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Wu L, He J, Shen N, Chen S. Molecular and cellular mechanisms underlying peripheral nerve injury-induced cellular ecological shifts: Implications for neuroregeneration. IBRO Neurosci Rep 2025; 18:120-129. [PMID: 39877591 PMCID: PMC11773043 DOI: 10.1016/j.ibneur.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
The peripheral nervous system is a complex ecological network, and its injury triggers a series of fine-grained intercellular regulations that play a crucial role in the repair process. The peripheral nervous system is a sophisticated ecological network, and its injury initiates a cascade of intricate intercellular regulatory processes that are instrumental in the repair process. Despite the advent of sophisticated microsurgical techniques, the repair of peripheral nerve injuries frequently proves inadequate, resulting in adverse effects on patients' quality of life. Accordingly, the continued pursuit of more efficacious treatments is of paramount importance. In this paper, a review of the relevant literature from recent years was conducted to identify the key cell types involved after peripheral nerve injury. These included Schwann cells, macrophages, neutrophils, endothelial cells, and fibroblasts. The review was conducted in depth. This paper analyses the phenotypic changes of these cells after injury, the relevant factors affecting these changes, and how they coordinate with neurons and other cell types. In addition, it explores the potential mechanisms that mediate the behaviour of these cells. Understanding the interactions between these cells and their mutual regulation with neurons is of great significance for the discovery of new neuroregenerative treatments and the identification of potential therapeutic targets.
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Affiliation(s)
- Limao Wu
- School of Clinical Medicine, Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 056004, China
| | - Jinglan He
- Affiliated Hospital of Hebei University of Engineering, No. 80, Jianshe Street, Fuxing District, Handan City, Hebei Province 056003, China
| | - Na Shen
- Department of Science and Education, Affiliated Hospital of Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 056004, China
| | - Song Chen
- Orthopaedic Center, Affiliated Hospital of Hebei University of Engineering, No.81 Congtai Road, Congtai District, Handan City, Hebei Province 56004, China
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Yalçın G, Kaya BB, Ata E, Demirtaş C, Beyaztas H, Ay G, Zerk PE, Guler EM. Melatonin and Methylprednisolone Combination Ameliorates Inflammation and Enhances Recovery After Sciatic Nerve Crush Injury. Eur J Neurosci 2025; 61:e70116. [PMID: 40275820 DOI: 10.1111/ejn.70116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025]
Abstract
This sham-controlled animal study aimed to investigate the effects of melatonin and methylprednisolone combination on motor function, nerve conduction and histopathological and biochemical findings in rats with sciatic nerve crush injury. Forty-eight male Sprague-Dawley rats were divided into 6 groups (n = 8): CT: control, VEH: sciatic nerve injury, LMP: 15-mg/kg methylprednisolone, high-dose methylprednisolone (HMP): 30-mg/kg methylprednisolone, MEL: 15-mg/kg melatonin, MMP: 15-mg/kg methylprednisolone+15-mg/kg melatonin. The rats were evaluated with Sciatic Functional Index (SFI), nerve conduction study, interleukin-1β (IL-1ß), nerve growth factor (NGF), total antioxidant status (TAS), total oxidant status (TOS) and histopathological scores. There were no significant intergroup differences in baseline tests. SFI significantly improved in all treated groups with no significant intergroup differences. Motor amplitude improved most in MMP, LMP and MEL, respectively. Nerve conduction velocity significantly improved in MMP compared to VEH. There were no significant intergroup differences regarding serum NGF, TAS and TOS. Tissue NGF levels were higher in LMP, HMP and MEL. IL-1ß levels were significantly lower in CT and MMP. Tissue oxidative stress levels were significantly lower in treated groups compared to VEH, with no significant difference among them. MMP showed greater histopathological improvement. Melatonin combination therapy in sciatic nerve crush injury provided adequate functional improvement, superior electrophysiological and histopathological recovery compared to high-dose methylprednisolone and exhibited better anti-inflammatory activity through IL-1ß.
