating electric fields can be assumed.
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Affiliation(s)
- Franziska Sahm
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
- *Correspondence: Franziska Sahm, ; Anika Jonitz-Heincke,
| | - Vivica Freiin Grote
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
| | - Julius Zimmermann
- Chair of Theoretical Electrical Engineering, Institute for General Electrical Engineering, University of Rostock, Rostock, Germany
| | - Fiete Haack
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Adelinde M. Uhrmacher
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Ursula van Rienen
- Chair of Theoretical Electrical Engineering, Institute for General Electrical Engineering, University of Rostock, Rostock, Germany
- Department Life, Light and Matter, University of Rostock, Rostock, Germany
- Department Ageing of Individuals and Society, University of Rostock, Rostock, Germany
| | - Rainer Bader
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
| | - Rainer Detsch
- Department of Materials Science and Engineering, Institute of Biomaterials, Friedrich Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Anika Jonitz-Heincke
- Biomechanics and Implant Technology Research Laboratory, Department of Orthopedics, Rostock University Medical Centre, Rostock, Germany
- *Correspondence: Franziska Sahm, ; Anika Jonitz-Heincke,
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24
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Wen C, Wang C, Hu C, Qi T, Jing R, Wang Y, Zhang M, Shao Y, Pei C. REPS2 downregulation facilitates FGF-induced adhesion and migration in human lens epithelial cells through FAK/Cdc42 signaling and contributes to posterior capsule opacification. Cell Signal 2022; 97:110378. [PMID: 35690292 DOI: 10.1016/j.cellsig.2022.110378] [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: 02/22/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 11/28/2022]
Abstract
Posterior capsular opacification (PCO) can cause postoperative visual loss after cataract surgery. Residual human lens epithelial cell (HLEC) proliferation, migration, epithelial-mesenchymal transition (EMT) and synthesis of extracellular matrix (ECM) are the entitative reasons for PCO. Low expression of Ral-binding protein 1-associated Eps domain-containing 2 (REPS2) and high levels of basic fibroblast growth factor (b-FGF) were observed in the lens and postoperative aqueous humor of cataract patients. REPS2 was identified as a negative regulator in growth factor signaling; however, its function in HLECs is unknown. This was first investigated in the present study by evaluating REPS2 expression in anterior lens capsules from cataract patients, a mouse cataract model, and HLE-b3 cells. The biological function of REPS2 in HLE-B3 cells was assessed by REPS2 silencing and Cell Counting Kit 8, wound healing, Transwell migration, F-actin staining, G-protein pulldown and western blot assays. In the present study, REPS2 was significantly downregulated in human and mouse cataract capsules and H2O2-treated HLE-B3 cells. REPS2 knockdown increased fibronectin, type I collagen, and α-smooth muscle actin expression levels and stimulated HLECs proliferation and migration; these effects were enhanced by FGF treatment and accompanied with focal adhesion kinase (FAK) phosphorylation, cell division cycle 42 (Cdc42) activation, focal adhesion protein upregulation, and F-actin cytoskeleton reorganization. However, treatment with the FAK inhibitor PF573228 abolished these effects. Thus, REPS2 downregulation in cataract HLECs induces their proliferation and facilitates FGF-induced ECM synthesis, EMT, cell adhesion and migration by activating FAK/Cdc42 signaling, which may underlie PCO pathogenesis.
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Affiliation(s)
- Chan Wen
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Chen Wang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, PR China
| | - Conghui Hu
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Tiantian Qi
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Ruihua Jing
- Department of Ophthalmology, second affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Yunqing Wang
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Ming Zhang
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China
| | - Yongping Shao
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, PR China.
| | - Cheng Pei
- Department of Ophthalmology, first affiliated hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China.
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25
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Hamid HA, Sarmadi VH, Prasad V, Ramasamy R, Miskon A. Electromagnetic field exposure as a plausible approach to enhance the proliferation and differentiation of mesenchymal stem cells in clinically relevant scenarios. J Zhejiang Univ Sci B 2022; 23:42-57. [PMID: 35029087 PMCID: PMC8758935 DOI: 10.1631/jzus.b2100443] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has been regarded as one of the most revolutionary breakthroughs in the history of modern medicine owing to its myriad of immunoregulatory and regenerative properties. With the rapid progress in the fields of osteo- and musculoskeletal therapies, the demand for MSC-based treatment modalities is becoming increasingly prominent. In this endeavor, researchers around the world have devised new and innovative techniques to support the proliferation of MSCs while minimizing the loss of hallmark features of stem cells. One such example is electromagnetic field (EMF) exposure, which is an alternative approach with promising potential. In this review, we present a critical discourse on the efficiency, practicability, and limitations of some of the relevant methods, with insurmountable evidence backing the implementation of EMF as a feasible strategy for the clinically relevant expansion of MSCs.
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Affiliation(s)
- Haslinda Abdul Hamid
- Bio-artificial Organ and Regenerative Medicine Unit, National Defense University of Malaysia, Kuala Lumpur 57000, Malaysia
| | - Vahid Hosseinpour Sarmadi
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran 144961 4535, Iran.,Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran 199671 4353, Iran
| | - Vivek Prasad
- Stem Cell and Immunity Research Group, Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Selangor 43400, Malaysia
| | - Rajesh Ramasamy
- Stem Cell and Immunity Research Group, Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Selangor 43400, Malaysia
| | - Azizi Miskon
- Bio-artificial Organ and Regenerative Medicine Unit, National Defense University of Malaysia, Kuala Lumpur 57000, Malaysia.