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Affiliation(s)
- Gökçenur Yalçın
- Department of Physical Medicine and Rehabilitation, Marmara University Training and Research Hospital, Istanbul, Turkiye
| | - Başak Bilir Kaya
- Ministry of Health Erenköy Physical Medicine and Rehabilitation Hospital, Istanbul, Turkiye
- University of Health Sciences, Istanbul, Turkiye
- Department of Physical Medicine and Rehabilitation, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkiye
| | - Emre Ata
- Department of Physical Medicine and Rehabilitation, Sultan 2. Abdulhamid Han Training and Research Hospital, Istanbul, Turkiye
- Department of Physical Medicine and Rehabilitation, University of Health Sciences, Istanbul, Turkiye
| | - Cumaali Demirtaş
- University of Health Sciences, Istanbul, Turkiye
- Hamidiye Institute of Health Sciences, Istanbul, Turkiye
| | - Hakan Beyaztas
- Department of Medical Biochemistry, Hamidiye Institute of Health Sciences, University of Health Sciences Turkiye, Istanbul, Turkiye
- Department of Medical Biochemistry, Hamidiye Faculty of Medicine, University of Health Sciences Turkiye, Istanbul, Turkiye
| | - Gülnihal Ay
- Department of Medical Pathology, Goztepe Suleyman Yalcin City Hospital, Istanbul, Turkiye
| | - Pınar Engin Zerk
- Department of Medical Pathology, Goztepe Suleyman Yalcin City Hospital, Istanbul, Turkiye
| | - Eray Metin Guler
- Department of Medical Biochemistry, Hamidiye Faculty of Medicine, University of Health Sciences Turkiye, Istanbul, Turkiye
- Department of Medical Biochemistry, Haydarpaşa Numune Health Application and Research Center, University of Health Sciences Turkiye, Istanbul, Turkiye
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Tan X, Zhang Z, Cao X, Qu L, Xiong Y, Li H, Wang Y, Chen Z, Shi C. Reprogramming of skin fibroblasts by 3D spheroid culture promotes peripheral nerve regeneration via the ID3/semaphorin7a pathway. Stem Cells Transl Med 2025; 14:szaf005. [PMID: 40213860 PMCID: PMC11986420 DOI: 10.1093/stcltm/szaf005] [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: 10/07/2024] [Accepted: 01/31/2025] [Indexed: 04/14/2025] Open
Abstract
Peripheral nerve injury remains an intractable clinical issue with high morbidity, causing an excessive burden on the economy and society. Peripheral nerve tissue engineering combined with nerve conduits and supporting seed cells is considered a promising strategy for treating of long nerve defects. However, supporting seed cell sources that are easily accessible, capable of rapid expansion, and do not require genetic intervention are still urgently needed. This study intended to clarify whether the easily accessible and rapid expansion skin fibroblasts are the ideal supporting seed cells and can be reprogrammed into neural progenitor-like cells (NPCs) by forcing them to grow into a three-dimensional (3D) spheroid morphology. Results showed that 3D spheroid mouse dermal fibroblasts (MDFs) exhibited neural cell-like properties and could efficiently induce dorsal root ganglion neurons to extend the neurites. Transplantation of 3D spheroid MDFs significantly accelerated the regeneration of the sciatic nerve and improved the motor function of rats after transection compared to monolayer MDFs. Mechanism studies revealed that 3D spheroid culture significantly upregulated the expressions of the inhibitor of DNA binding 3 (ID3) and the hypoxia-inducible factor-1α (HIF-1α). The upregulation of the inhibitor of DNA binding 3 in 3D spheroid MDFs plays a critical role in acquiring NPC properties. Meanwhile, the upregulated ID3 and HIF-1α could synergistically upregulate semaphorin7a expression, which finally improved the extending of nerve axon in vitro and in vivo. This study may shed new light on treatments for peripheral nerve injury.
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Affiliation(s)
- Xu Tan
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Zhou Zhang
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guizhou 550004, People’s Republic of China
| | - Xiaohui Cao
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Langfan Qu
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Yinchun Xiong
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Huijuan Li
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Yu Wang
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Zelin Chen
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Chunmeng Shi
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, College of Preventive Medicine, Army Medical University, Chongqing 400038, People’s Republic of China
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Han Y, Liu Z, Song C. Fenugreek seed extract combined with acellular nerve allografts promotes peripheral nerve regeneration and neovascularization in sciatic nerve defects. Regen Ther 2025; 28:383-393. [PMID: 39896442 PMCID: PMC11787413 DOI: 10.1016/j.reth.2024.12.015] [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: 07/10/2024] [Revised: 12/02/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025] Open
Abstract
Background Acellular nerve allografts (ANAs) have been confirmed to improve the repair and reconstruction of long peripheral nerve defects. However, its efficacy is not comparable to that of autologous nerve grafts, which are used as the gold standard for treating peripheral nerve defects. Our study investigated whether fenugreek seed extract (FSE) exhibits neuroprotective potential and enhances the therapeutic outcomes of ANA repair in peripheral nerve defects. Methods Rat Schwann cells were treated with FSE to assess the effects of FSE on cell proliferation and their secretion function of neurotrophic factors in vitro. Sprague-Dawley rats with a unilateral 15-mm sciatic nerve defect were randomized into the ANA group (the 15-mm defect was replaced by an 18-mm ANA), the ANA + FSE group (the 15-mm defect was repaired with an 18-mm ANA with FSE administration for four weeks), and the Auto group (the 15-mm defect was repaired with an autologous graft). After four weeks post-surgery, various behavioral tests and electrophysiological assays were performed to evaluate the motor and sensory behavior as well as nerve conduction of rats. Then, rats were sacrificed, and the nerve grafts were collected for toluidine blue staining, RT-qPCR, immunofluorescence staining, immunohistochemical staining to evaluate nerve regeneration, neovascularization, and neuroinflammation. Their gastrocnemius was harvested for Masson's trichrome staining to examine gastrocnemius muscle recovery. Results FSE treatment promoted Schwann cell proliferation and its secretion of neurotrophic factors in vitro. Compared with ANAs alone, FSE treatment combined with ANAs enhanced axonal regeneration, upregulated S100, NF200, P0, MBP, and GAP43 expression, facilitated angiogenesis, and elevated neurotrophic factor expression in regenerating nerves of rats with sciatic nerve defects. In addition, FSE treatment promoted gastrocnemius muscle recovery, stimulated motor and sensory functional recovery and nerve conduction, and mitigated neuroinflammation in rats with sciatic nerve defects after repair with ANAs. Conclusion FSE treatment improves the beneficial effects of ANA repair on sciatic nerve defects.