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26
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Wu H, Xie X, Sun M, Chen M, Tao X, Fang X, Meng X, Wei W, Yu M. Modification of mesenchymal stem cells by HMGB1 promotes the activity of Cav3.2 T-type calcium channel via PKA/β-catenin/γ-cystathionase pathway. Stem Cell Res Ther 2022; 13:4. [PMID: 35012644 PMCID: PMC8744322 DOI: 10.1186/s13287-021-02677-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/10/2021] [Indexed: 11/10/2022] Open
Abstract
Background Mesenchymal stem cells (MSC) hold great promise for treating cardiovascular disease. Recently, we genetically modified MSCs with high mobility group box 1 (HMGB1), and these cells demonstrated high mobility by efficient migrating and homing to target neointima. The possible mechanism was investigated in the current study. Methods Rat MSCs were transfected with lentivirus containing HMGB1 cDNA to yield MSC-H cell line stably overexpressing HMGB1. The MSC-C cells which were transfected with empty lentivirus served as negative control, and the differentially expressed genes were analyzed by microarray. The cell mobility was determined by transwell migration assay. Intracellular free calcium and the expression of Cav3.2 T-type calcium channel (CACNA1H) were assayed to analyze activity of CACNA1H-mediated calcium influx. H2S production and γ-cystathionase expression were examined to assess the activity of γ-cystathionase/H2S signaling. The interaction of HMGB1 with γ-cystathionase in MSC-H cells was analyzed by co-immunoprecipitation. Luciferase reporter assay was performed to determine whether the promoter activity of γ-cystathionase was regulated by interaction of β-catenin and TCF/LEF binding site. Intercellular cAMP, PKA activity, phosphorylation of β-catenin, and GSK3β were investigated to reveal cAMP/PKA mediated β-catenin activation. Result Microarray analysis revealed that differentially expressed genes were enriched in cAMP signaling and calcium signaling. CACNA1H was upregulated to increase intracellular free calcium and MSC-H cell migration. Blockage of CACNA1H by ABT-639 significantly reduced intracellular free calcium and cell migration. The γ-cystathionase/H2S signaling was responsible for CACNA1H activation. H2S production was increased with high expression of γ-cystathionase in MSC-H cells, which was blocked by γ-cystathionase inhibitor DL-propargylglycine. Upregulation of γ-cystathionase was not attributed to interaction with HMGB1 overexpressed in MSC-H cells although γ-cystathionase was suggested to co-immunoprecipitate with oxidized HMGB1. Bioinformatics analysis identified a conserved TCF/LEF binding site in the promoter of γ-cystathionase gene. Luciferase reporter assay confirmed that the promoter had positive response to β-catenin which was activated in MSC-H cells. Finally, cAMP/PKA was activated to phosphorylate β-catenin at Ser657 and GSK3β, enabling persisting activation of Wnt/β-catenin signaling in MSC-H cells. Conclusion Our study revealed that modification of MSCs with HMGB1 promoted CACNA1H-mediated calcium influx via PKA/β-catenin/γ-cystathionase pathway. This was a plausible mechanism for high mobility of MSC-H cell line. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02677-z.
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Affiliation(s)
- Hao Wu
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaodong Xie
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mingyang Sun
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Chen
- Department of Gastroenterology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
| | - Xuan Tao
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Fang
- Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohu Meng
- Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wei
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Min Yu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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27
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Abstract
Due to the ability to differentiate into variety of cell types, mesenchymal stem cells (MSCs) hold promise as source in cell-based therapy for treating injured tissue and degenerative diseases. The potential use of MSCs to replace or repair damaged tissues may depend on the efficient differentiation protocols to derive specialized cells without any negative side effects. Identification of appropriate cues that support the lineage-specific differentiation of stem cells is critical for tissue healing and cellular therapy. Recently, a number of stimuli have been utilized to direct the differentiation of stem cells. Biochemical stimuli such as small molecule, growth factor and miRNA have been traditionally used to regulate the fate of stem cells. In recent years, many studies have reported that biophysical stimuli including cyclic mechanical strain, fluid shear stress, microgravity, electrical stimulation, matrix stiffness and topography can also be sensed by stem cells through mechanical receptors, thus affecting the stem cell behaviors including their differentiation potential. In this paper, we review all the most recent literature on the application of biochemical and biophysical cues on regulating MSC differentiation. An extensive literature search was done using electronic database (Medline/Pubmed). Although there are still some challenges that need to be taken into consideration before translating these methods into clinics, biochemical and biophysical stimulation appears to be an attractive method to manipulate the lineage commitment of MSCs.
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28
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Khorsandi K, Hosseinzadeh R, Abrahamse H, Fekrazad R. Biological Responses of Stem Cells to Photobiomodulation Therapy. Curr Stem Cell Res Ther 2021; 15:400-413. [PMID: 32013851 DOI: 10.2174/1574888x15666200204123722] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/26/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Stem cells have attracted the researchers interest, due to their applications in regenerative medicine. Their self-renewal capacity for multipotent differentiation, and immunomodulatory properties make them unique to significantly contribute to tissue repair and regeneration applications. Recently, stem cells have shown increased proliferation when irradiated with low-level laser therapy or Photobiomodulation Therapy (PBMT), which induces the activation of intracellular and extracellular chromophores and the initiation of cellular signaling. The purpose of this study was to evaluate this phenomenon in the literature. METHODS The literature investigated the articles written in English in four electronic databases of PubMed, Scopus, Google Scholar and Cochrane up to April 2019. Stem cell was searched by combining the search keyword of "low-level laser therapy" OR "low power laser therapy" OR "low-intensity laser therapy" OR "photobiomodulation therapy" OR "photo biostimulation therapy" OR "LED". In total, 46 articles were eligible for evaluation. RESULTS Studies demonstrated that red to near-infrared light is absorbed by the mitochondrial respiratory chain. Mitochondria are significant sources of reactive oxygen species (ROS). Mitochondria play an important role in metabolism, energy generation, and are also involved in mediating the effects induced by PBMT. PBMT may result in the increased production of (ROS), nitric oxide (NO), adenosine triphosphate (ATP), and cyclic adenosine monophosphate (cAMP). These changes, in turn, initiate cell proliferation and induce the signal cascade effect. CONCLUSION The findings of this review suggest that PBMT-based regenerative medicine could be a useful tool for future advances in tissue engineering and cell therapy.
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Affiliation(s)
- Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran;
and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Reza Hosseinzadeh
- Department of Medical Laser, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran
| | - Heidi Abrahamse
- Laser Research Centre, NRF SARChI Chair: Laser Applications in Health, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Reza Fekrazad
- Department of Periodontology, Dental Faculty - Radiation Sciences Research Center, Laser Research
Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran,International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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29
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Zhang LL, Xiong YY, Yang YJ. The Vital Roles of Mesenchymal Stem Cells and the Derived Extracellular Vesicles in Promoting Angiogenesis After Acute Myocardial Infarction. Stem Cells Dev 2021; 30:561-577. [PMID: 33752473 DOI: 10.1089/scd.2021.0006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Acute myocardial infarction (AMI) is an event of ischemic myocardial necrosis caused by acute coronary artery occlusion, which ultimately leads to a large loss of cardiomyocytes. The prerequisite of salvaging ischemic myocardium and improving cardiac function of patients is to provide adequate blood perfusion in the infarcted area. Apart from reperfusion therapy, it is also urgent and imperative to promote angiogenesis. Recently, growing evidence based on promising preclinical data indicates that mesenchymal stem cells (MSCs) can provide therapeutic effects on AMI by promoting angiogenesis. Extracellular vesicles (EVs), membrane-encapsulated vesicles with complex cargoes, including proteins, nucleic acids, and lipids, can be derived from MSCs and represent part of their functions, so EVs also possess the ability to promote angiogenesis. However, poor control of the survival and localization of MSCs hindered clinical transformation and made scientists start looking for new approaches based on MSCs. Identifying the role of MSCs and their derived EVs in promoting angiogenesis can provide a theoretical basis for improved MSC-based methods, and ultimately promote the clinical treatment of AMI. This review highlights potential proangiogenic mechanisms of transplanted MSCs and the derived EVs after AMI and summarizes the latest literature concerning the novel methods based on MSCs to maximize the angiogenesis capability.