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Affiliation(s)
- Yuanyuan Han
- Department of Neurology, Suqian First Hospital, Suzhi Road 120, Suqian, 223800 Jiangsu Province, China
| | - Zhiwei Liu
- Department of Neurology, Suqian First Hospital, Suzhi Road 120, Suqian, 223800 Jiangsu Province, China
| | - Chunjie Song
- Department of Neurology, Suqian First Hospital, Suzhi Road 120, Suqian, 223800 Jiangsu Province, China
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de Oliveira Ferreira LV, Maia L, de Andrade DGA, da Costa Kamura B, de Carvalho M, Amorim RM. Therapeutic potential of mesenchymal stem cells transplantation on traumatic facial nerve paralysis in two horses. Vet Res Commun 2025; 49:118. [PMID: 39998709 DOI: 10.1007/s11259-025-10692-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Cell-based therapy has emerged as a promising strategy for treating peripheral nervous system (PNS) injuries across different species. However, there is a scarcity in the literature regarding the transplantation of mesenchymal stem cells (MSCs) for treating PNS injuries in horses. This report aims to describe the therapeutic potential of equine MSC transplantation in two horses with chronic traumatic facial nerve paralysis. Both horses presented with lip ptosis and right deviation of the nostril and upper lip, being clinically diagnosed with left facial nerve paralysis. Due to the refractoriness to conventional anti-inflammatory treatments, cell-based therapy was chosen. One horse received an autologous transplant of equine bone marrow-derived MSCs (EqBM-MSCs) four months after the traumatic event, while the other underwent three transplants of allogeneic equine adipose tissue-derived MSCs (EqAT-MSCs) at 30-day intervals, starting two months after the injury. All transplants were performed at three different sites around the facial nerve, at the level of bifurcation of the buccal branch in both horses. Physical and neurological assessments revealed significant clinical recovery within three months for the first horse and four months for the second. These findings demonstrated that equine MSCs transplants have great therapeutic potential for chronic traumatic facial nerve paralysis in horses, highlighting the relevance of MSCs- based therapy for peripheral nerve injuries.
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Affiliation(s)
| | - Leandro Maia
- School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Danilo Giorgi Abranches de Andrade
- School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Beatriz da Costa Kamura
- School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Márcio de Carvalho
- School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Rogério Martins Amorim
- School of Veterinary Medicine and Animal Science, Department of Veterinary Clinic, São Paulo State University, Botucatu, São Paulo, Brazil.
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Zhang L, Xie J, Dai W, Lu B, Yi S. Schwann cells in regeneration and cancer. Front Pharmacol 2025; 16:1506552. [PMID: 39981185 PMCID: PMC11840318 DOI: 10.3389/fphar.2025.1506552] [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: 10/05/2024] [Accepted: 01/09/2025] [Indexed: 02/22/2025] Open
Abstract
Schwann cells are specific peripheral glial cells with remarkable plasticity following peripheral nerve injury. Injury responses stimulate c-Jun activation in Schwann cells, drive epithelial-mesenchymal transition and cellular phenotypic changes, and induce the generation of reprogrammed repair Schwann cells to orchestrate peripheral nerve regeneration process. Schwann cells and/or Schwann cell-derived molecules are commonly used as supporting cells and/or neurotrophic factors to construct Schwann cell-based tissue-engineered nerve grafts for repairing severe peripheral nerve injury with long defects. Transplantation of Schwann cells and/or Schwann cell-derived molecules also serves as a helpful approach for the treatment of other injured tissues, such as the spinal cord, skin, digit tip, and bone. Schwann cells are not only associated with tissue regeneration but also involved in tumorigenesis and tumor progression. Schwann cells are the major cellular component of neurofibromatosis type 1 and the sole cell type in neurofibromatosis type 2 and schwannomatosis. In addition, Schwann cells also function as an important player in the tumor microenvironment and aid in the growth and invasiveness of many other solid cancers. In the present review, we outline the physiological and pathological activities of Schwann cells and discuss the functional roles of Schwann cells in homeostasis, regeneration, and cancer.