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Affiliation(s)
- Li-Li Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yu-Yan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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30
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Ahamad N, Singh BB. Calcium channels and their role in regenerative medicine. World J Stem Cells 2021; 13:260-280. [PMID: 33959218 PMCID: PMC8080543 DOI: 10.4252/wjsc.v13.i4.260] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types. Based on their plasticity potential, they are divided into totipotent (morula stage cells), pluripotent (embryonic stem cells), multipotent (hematopoietic stem cells, multipotent adult progenitor stem cells, and mesenchymal stem cells [MSCs]), and unipotent (progenitor cells that differentiate into a single lineage) cells. Though bone marrow is the primary source of multipotent stem cells in adults, other tissues such as adipose tissues, placenta, amniotic fluid, umbilical cord blood, periodontal ligament, and dental pulp also harbor stem cells that can be used for regenerative therapy. In addition, induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells, and thus could be another source for regenerative medicine. Several diseases including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, virus infection (also coronavirus disease 2019) have limited success with conventional medicine, and stem cell transplantation is assumed to be the best therapy to treat these disorders. Importantly, MSCs, are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair. Moreover, MSCs have the potential to migrate towards the damaged area, which is regulated by various factors and signaling processes. Recent studies have shown that extracellular calcium (Ca2+) promotes the proliferation of MSCs, and thus can assist in transplantation therapy. Ca2+ signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors, Ca2+ channels/pumps/exchangers, Ca2+ buffers, and Ca2+ sensors, which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity, which will be discussed in this review.
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Affiliation(s)
- Nassem Ahamad
- School of Dentistry, UT Health Science Center San Antonio, San Antonio, TX 78257, United States
| | - Brij B Singh
- School of Dentistry, UT Health Science Center San Antonio, San Antonio, TX 78257, United States
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Li W, Liu W, Wang W, Wang J, Ma T, Chen J, Wu H, Liu C. Sinusoidal electromagnetic fields accelerate bone regeneration by boosting the multifunctionality of bone marrow mesenchymal stem cells. Stem Cell Res Ther 2021; 12:234. [PMID: 33849651 PMCID: PMC8042357 DOI: 10.1186/s13287-021-02302-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/22/2021] [Indexed: 12/26/2022] Open
Abstract
Background The repair of critical-sized bone defects is always a challenging problem. Electromagnetic fields (EMFs), used as a physiotherapy for bone defects, have been suspected to cause potential hazards to human health due to the long-term exposure. To optimize the application of EMF while avoiding its adverse effects, a combination of EMF and tissue engineering techniques is critical. Furthermore, a deeper understanding of the mechanism of action of EMF will lead to better applications in the future. Methods In this research, bone marrow mesenchymal stem cells (BMSCs) seeded on 3D-printed scaffolds were treated with sinusoidal EMFs in vitro. Then, 5.5 mm critical-sized calvarial defects were created in rats, and the cell scaffolds were implanted into the defects. In addition, the molecular and cellular mechanisms by which EMFs regulate BMSCs were explored with various approaches to gain deeper insight into the effects of EMFs. Results The cell scaffolds treated with EMF successfully accelerated the repair of critical-sized calvarial defects. Further studies revealed that EMF could not directly induce the differentiation of BMSCs but improved the sensitivity of BMSCs to BMP signals by upregulating the quantity of specific BMP (bone morphogenetic protein) receptors. Once these receptors receive BMP signals from the surrounding milieu, a cascade of reactions is initiated to promote osteogenic differentiation via the BMP/Smad signalling pathway. Moreover, the cytokines secreted by BMSCs treated with EMF can better facilitate angiogenesis and osteoimmunomodulation which play fundamental roles in bone regeneration. Conclusion In summary, EMF can promote the osteogenic potential of BMSCs and enhance the paracrine function of BMSCs to facilitate bone regeneration. These findings highlight the profound impact of EMF on tissue engineering and provide a new strategy for the clinical treatment of bone defects.
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Affiliation(s)
- Weigang Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Wenbin Liu
- Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China
| | - Wei Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Jiachen Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Tian Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Jingyuan Chen
- Department of Cardiothoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Chaoxu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Naffa R, Padányi R, Ignácz A, Hegyi Z, Jezsó B, Tóth S, Varga K, Homolya L, Hegedűs L, Schlett K, Enyedi A. The Plasma Membrane Ca 2+ Pump PMCA4b Regulates Melanoma Cell Migration through Remodeling of the Actin Cytoskeleton. Cancers (Basel) 2021; 13:cancers13061354. [PMID: 33802790 PMCID: PMC8002435 DOI: 10.3390/cancers13061354] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/08/2021] [Accepted: 03/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Earlier we demonstrated that the plasma membrane Ca2+ pump PMCA4b inhibits migration and metastatic activity of BRAF mutant melanoma cells, however, the exact mechanism has not been fully understood. Here we demonstrate that PMCA4b acted through actin cytoskeleton remodeling in generating a low migratory melanoma cell phenotype resulting in increased cell–cell connections, lamellipodia and stress fiber formation. Both proper trafficking and calcium transporting activity of the pump were essential to complete these tasks indicating that controlling Ca2+ concentration levels at specific plasma membrane locations such as the cell front played a role. Our findings suggest that PMCA4b downregulation is likely one of the mechanisms that leads to the perturbed cancer cell cytoskeleton organization resulting in enhanced melanoma cell migration and metastasis. Abstract We demonstrated that the plasma membrane Ca2+ ATPase PMCA4b inhibits migration and metastatic activity of BRAF mutant melanoma cells. Actin dynamics are essential for cells to move, invade and metastasize, therefore, we hypothesized that PMCA4b affected cell migration through remodeling of the actin cytoskeleton. We found that expression of PMCA4b in A375 BRAF mutant melanoma cells induced a profound change in cell shape, cell culture morphology, and displayed a polarized migratory character. Along with these changes the cells became more rounded with increased cell–cell connections, lamellipodia and stress fiber formation. Silencing PMCA4b in MCF-7 breast cancer cells had a similar effect, resulting in a dramatic loss of stress fibers. In addition, the PMCA4b expressing A375 cells maintained front-to-rear Ca2+ concentration gradient with the actin severing protein cofilin localizing to the lamellipodia, and preserved the integrity of the actin cytoskeleton from a destructive Ca2+ overload. We showed that both PMCA4b activity and trafficking were essential for the observed morphology and motility changes. In conclusion, our data suggest that PMCA4b plays a critical role in adopting front-to-rear polarity in a normally spindle-shaped cell type through F-actin rearrangement resulting in a less aggressive melanoma cell phenotype.