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Affiliation(s)
- Lan Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Jiale Xie
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Wenyu Dai
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Bing Lu
- Department of Clinical Biobank and Institute of Oncology, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, China
| | - Sheng Yi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
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7
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Sharifi M, Salehi M, Ebrahimi-Barough S, Alizadeh M, Jahromi HK, Kamalabadi-Farahani M. Synergic effects of core-shell nanospheres and magnetic field for sciatic nerve regeneration in decellularized artery conduits with Schwann cells. J Nanobiotechnology 2024; 22:776. [PMID: 39696412 DOI: 10.1186/s12951-024-03048-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/29/2024] [Indexed: 12/20/2024] Open
Abstract
Numerous conduits have been developed to improve peripheral nerve regeneration. However, challenges remain, including remote control of conduit function, and programmed cell behaviors like orientation. We synthesized Fe3O4-MnO2@Zirconium-based Metal-organic frameworks@Retinoic acid (FMZMR) core-shell and assessed their impact on Schwann cell function and behavior within conduits made from decellularized human umbilical arteries (DHUCA) under magnetic field (MF). FMZMR core-shell, featuring a spherical porous structure and catalytic properties, effectively scavenges radicals and facilitates controlled drug release under MF. The histology of the DHUCA indicates effective decellularization with adequate tensile strength and Young's modulus for sciatic nerve regeneration. In-vitro results demonstrate that FMZMR core-shell is biocompatible and promotes Schwann cell proliferation through remotely controlled drug release. Furthermore, its synergy with MF enhances cell orientation and increases neurite length by ~ 1.93-fold. Functional and histological evaluations indicate that the FMZMR core-shell combined with MF promotes nerve regeneration, decreases muscle atrophy, and enhances new neuron growth and myelin formation, without negatively affecting vital tissues. This study suggests that the synergistic effect of FMZMR core-shell with MF can alleviate some of the treatment challenges.
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Affiliation(s)
- Majid Sharifi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Salehi
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Mohammad Kamalabadi-Farahani
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
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8
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Sousa P, Lopes B, Sousa AC, Coelho A, de Sousa Moreira A, Rêma A, Gonçalves-Maia M, Amorim I, Alvites R, Alves N, Geuna S, Maurício AC. Isolation, Expansion, and Characterization of Rat Hair Follicle Stem Cells and Their Secretome: Insights into Wound Healing Potential. Biomedicines 2024; 12:2854. [PMID: 39767760 PMCID: PMC11672956 DOI: 10.3390/biomedicines12122854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/23/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Stem cells are capable of self-renewal and differentiation into various specialized cells, making them a potential therapeutic option in regenerative medicine. This study establishes a comprehensive methodology for isolating, culturing, and characterizing rat hair follicle stem cells. Methods and Results: Hair follicles were harvested from Sprague-Dawley rats and subjected to two different isolation techniques. Immunohistochemical analysis and real-time PCR confirm the expression of specific surface markers and genes, validating the cells' identity. Growth kinetics, colony formation units (CFU), and tri-differentiation capacity were also assessed. Additionally, the cells' secretome was analyzed, regarding its content in biofactors with wound healing properties. Conclusions: These findings highlight the potential of these cells as a valuable cell source for skin regeneration applications. They contribute to advancing our understanding of stem cell applications in regenerative medicine and hold promise for therapeutic interventions in various clinical contexts, aligning with broader research on the diverse capabilities of hair follicle stem cells.
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Affiliation(s)
- Patrícia Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Bruna Lopes
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Ana Catarina Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - André Coelho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Alícia de Sousa Moreira
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Alexandra Rêma
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Maria Gonçalves-Maia
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Maia & Muller-Biotech, Rua Alfredo Allen, 455/461, 4200-135 Porto, Portugal
| | - Irina Amorim
- Departamento de Patologia e Imunologia Molecular, ICBAS—School of Medicine and Biomedical Sciences, University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal;
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Rui Alvites
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Instituto Universitário de Ciências da Saúde (CESPU), Avenida Central de Gandra 1317, 4585-116 Paredes, Portugal
| | - Nuno Alves
- Centre for Rapid and Sustainable Product Development, Polytechnic of Leiria, 2430-028 Marinha Grande, Portugal;
| | - Stefano Geuna
- Department of Clinical and Biological Sciences, Cavalieri Ottolenghi Neuroscience Institute, University of Turin, Ospedale San Luigi, 10043 Turin, Italy;
| | - Ana Colette Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
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Wynne TM, Fritz VG, Simmons ZT, Zahed M, Seth A, Abbasi T, Reymundi MJ, Roballo KCS. Potential of Stem-Cell-Induced Peripheral Nerve Regeneration: From Animal Models to Clinical Trials. Life (Basel) 2024; 14:1536. [PMID: 39768245 PMCID: PMC11679741 DOI: 10.3390/life14121536] [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: 09/25/2024] [Revised: 11/11/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025] Open
Abstract
Peripheral nerve injury has become an increasingly prevalent clinical concern, causing great morbidity in the community. Although there have been significant advancements in the treatment of peripheral nerve damage in recent years, the issue of long-term nerve regeneration remains. Furthermore, Wallerian degeneration has created an obstacle to long-term nerve regeneration. For this reason, there has been extensive research on the use of exogenous and endogenous stem cells as an adjunct or even primary treatment option for peripheral nerve injury. The plasticity and inducibility of stem cells make them an enticing option for initiating neuronal cell regrowth and optimal sensory and functional nerve regeneration. Peripheral nerve injury has a broad range of causative factors and etiologies. As such, unique stem cell-induced peripheral nerve treatments are being investigated to ameliorate the damage incited by all causes, including trauma, neuropathy, and systemic neurodegenerative diseases. This review is oriented to outline the potential role of stem cell therapies in peripheral nerve injury versus the current standards of care, compare the benefits and drawbacks of specific stem cell lines under investigation, and highlight the current models of stem cell therapy in the peripheral nervous system, with the ultimate goal of narrowing down and optimizing the role and scope of stem cell therapy in peripheral nerve injury.
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Affiliation(s)
- Taylor M. Wynne
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Virginia Grey Fritz
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Zachary T. Simmons
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Malek Zahed
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Ananya Seth
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Tamir Abbasi
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Michael J. Reymundi
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
| | - Kelly C. S. Roballo
- Department of Biomedical, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA; (T.M.W.); (V.G.F.); (Z.T.S.); (M.Z.); (A.S.); (T.A.); (M.J.R.)
- Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA
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10
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Zhou Q, Lei Y. ARMCX3 regulates ROS signaling, affects neural differentiation and inflammatory microenvironment in dental pulp stem cells. Heliyon 2024; 10:e37079. [PMID: 39296219 PMCID: PMC11407977 DOI: 10.1016/j.heliyon.2024.e37079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Background The neural differentiation of dental pulp stem cells (DPSCs) exhibits great potential in the treatment of dental pulp repair and neurodegenerative diseases. However, the precise molecular mechanisms underlying this process remain unclear. This study was designed to reveal the roles and regulatory mechanisms of the armadillo repeat-containing X-linked 3 (ARMCX3) in neural differentiation and inflammatory microenvironment in human DPSCs (hDPSCs). Methods We treated hDPSCs with porphyromonas gingivalis lipopolysaccharide (Pg-LPS) to simulate the inflammatory microenvironment. Then the lentiviral vectors were introduced to construct stable cell lines with ARMCX3 knockdown or overexpression. The expression of neural-specific markers, ARMCX3 and inflammation factors were estimated by immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) assays. Additionally, we used IF assays and specific kits to investigate the regulatory role of ARMCX3 on reactive oxygen species (ROS) signaling. Moreover, a ROS inhibitor was utilized to verify whether ROS inhibition reversed the effects of ARMCX3 in Pg-LPS-treated hDPSCs. Results This work illustrated that Pg-LPS treatment significantly enhanced ARMCX3 expression and inflammatory response, and inhibited neural differentiation in hDPSCs. ARMCX3 knockdown effectively accelerated neural differentiation and controlled inflammatory cytokines at a lower level in hDPSCs in the presence of Pg-LPS. Additionally, knockdown of ARMCX3 notably reduced ROS production and ROS inhibition effectively eliminated the roles of ARMCX3 overexpression in hDPSCs. Besides, all results were proved to be statistically significant. Conclusion This investigation proved that ARMCX3 affected neural differentiation and inflammation microenvironment in hDPSCs at least partly by mediating ROS signal. These findings provided a new perspective on the mechanism of neural differentiation of hDPSCs and help to better explore the therapeutic schedule of pulpitis and neurodegenerative diseases.
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Affiliation(s)
- Quanying Zhou
- Department of Stomatology, Wuhan Ninth Hospital, Wuhan, Hubei, 430080, China
| | - Yi Lei
- Department of Stomatology, Wuhan Ninth Hospital, Wuhan, Hubei, 430080, China
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11
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Zou XF, Zhang BZ, Qian WW, Cheng FM. Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury. World J Stem Cells 2024; 16:799-810. [PMID: 39219723 PMCID: PMC11362854 DOI: 10.4252/wjsc.v16.i8.799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.