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Affiliation(s)
- Randa Naffa
- Department of Transfusiology, Semmelweis University, H-1089 Budapest, Hungary; (R.N.); (S.T.)
| | - Rita Padányi
- Department of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, Hungary;
| | - Attila Ignácz
- Department of Physiology and Neurobiology, Eötvös Loránd University, H-1117 Budapest, Hungary; (A.I.); (K.S.)
| | - Zoltán Hegyi
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt.2, H-1117 Budapest, Hungary; (Z.H.); (B.J.); (L.H.)
| | - Bálint Jezsó
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt.2, H-1117 Budapest, Hungary; (Z.H.); (B.J.); (L.H.)
| | - Sarolta Tóth
- Department of Transfusiology, Semmelweis University, H-1089 Budapest, Hungary; (R.N.); (S.T.)
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, H-1117 Budapest, Hungary
| | | | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt.2, H-1117 Budapest, Hungary; (Z.H.); (B.J.); (L.H.)
| | - Luca Hegedűs
- Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, 45239 Essen, Germany;
| | - Katalin Schlett
- Department of Physiology and Neurobiology, Eötvös Loránd University, H-1117 Budapest, Hungary; (A.I.); (K.S.)
| | - Agnes Enyedi
- Department of Transfusiology, Semmelweis University, H-1089 Budapest, Hungary; (R.N.); (S.T.)
- Correspondence:
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Yan Z, Zhang W, Xu P, Zheng W, Lin X, Zhou J, Chen J, He QY, Zhong J, Guo J, Cheng B, Wang T. Phosphoproteome and Biological Evidence Revealed Abnormal Calcium Homeostasis in Keloid Fibroblasts and Induction of Aberrant Platelet Aggregation. J Proteome Res 2021; 20:2521-2532. [PMID: 33710899 DOI: 10.1021/acs.jproteome.0c00984] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Keloid is a benign tumor characterized by persistent inflammation, increased fibroblast proliferation, and abnormal deposition of collagen in the wound. The etiology of keloid is unclear. Here, we explored the phospho-signaling changes in human keloid fibroblasts via phosphoproteome mass spectrometry analysis. We found that comparative phosphoproteomics could statistically distinguish keloid from control fibroblasts. Differentially expressed phosphoproteins could predict the activation of known keloid-relevant upstream regulators including transforming growth factor-β1, interleukin (IL)-4, and IL-5. With multiple bioinformatics analyses, phosphorylated FLNA, TLN1, and VCL were significantly enriched in terms of calcium homeostasis and platelet aggregation. We biologically verified that keloid fibroblasts had a higher level of Ca2+ influx than the control fibroblasts upon ionomycin stimulation. Via co-cultivation analysis, we found that human keloid fibroblasts could directly promote platelet aggregation. As suggested by PhosphoPath and gene set enrichment analysis, pFLNA was centered as the top phosphoproteins associated with keloid phenotypes. We validated that pFLNA was upregulated both in keloid fibroblasts and keloid tissue section, implicating its biomarker potential. In conclusion, we reported the first phosphoproteome on keloid fibroblasts, based on which we revealed that keloid fibroblasts had aberrant calcium homeostasis and could directly induce platelet aggregation.
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Affiliation(s)
- Ziqi Yan
- MOE Key Laboratory of Tumor Molecular Biology and Institute of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, China.,The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Wanling Zhang
- MOE Key Laboratory of Tumor Molecular Biology and Institute of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, China.,The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Pengcheng Xu
- Department of Plastic Surgery, The Key Laboratory of Trauma Treatment and Tissue Repair of Tropical Area, General Hospital of Southern Theater Command, PLA, Guangzhou, Guangdong 510010, P. R. China
| | - Wenting Zheng
- The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Xinyi Lin
- The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jian Zhou
- The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jianwu Chen
- Department of Plastic Surgery, The Key Laboratory of Trauma Treatment and Tissue Repair of Tropical Area, General Hospital of Southern Theater Command, PLA, Guangzhou, Guangdong 510010, P. R. China
| | - Qing-Yu He
- The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jingxiang Zhong
- MOE Key Laboratory of Tumor Molecular Biology and Institute of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, China
| | - Jiahui Guo
- The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
| | - Biao Cheng
- Department of Plastic Surgery, The Key Laboratory of Trauma Treatment and Tissue Repair of Tropical Area, General Hospital of Southern Theater Command, PLA, Guangzhou, Guangdong 510010, P. R. China
| | - Tong Wang
- MOE Key Laboratory of Tumor Molecular Biology and Institute of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, China.,The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China
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Li W, Huang C, Ma T, Wang J, Liu W, Yan J, Sheng G, Zhang R, Wu H, Liu C. Low-frequency electromagnetic fields combined with tissue engineering techniques accelerate intervertebral fusion. Stem Cell Res Ther 2021; 12:143. [PMID: 33597006 PMCID: PMC7890873 DOI: 10.1186/s13287-021-02207-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/02/2021] [Indexed: 12/26/2022] Open
Abstract
Background Intervertebral fusion is the most common surgery to treat lumbar degenerative disease (LDD). And the graft material used in the operation is derived from the iliac crest to promote fusion. However, autografts possess the fatal disadvantage of lack of source. Therefore, economical and practical bone substitutes are urgently needed to be developed. Sinusoidal electromagnetic fields (EMF) combined with tissue engineering techniques may be an appropriate way to promote intervertebral fusion. Methods In this research, porous scaffolds made of polycaprolactone (PCL) and nano-hydroxyapatite (nHA) were used as cell carriers. Then, the scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were treated with sinusoidal electromagnetic field and the osteogenic capability of BMSCs was tested later. In addition, an intervertebral disc of the tail vertebra of the rat was removed to construct a spinal intervertebral fusion model with a cell-scaffold implanted. The intervertebral fusion was observed and analyzed by X-ray, micro-CT, and histological methods. Results BMSCs stimulated by EMF possess splendid osteogenic capability under an osteogenic medium (OM) in vitro. And the conditioned medium of BMSCs treated with EMF can further promote osteogenic differentiation of the primitive BMSCs. Mechanistically, EMF regulates BMSCs via BMP/Smad and mitogen-activated protein kinase (MAPK)-associated p38 signaling pathways. In vivo experiments revealed that the scaffold loaded with BMSCs stimulated by EMF accelerated intervertebral fusion successfully. Conclusion In summary, EMF accelerated intervertebral fusion by improving the osteogenic capacity of BMSCs seeded on scaffolds and might boost the paracrine function of BMSCs to promote osteogenic differentiation of the homing BMSCs at the injured site. EMF combined with tissue engineering techniques may become a new clinical treatment for LDD.
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Affiliation(s)
- Weigang Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Chunwei Huang
- Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Tian Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Jiachen Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Wenbin Liu
- Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China
| | - Jiyuan Yan
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Gaohong Sheng
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Ruizhuo Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Chaoxu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Emelianov VY, Preobrazhenskaia EV, Nikolaev NS. Evaluating the Effectiveness of Biophysical Methods of Osteogenesis Stimulation: Review. TRAUMATOLOGY AND ORTHOPEDICS OF RUSSIA 2021; 27:86-96. [DOI: https:/doi.org/10.21823/2311-2905-2021-27-1-86-96] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Background. Stimulation of osteogenesis (SO) by biophysical methods has been widely used in practice to accelerate healing or stimulate the healing of fractures with non-unions, since the middle of the XIX century. SO can be carried out by direct current electrostimulation, or indirectly by low-intensity pulsed ultrasound, capacitive electrical coupling stimulation, and pulsed electromagnetic field stimulation. SO simulates natural physiological processes: in the case of electrical stimulation, it changes the electromagnetic potential of damaged cell tissues in a manner similar to normal healing processes, or in the case of low-intensity pulsed ultrasound, it produces weak mechanical effects on the fracture area. SO increases the expression of factors and signaling pathways responsible for tissue regeneration and bone mineralization and ultimately accelerates bone union.The purpose of this review was to present the most up-to-date data from laboratory and clinical studies of the effectiveness of SO.Material and Methods. The results of laboratory studies and the final results of metaanalyses for each of the four SO methods published from 1959 to 2020 in the PubMed, EMBASE, and eLibrary databases are reviewed.Conclusion. The use of SO effectively stimulates the healing of fractures with the correct location of the sensors, compliance with the intensity and time of exposure, as well as the timing of use for certain types of fractures. In case of non-union or delayed union of fractures, spondylodesis, arthrodesis, preference should be given to non-invasive methods of SO. Invasive direct current stimulation can be useful for non-union of long bones, spondylodesis with the risk of developing pseudoarthrosis.
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Emelianov VY, Preobrazhenskaia EV, Nikolaev NS. Evaluating the Effectiveness of Biophysical Methods of Osteogenesis Stimulation: Review. TRAUMATOLOGY AND ORTHOPEDICS OF RUSSIA 2021; 27:86-96. [DOI: 10.21823/2311-2905-2021-27-1-86-96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Background. Stimulation of osteogenesis (SO) by biophysical methods has been widely used in practice to accelerate healing or stimulate the healing of fractures with non-unions, since the middle of the XIX century. SO can be carried out by direct current electrostimulation, or indirectly by low-intensity pulsed ultrasound, capacitive electrical coupling stimulation, and pulsed electromagnetic field stimulation. SO simulates natural physiological processes: in the case of electrical stimulation, it changes the electromagnetic potential of damaged cell tissues in a manner similar to normal healing processes, or in the case of low-intensity pulsed ultrasound, it produces weak mechanical effects on the fracture area. SO increases the expression of factors and signaling pathways responsible for tissue regeneration and bone mineralization and ultimately accelerates bone union.The purpose of this review was to present the most up-to-date data from laboratory and clinical studies of the effectiveness of SO.Material and Methods. The results of laboratory studies and the final results of metaanalyses for each of the four SO methods published from 1959 to 2020 in the PubMed, EMBASE, and eLibrary databases are reviewed.Conclusion. The use of SO effectively stimulates the healing of fractures with the correct location of the sensors, compliance with the intensity and time of exposure, as well as the timing of use for certain types of fractures. In case of non-union or delayed union of fractures, spondylodesis, arthrodesis, preference should be given to non-invasive methods of SO. Invasive direct current stimulation can be useful for non-union of long bones, spondylodesis with the risk of developing pseudoarthrosis.
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Pulsed Electromagnetic Field Stimulation in Osteogenesis and Chondrogenesis: Signaling Pathways and Therapeutic Implications. Int J Mol Sci 2021; 22:ijms22020809. [PMID: 33467447 PMCID: PMC7830993 DOI: 10.3390/ijms22020809] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/30/2020] [Accepted: 01/11/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are the main cell players in tissue repair and thanks to their self-renewal and multi-lineage differentiation capabilities, they gained significant attention as cell source for tissue engineering (TE) approaches aimed at restoring bone and cartilage defects. Despite significant progress, their therapeutic application remains debated: the TE construct often fails to completely restore the biomechanical properties of the native tissue, leading to poor clinical outcomes in the long term. Pulsed electromagnetic fields (PEMFs) are currently used as a safe and non-invasive treatment to enhance bone healing and to provide joint protection. PEMFs enhance both osteogenic and chondrogenic differentiation of MSCs. Here, we provide extensive review of the signaling pathways modulated by PEMFs during MSCs osteogenic and chondrogenic differentiation. Particular attention has been given to the PEMF-mediated activation of the adenosine signaling and their regulation of the inflammatory response as key player in TE approaches. Overall, the application of PEMFs in tissue repair is foreseen: (1) in vitro: to improve the functional and mechanical properties of the engineered construct; (2) in vivo: (i) to favor graft integration, (ii) to control the local inflammatory response, and (iii) to foster tissue repair from both implanted and resident MSCs cells.