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Affiliation(s)
- Xiong-Fei Zou
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Bao-Zhong Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
| | - Wen-Wei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Florence Mei Cheng
- College of Nursing, The Ohio State University, Ohio, OH 43210, United States
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12
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Aisaiti A, Aierxiding S, Shoukeer K, Muheremu A. Mesenchymal stem cells for peripheral nerve injury and regeneration: a bibliometric and visualization study. Front Neurol 2024; 15:1420402. [PMID: 39161869 PMCID: PMC11330774 DOI: 10.3389/fneur.2024.1420402] [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: 04/20/2024] [Accepted: 06/10/2024] [Indexed: 08/21/2024] Open
Abstract
Objective To use bibliometric methods to analyze the research hotspots and future development trends regarding the application of mesenchymal stem cells in peripheral nerve injury and regeneration. Methods Articles published from January 1, 2013, to December 31, 2023, were meticulously screened using the MeSH terms: TS = ("Mesenchymal stem cells" AND "Peripheral nerve injury") OR TS = ("Mesenchymal stem cells" AND "Peripheral nerve regeneration") within the Web of Science database. The compiled data was then subjected to in-depth analysis with the aid of VOSviewer and Cite Space software, which facilitated the identification of the most productive countries, organizations, authors, and the predominant keywords prevalent within this research domain. Results An extensive search of the Web of Science database yielded 350 relevant publications. These scholarly works were authored by 2,049 collaborative researchers representing 41 countries and affiliated with 585 diverse academic and research institutions. The findings from this research were disseminated across 167 various journals, and the publications collectively cited 21,064 references from 3,339 distinct journals. Conclusion Over the past decade, there has been a consistent upward trajectory in the number of publications and citations pertaining to the use of mesenchymal stem cells in the realm of peripheral nerve injury and regeneration. The domain of stem cell therapy for nerve injury has emerged as a prime focus of research, with mesenchymal stem cell therapy taking center stage due to its considerable promise in the treatment of nerve injuries. This therapeutic approach holds the potential to significantly enhance treatment options and rehabilitation prospects for patients suffering from such injuries.
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Affiliation(s)
- Aikebaierjiang Aisaiti
- Key Laboratory of Orthopedic Regenerative Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China
| | - Shalayiding Aierxiding
- Key Laboratory of Orthopedic Regenerative Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China
| | - Kutiluke Shoukeer
- Key Laboratory of Orthopedic Regenerative Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China
| | - Aikeremujiang Muheremu
- Key Laboratory of Orthopedic Regenerative Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China
- Beijing Darwin Cell Biotechnology Co., Ltd., Beijing, China
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13
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Soltani Khaboushan A, Azimzadeh A, Behboodi Tanourlouee S, Mamdoohi M, Kajbafzadeh AM, Slavin KV, Rahimi-Movaghar V, Hassannejad Z. Electrical stimulation enhances sciatic nerve regeneration using a silk-based conductive scaffold beyond traditional nerve guide conduits. Sci Rep 2024; 14:15196. [PMID: 38956215 PMCID: PMC11219763 DOI: 10.1038/s41598-024-65286-9] [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: 04/03/2024] [Accepted: 06/18/2024] [Indexed: 07/04/2024] Open
Abstract
Despite recent advancements in peripheral nerve regeneration, the creation of nerve conduits with chemical and physical cues to enhance glial cell function and support axonal growth remains challenging. This study aimed to assess the impact of electrical stimulation (ES) using a conductive nerve conduit on sciatic nerve regeneration in a rat model with transection injury. The study involved the fabrication of conductive nerve conduits using silk fibroin and Au nanoparticles (AuNPs). Collagen hydrogel loaded with green fluorescent protein (GFP)-positive adipose-derived mesenchymal stem cells (ADSCs) served as the filling for the conduit. Both conductive and non-conductive conduits were applied with and without ES in rat models. Locomotor recovery was assessed using walking track analysis. Histological evaluations were performed using H&E, luxol fast blue staining and immunohistochemistry. Moreover, TEM analysis was conducted to distinguish various ultrastructural aspects of sciatic tissue. In the ES + conductive conduit group, higher S100 (p < 0.0001) and neurofilament (p < 0.001) expression was seen after 6 weeks. Ultrastructural evaluations showed that conductive scaffolds with ES minimized Wallerian degeneration. Furthermore, the conductive conduit with ES group demonstrated significantly increased myelin sheet thickness and decreased G. ratio compared to the autograft. Immunofluorescent images confirmed the presence of GFP-positive ADSCs by the 6th week. Locomotor recovery assessments revealed improved function in the conductive conduit with ES group compared to the control group and groups without ES. These results show that a Silk/AuNPs conduit filled with ADSC-seeded collagen hydrogel can function as a nerve conduit, aiding in the restoration of substantial gaps in the sciatic nerve with ES. Histological and locomotor evaluations indicated that ES had a greater impact on functional recovery compared to using a conductive conduit alone, although the use of conductive conduits did enhance the effects of ES.