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Zhang Z, Zheng T, Zhu R. Microchip with Single-Cell Impedance Measurements for Monitoring Osteogenic Differentiation of Mesenchymal Stem Cells under Electrical Stimulation. Anal Chem 2020; 92:12579-12587. [PMID: 32859132 DOI: 10.1021/acs.analchem.0c02556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Effective induction methods and in situ monitoring are essential for studying the mechanism of biological responses in stem cell differentiation. This article proposes an induction method incorporating electrical stimulation under an inhomogeneous field with single-cell impedance monitoring for studying osteogenic differentiation of mesenchymal stem cells (MSCs) using a microchip. The microchip contains an array of sextupole-electrode units for implementing a combination of controllable electrical stimulation and single-cell impedance measurements. MSCs are inducted to osteogenic differentiation under electrical stimulation using quadrupole electrodes and single-cell impedances are monitored in situ using a pair of microelectrodes at each unit center. The proposed microchip adopts an array design to monitor a number of MSCs in parallel, which improves measurement throughput and facilitates to carry out statistic tests. We perform osteogenic differentiation of MSCs on the microchip with and without electrical stimulation meanwhile monitoring single-cell impedance in real time for 21 days. The recorded impedance results show the detailed characteristic change of MSCs at the single-cell level during osteogenic differentiation, which demonstrates a significant difference between the conditions with and without electrical stimulation. The cell morphology and various staining analyses are also used to validate osteogenesis and correlate with the impedance expression. Correlation analysis of the impedance measurement, cell morphology, and various staining assays proves the great acceleration effect of the proposed electrical stimulation on osteogenic differentiation of MSCs. The proposed impedance method can monitor the dynamic process of cell development and study heterogeneity of stem cell differentiation at the single-cell level.
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Affiliation(s)
- Zhizhong Zhang
- State Key Laboratory of Precision Measurements Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China
| | - Tianyang Zheng
- State Key Laboratory of Precision Measurements Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China
| | - Rong Zhu
- State Key Laboratory of Precision Measurements Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China
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Huang W, Tan M, Wang Y, Liu L, Pan Y, Li J, Ouyang M, Long C, Qu X, Liu H, Liu C, Wang J, Deng L, Xiang Y, Qin X. Increased intracellular Cl - concentration improves airway epithelial migration by activating the RhoA/ROCK Pathway. Theranostics 2020; 10:8528-8540. [PMID: 32754261 PMCID: PMC7392015 DOI: 10.7150/thno.46002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/24/2020] [Indexed: 12/19/2022] Open
Abstract
In the airway, Cl- is the most abundant anion and is critically involved in transepithelial transport. The correlation of the abnormal expression and activation of chloride channels (CLCs), such as cystic fibrosis transmembrane conductance regulators (CFTRs), anoctamin-1, and CLC-2, with cell migration capability suggests a relationship between defective Cl- transport and epithelial wound repair. However, whether a correlation exists between intracellular Cl- and airway wound repair capability has not been explored thus far, and the underlying mechanisms involved in this relationship are not fully defined. Methods: In this work, the alteration of intracellular chloride concentration ([Cl-]i) was measured by using a chloride-sensitive fluorescent probe (N-[ethoxycarbonylmethyl]-6-methoxyquinolium bromide). Results: We found that clamping with high [Cl-]i and 1 h of treatment with the CLC inhibitor CFTR blocker CFTRinh-172 and chloride intracellular channel inhibitor IAA94 increased intracellular Cl- concentration ([Cl-]i) in airway epithelial cells. This effect improved epithelial cell migration. In addition, increased [Cl-]i in cells promoted F-actin reorganization, decreased cell stiffness, and improved RhoA activation and LIMK1/2 phosphorylation. Treatment with the ROCK inhibitor of Y-27632 and ROCK1 siRNA significantly attenuated the effects of increased [Cl-]i on LIMK1/2 activation and cell migration. In addition, intracellular Ca2+ concentration was unaffected by [Cl-]i clamping buffers and CFTRinh-172 and IAA94. Conclusion: Taken together, these results suggested that Cl- accumulation in airway epithelial cells could activate the RhoA/ROCK/LIMK cascade to induce F-actin reorganization, down-regulate cell stiffness, and improve epithelial migration.
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Affiliation(s)
- Wenjie Huang
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
- Affiliated Liutie Central Hospital of Guangxi medical university, Liuzhou, Guangxi 545007, China
| | - Meiling Tan
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yue Wang
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
- School of Nursing, Changzhou University, Changzhou, Jiangsu 213164, China
| | - Lei Liu
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
| | - Yan Pan
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
| | - Jingjing Li
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
| | - Mingxing Ouyang
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
| | - Chunjiao Long
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Xiangping Qu
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Huijun Liu
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Chi Liu
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Jia Wang
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Linhong Deng
- Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou, Jiangsu 213164, China
| | - Yang Xiang
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Xiaoqun Qin
- School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
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Aguilar Garcia IG, Dueñas-Jiménez JM, Castillo L, Osuna-Carrasco LP, De La Torre Valdovinos B, Castañeda-Arellano R, López-Ruiz JR, Toro-Castillo C, Treviño M, Mendizabal-Ruiz G, Duenas-Jimenez SH. Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats. Front Neural Circuits 2020; 14:1. [PMID: 32174815 PMCID: PMC7056700 DOI: 10.3389/fncir.2020.00001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/03/2020] [Indexed: 11/13/2022] Open
Abstract
Background: The spinal cord’s central pattern generators (CPGs) have been explained by the symmetrical half-center hypothesis, the bursts generator, computational models, and more recently by connectome circuits. Asymmetrical models, at odds with the half-center paradigm, are composed of extensor and flexor CPG modules. Other models include not only flexor and extensor motoneurons but also motoneuron pools controlling biarticular muscles. It is unknown whether a preferred model can explain some particularities that fictive scratching (FS) in the cat presents. The first aim of this study was to investigate FS patterns considering the aiming and the rhythmic periods, and second, to examine the effects of serotonin (5HT) on and segmental inputs to FS. Methods: The experiments were carried out first in brain cortex-ablated cats (BCAC), then spinalized (SC), and for the midcollicular (MCC) preparation. Subjects were immobilized and the peripheral nerves were used to elicit the Monosynaptic reflex (MR), to modify the scratching patterns and for electroneurogram recordings. Results: In BCAC, FS was produced by pinna stimulation and, in some cases, by serotonin. The scratching aiming phase (AP) initiates with the activation of either flexor or extensor motoneurons. Serotonin application during the AP produced simultaneous extensor and flexor bursts. Furthermore, WAY 100635 (5HT1A antagonist) produced a brief burst in the tibialis anterior (TA) nerve, followed by a reduction in its electroneurogram (ENG), while the soleus ENG remained silent. In SC, rhythmic phase (RP) activity was recorded in the soleus motoneurons. Serotonin or WAY produced FS bouts. The electrical stimulation of Ia afferent fibers produced heteronymous MRes waxing and waning during the scratch cycle. In MCC, FS began with flexor activity. Electrical stimulation of either deep peroneus (DP) or superficial peroneus (SP) nerves increased the duration of the TA electroneurogram. Medial gastrocnemius (MG) stretching or MG nerve electrical stimulation produced a reduction in the TA electroneurogram and an initial MG extensor burst. MRes waxed and waned during the scratch cycle. Conclusion: Descending pathways and segmental afferent fibers, as well as 5-HT and WAY, can change the FS pattern. To our understanding, the half-center hypothesis is the most suitable for explaining the AP in MCC.