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Affiliation(s)
- Alireza Soltani Khaboushan
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, Keshavarz Boulevard, Tehran, 1419733151, Iran
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ashkan Azimzadeh
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, Keshavarz Boulevard, Tehran, 1419733151, Iran
| | - Saman Behboodi Tanourlouee
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, Keshavarz Boulevard, Tehran, 1419733151, Iran
| | - Melina Mamdoohi
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Abdol-Mohammad Kajbafzadeh
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, Keshavarz Boulevard, Tehran, 1419733151, Iran
| | - Konstantin V Slavin
- Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL, USA
| | - Vafa Rahimi-Movaghar
- Sina Trauma and Surgery Research Center, Sina Hospital, Tehran University of Medical Sciences, Hassan-Abad Square, Imam Khomeini Ave., Tehran, 11365-3876, Iran.
| | - Zahra Hassannejad
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, No. 62, Dr. Gharib's Street, Keshavarz Boulevard, Tehran, 1419733151, Iran.
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14
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Shoukeer K, Aierxiding S, Aisaiti A, Haibier A, Liu C, Jia Z, Aili A, Shu L, Jiang K, Muheremu A. The role of microRNAs in axon regeneration after peripheral nerve injury: a bibliometric analysis. Front Neurol 2024; 15:1348048. [PMID: 38510377 PMCID: PMC10953685 DOI: 10.3389/fneur.2024.1348048] [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: 12/01/2023] [Accepted: 02/12/2024] [Indexed: 03/22/2024] Open
Abstract
Objective This study analyzed the current research hotspots and future development trends of the therapeutic effects of microRNA on PNI axonal regeneration through bibliometric methods. Moreover, the current advantages and disadvantages of this field as well as future development prospects are discussed in depth. Methods CiteSpace V and VOSviewer were used as bibliometric tools to complete the analysis of the research focus and direction of the published articles. To supplement, sort out, and summarize, we analyzed the research status of the study on the application of microRNAs for axonal regeneration after peripheral nerve injury from 2013 to 2023. Results A total of 207 publications were retrieved from the Web of Science database. After exclusion and screening, a final selection of 174 articles that met the research criteria. These 174 articles were authored by a total of 846 individuals, representing 24 countries and 199 institutions. Additionally, this study presents information on the annual publication output, country distribution, top 5 contributing authors, top 5 most cited articles, and top 10 contributing institutions. Conclusion As one of the hottest topics today, microRNAs have become the current research hotspot in neural inflammation, neural cell repair and regeneration, neural protection, and functional recovery. With more investment in research in this field, more high-quality articles will be published in both domestic and international outstanding journals, which will bring a new era for the treatment of peripheral nerve injury.
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Affiliation(s)
- Kutiluke Shoukeer
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
- Research Department of Beijing Darwin Cell Biotechnology Co., Ltd, Beijing, China
| | - Shalayiding Aierxiding
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Aikebaierjiang Aisaiti
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Abuduwupuer Haibier
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Chunhua Liu
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Zhiwei Jia
- Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Abudunaibi Aili
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Li Shu
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Kan Jiang
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Aikeremujiang Muheremu
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
- Research Department of Beijing Darwin Cell Biotechnology Co., Ltd, Beijing, China
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15
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Kong J, Teng C, Liu F, Wang X, Zhou Y, Zong Y, Wan Z, Qin J, Yu B, Mi D, Wang Y. Enhancing regeneration and repair of long-distance peripheral nerve defect injuries with continuous microcurrent electrical nerve stimulation. Front Neurosci 2024; 18:1361590. [PMID: 38406586 PMCID: PMC10885699 DOI: 10.3389/fnins.2024.1361590] [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: 12/26/2023] [Accepted: 01/29/2024] [Indexed: 02/27/2024] Open
Abstract
Introduction Peripheral nerve injuries, especially those involving long-distance deficits, pose significant challenges in clinical repair. This study explores the potential of continuous microcurrent electrical nerve stimulation (cMENS) as an adjunctive strategy to promote regeneration and repair in such cases. Methods The study initially optimized cMENS parameters and assessed its impact on Schwann cell activity, neurotrophic factor secretion, and the nerve regeneration microenvironment. Subsequently, a rat sciatic nerve defect-bridge repair model was employed to evaluate the reparative effects of cMENS as an adjuvant treatment. Functional recovery was assessed through gait analysis, motor function tests, and nerve conduction assessments. Additionally, nerve regeneration and denervated muscle atrophy were observed through histological examination. Results The study identified a 10-day regimen of 100uA microcurrent stimulation as optimal. Evaluation focused on Schwann cell activity and the microenvironment, revealing the positive impact of cMENS on maintaining denervated Schwann cell proliferation and enhancing neurotrophic factor secretion. In the rat model of sciatic nerve defect-bridge repair, cMENS demonstrated superior effects compared to control groups, promoting motor function recovery, nerve conduction, and sensory and motor neuron regeneration. Histological examinations revealed enhanced maturation of regenerated nerve fibers and reduced denervated muscle atrophy. Discussion While cMENS shows promise as an adjuvant treatment for long-distance nerve defects, future research should explore extended stimulation durations and potential synergies with tissue engineering grafts to improve outcomes. This study contributes comprehensive evidence supporting the efficacy of cMENS in enhancing peripheral nerve regeneration.