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Affiliation(s)
| | | | - Luis Castillo
- Centro Básico, Universidad de Aguascalientes, Aguascalientes, Mexico
| | | | | | | | | | - Carmen Toro-Castillo
- Departmento de Electrónica y Computación, CUCEI, Universidad de Guadalajara, Guadalajara, Mexico
| | - Mario Treviño
- Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Mexico
| | - Gerardo Mendizabal-Ruiz
- Departmento de Electrónica y Computación, CUCEI, Universidad de Guadalajara, Guadalajara, Mexico
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Parate D, Kadir ND, Celik C, Lee EH, Hui JHP, Franco-Obregón A, Yang Z. Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration. Stem Cell Res Ther 2020; 11:46. [PMID: 32014064 PMCID: PMC6998094 DOI: 10.1186/s13287-020-1566-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/15/2020] [Accepted: 01/20/2020] [Indexed: 12/17/2022] Open
Abstract
Background The mesenchymal stem cell (MSC) secretome, via the combined actions of its plethora of biologically active factors, is capable of orchestrating the regenerative responses of numerous tissues by both eliciting and amplifying biological responses within recipient cells. MSCs are “environmentally responsive” to local micro-environmental cues and biophysical perturbations, influencing their differentiation as well as secretion of bioactive factors. We have previously shown that exposures of MSCs to pulsed electromagnetic fields (PEMFs) enhanced MSC chondrogenesis. Here, we investigate the influence of PEMF exposure over the paracrine activity of MSCs and its significance to cartilage regeneration. Methods Conditioned medium (CM) was generated from MSCs subjected to either 3D or 2D culturing platforms, with or without PEMF exposure. The paracrine effects of CM over chondrocytes and MSC chondrogenesis, migration and proliferation, as well as the inflammatory status and induced apoptosis in chondrocytes and MSCs was assessed. Results We show that benefits of magnetic field stimulation over MSC-derived chondrogenesis can be partly ascribed to its ability to modulate the MSC secretome. MSCs cultured on either 2D or 3D platforms displayed distinct magnetic sensitivities, whereby MSCs grown in 2D or 3D platforms responded most favorably to PEMF exposure at 2 mT and 3 mT amplitudes, respectively. Ten minutes of PEMF exposure was sufficient to substantially augment the chondrogenic potential of MSC-derived CM generated from either platform. Furthermore, PEMF-induced CM was capable of enhancing the migration of chondrocytes and MSCs as well as mitigating cellular inflammation and apoptosis. Conclusions The findings reported here demonstrate that PEMF stimulation is capable of modulating the paracrine function of MSCs for the enhancement and re-establishment of cartilage regeneration in states of cellular stress. The PEMF-induced modulation of the MSC-derived paracrine function for directed biological responses in recipient cells or tissues has broad clinical and practical ramifications with high translational value across numerous clinical applications. Electronic supplementary material The online version of this article (10.1186/s13287-020-1566-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dinesh Parate
- Department of Surgery, National University of Singapore, Singapore, 119228, Singapore.,Biolonic Currents Electromagnetic Pulsing Systems Laboratory, BICEPS, National University of Singapore, Singapore, Singapore.,Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Nurul Dinah Kadir
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Cenk Celik
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Eng Hin Lee
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore
| | - James H P Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore
| | - Alfredo Franco-Obregón
- Department of Surgery, National University of Singapore, Singapore, 119228, Singapore. .,Biolonic Currents Electromagnetic Pulsing Systems Laboratory, BICEPS, National University of Singapore, Singapore, Singapore. .,Institute for Health Innovation & Technology, iHealthtech, National University of Singapore, Singapore, Singapore.
| | - Zheng Yang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore. .,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore.
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Li S, Wei C, Lv Y. Preparation and Application of Magnetic Responsive Materials in Bone Tissue Engineering. Curr Stem Cell Res Ther 2020; 15:428-440. [PMID: 31893995 DOI: 10.2174/1574888x15666200101122505] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/01/2019] [Accepted: 12/06/2019] [Indexed: 11/22/2022]
Abstract
At present, many kinds of materials are used for bone tissue engineering, such as polymer materials, metals, etc., which in general have good biocompatibility and mechanical properties. However, these materials cannot be controlled artificially after implantation, which may result in poor repair performance. The appearance of the magnetic response material enables the scaffolds to have the corresponding ability to the external magnetic field. Within the magnetic field, the magnetic response material can achieve the targeted release of the drug, improve the performance of the scaffold, and further have a positive impact on bone formation. This paper first reviewed the preparation methods of magnetic responsive materials such as magnetic nanoparticles, magnetic polymers, magnetic bioceramic materials and magnetic alloys in recent years, and then introduced its main applications in the field of bone tissue engineering, including promoting osteogenic differentiation, targets release, bioimaging, cell patterning, etc. Finally, the mechanism of magnetic response materials to promote bone regeneration was introduced. The combination of magnetic field treatment methods will bring significant progress to regenerative medicine and help to improve the treatment of bone defects and promote bone tissue repair.
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Affiliation(s)
- Song Li
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, China
| | - Changling Wei
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, China
| | - Yonggang Lv
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, China
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Wang R, Liu W, Wang Q, Li G, Wan B, Sun Y, Niu X, Chen D, Tian W. Anti-osteosarcoma effect of hydroxyapatite nanoparticles both in vitro and in vivo by downregulating the FAK/PI3K/Akt signaling pathway. Biomater Sci 2020; 8:4426-4437. [DOI: 10.1039/d0bm00898b] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Schematic representing the anti-cancer effects of nano-HAPs both in vitro and in vivo by downregulating the FAK/PI3K/Akt signaling pathway.
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Affiliation(s)
- Renxian Wang
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - WeiFeng Liu
- Depatment of Orthopaedic Oncology Surgery
- Beijing JiShuiTan Hospital
- Peking Universit
- Beijing 100035
- China
| | - Qian Wang
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - Guangping Li
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - Ben Wan
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - Yuyang Sun
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - Xiaohui Niu
- Depatment of Orthopaedic Oncology Surgery
- Beijing JiShuiTan Hospital
- Peking Universit
- Beijing 100035
- China
| | - Dafu Chen
- Laboratory of Bone Tissue Engineering
- Beijing Laboratory of Biomedical Materials
- Beijing Research Institute of Traumatology and Orthopaedics
- Beijing Jishuitan Hospital
- Beijing 100035
| | - Wei Tian
- Department of Spine Surgery
- Beijing JiShuiTan Hospital
- Peking University
- Beijing 100035
- China
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Cruciani S, Garroni G, Ventura C, Danani A, Nečas A, Maioli M. Stem cells and physical energies: can we really drive stem cell fate? Physiol Res 2019; 68:S375-S384. [PMID: 32118467 DOI: 10.33549/physiolres.934388] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Adult stem cells are undifferentiated elements able to self-renew or differentiate to maintain tissue integrity. Within this context, stem cells are able to divide in a symmetric fashion, feature characterising all the somatic cells, or in an asymmetric way, which leads daughter cells to different fates. It is worth highlighting that cell polarity have a critical role in regulating stem cell asymmetric division and the proper control of cell division depends on different proteins involved in cell development, differentiation and maintenance of tissue homeostasis. Moreover, the interaction between cells and the extracellular matrix are crucial in influencing cell behavior, included in terms of mechanical properties as cytoskeleton plasticity and remodelling, and membrane tension. Finally, the activation of specific transcriptional program and epigenetic modifications contributes to cell fate determination, through modulation of cellular signalling cascades. It is well known that physical and mechanical stimuli are able to influence biological systems, and in this context, the effects of electromagnetic fields (EMFs) have already shown a considerable role, even though there is a lack of knowledge and much remains to be done around this topic. In this review, we summarize the historical background of EMFs applications and the main molecular mechanism involved in cellular remodelling, with particular attention to cytoskeleton elasticity and cell polarity, required for driving stem cell behavior.
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Affiliation(s)
- S Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
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Zhang Y, Li W, Liu C, Yan J, Yuan X, Wang W, Wang H, Wu H, Yang Y. Electromagnetic field treatment increases purinergic receptor P2X7 expression and activates its downstream Akt/GSK3β/β-catenin axis in mesenchymal stem cells under osteogenic induction. Stem Cell Res Ther 2019; 10:407. [PMID: 31864409 PMCID: PMC6925409 DOI: 10.1186/s13287-019-1497-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 09/04/2019] [Accepted: 11/15/2019] [Indexed: 02/06/2023] Open
Abstract
Background Imbalance in bone formation and resorption is a crucial component of the pathological process leading to osteoporosis. Electromagnetic fields (EMFs) have been reported to be beneficial to osteogenesis, although the exact mechanism has not been fully clarified. Purinergic receptor P2X7 is expressed in osteoblasts and is reported to participate in the regulation of bone metabolism. Objectives To elucidate the link between EMFs and P2X7 expression and investigate its potential as a novel therapeutic target in osteoporosis. Method We investigated the effect of EMFs on P2X7 expression and downstream signaling in human bone marrow mesenchymal stem cells (h-MSCs). We also established an ovariectomized (OVX) osteoporosis rat model to evaluate the therapeutic efficacy of combining EMFs with P2X7 agonists. Results EMF treatment increased P2X7 expression in h-MSCs under conditions of osteogenic induction but not under regular culture conditions. P2X7 or PI3K/Akt inhibition partially inhibited the pro-osteogenic effect of EMF and lowered the EMF-stimulated activity of the Akt/GSK3β/β-catenin axis. No additive effect of this suppression was observed following simultaneous inhibition of P2X7 and PI3K/Akt. EMF treatment in the presence of a P2X7 agonist had a greater effect in increasing osteogenic marker expression than that of EMF treatment alone. In the OVX osteoporosis model, the therapeutic efficacy of combining EMFs with P2X7 agonists was superior to that of EMF treatment alone. Conclusions EMF treatment increases P2X7 expression by h-MSCs during osteogenic differentiation, leading to activation of the Akt/GSK3β/β-catenin axis, which promotes the osteogenesis. Our findings also indicate that combined EMF and P2X7 agonist treatment may be an effective novel strategy for osteoporosis therapy.
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Affiliation(s)
- Yingchi Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Wenkai Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Chaoxu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jiyuan Yan
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xuefeng Yuan
- Department of Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Wei Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Huaixi Wang
- Department of Spine and Spinal Cord Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, 7 Weiwu Road, Zhengzhou, 450003, China
| | - Hua Wu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Yong Yang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
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Sinulariolide Inhibits Gastric Cancer Cell Migration and Invasion through Downregulation of the EMT Process and Suppression of FAK/PI3K/AKT/mTOR and MAPKs Signaling Pathways. Mar Drugs 2019; 17:md17120668. [PMID: 31783709 PMCID: PMC6950622 DOI: 10.3390/md17120668] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/21/2019] [Accepted: 11/26/2019] [Indexed: 12/19/2022] Open
Abstract
Cancer metastasis is the main cause of death in cancer patients; however, there is currently no effective method to predict and prevent metastasis of gastric cancer. Therefore, gaining an understanding of the molecular mechanism of tumor metastasis is important for the development of new drugs and improving the survival rate of patients who suffer from gastric cancer. Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. We employed sinulariolide and gastric cancer cells in experiments such as MTT, cell migration assays, cell invasion assays, and Western blotting analysis. Analysis of cell migration and invasion capabilities showed that the inhibition effects on cell metastasis and invasion increased with sinulariolide concentration in AGS and NCI-N87 cells. Immunostaining analysis showed that sinulariolide significantly reduced the protein expressions of MMP-2, MMP-9, and uPA, but the expressions of TIMP-1 and TIMP-2 were increased, while FAK, phosphorylated PI3K, phosphorylated AKT, phosphorylated mTOR, phosphorylated JNK, phosphorylated p38MAPK, and phosphorylated ERK decreased in expression with increasing sinulariolide concentration. From the results, we inferred that sinulariolide treatment in AGS and NCI-N87 cells reduced the activities of MMP-2 and MMP-9 via the FAK/PI3K/AKT/mTOR and MAPKs signaling pathways, further inhibiting the invasion and migration of these cells. Moreover, sinulariolide altered the protein expressions of E-cadherin and N-cadherin in the cytosol and Snail in the nuclei of AGS and NCI-N87 cells, which indicated that sinulariolide can avert the EMT process. These findings suggested that sinulariolide is a potential chemotherapeutic agent for development as a new drug for the treatment of gastric cancer.
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