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Affiliation(s)
- Junjie Kong
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Cheng Teng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Fenglan Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xuzhaoyu Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yi Zhou
- Department of Orthopedics, Nantong City Hospital of Traditional Chinese Medicine, Nantong, China
| | - Ying Zong
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Zixin Wan
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jun Qin
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Bin Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Daguo Mi
- Department of Orthopedics, Nantong City Hospital of Traditional Chinese Medicine, Nantong, China
| | - Yaxian Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Hospital and Medical School, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
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Mehrotra P, Jablonski J, Toftegard J, Zhang Y, Shahini S, Wang J, Hung CW, Ellis R, Kayal G, Rajabian N, Liu S, Roballo K, Udin SB, Andreadis ST, Personius KE. Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury. RESEARCH SQUARE 2024:rs.3.rs-3463557. [PMID: 38260278 PMCID: PMC10802751 DOI: 10.21203/rs.3.rs-3463557/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. The onset of PNI is characterized by nerve degeneration distal to the nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generated a mouse model in which NANOG, a pluripotency-associated transcription factor can be expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulated the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression led to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation, and downregulation of key muscle atrophy genes. Further, NANOG mice demonstrated extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice showed greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming the muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.
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Affiliation(s)
- Pihu Mehrotra
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
| | - James Jablonski
- Department of Department of Rehabilitation Science, University at Buffalo, Buffalo, NY 14214, USA
| | - John Toftegard
- Department of Biomedical Engineering, University at Buffalo, NY, Buffalo, NY 14260, USA
| | - Yali Zhang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Shahryar Shahini
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
| | - Jianmin Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Carey W Hung
- Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA
| | - Reilly Ellis
- Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA
| | - Gabriella Kayal
- Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA
| | - Nika Rajabian
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Kelly Roballo
- Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, USA
- Department of Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA
| | - Susan B. Udin
- Department of Physiology and Biophysics, University at Buffalo, Amherst, NY 14203, USA
| | - Stelios T. Andreadis
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, NY 14260, USA
- Department of Biomedical Engineering, University at Buffalo, NY, Buffalo, NY 14260, USA
- Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at Buffalo, Buffalo, NY 14260, USA
| | - Kirkwood E. Personius
- Department of Department of Rehabilitation Science, University at Buffalo, Buffalo, NY 14214, USA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at Buffalo, Buffalo, NY 14260, USA
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17
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Widodo W, Widyahening IS, Pratama IK, Kuncoro MW. Prospect of Mesenchymal Stem Cells in Enhancing Nerve Regeneration in Brachial Plexus Injury in Animals: A Systematic Review. THE ARCHIVES OF BONE AND JOINT SURGERY 2024; 12:149-158. [PMID: 38577510 PMCID: PMC10989726 DOI: 10.22038/abjs.2024.68053.3224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/14/2024] [Indexed: 04/06/2024]
Abstract
Objectives Brachial plexus injuries (BPI), although rare, often results in significant morbidity. Stem cell was thought to be one of BPI treatment modalities because of their nerve-forming regeneration potential. Although there is a possibility for the use of mesenchymal stem cells as one of BPI treatment, it is still limited on animal studies. Therefore, this systematic review aimed to analyze the role of mesenchymal stem cells in nerve regeneration in animal models of brachial plexus injury. Method This study is a systematic review with PROSPERO registration number CRD4202128321. Literature searching was conducted using keywords experimental, animal, brachial plexus injury, mesenchymal stem cell implantation, clinical outcomes, electrophysiological outcomes, and histologic outcomes. Searches were performed in the PubMed, Scopus, and ScienceDirect databases. The risk of bias was assessed using SYRCLE's risk of bias tool for animal studies. The data obtained were described and in-depth analysis was performed. Result Four studies were included in this study involving 183 animals from different species those are rats and rabbits. There was an increase in muscle weight and shortened initial onset time of muscle contraction in the group treated with stem cells. Electrophysiological results showed that mesenchymal stem cells exhibited higher (Compound muscle action potential) CMAP amplitude and shorter CMAP latency than control but not better than autograft. Histological outcomes showed an increase in axon density, axon number, and the formation of connections between nerve cells and target muscles. Conclusion Mesenchymal stem cell implantation to animals with brachial plexus injury showed its ability to regenerate nerve cells as evidenced by clinical, electrophysiological, and histopathological results. However, this systematic study involved experimental animals from various species so that the results cannot be uniformed, and conclusion should be drawn cautiously.
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Affiliation(s)
- Wahyu Widodo
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Indah Suci Widyahening
- Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Irfan Kurnia Pratama
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Mohamad Walid Kuncoro
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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Convertino D, Trincavelli ML, Giacomelli C, Marchetti L, Coletti C. Graphene-based nanomaterials for peripheral nerve regeneration. Front Bioeng Biotechnol 2023; 11:1306184. [PMID: 38164403 PMCID: PMC10757979 DOI: 10.3389/fbioe.2023.1306184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
Emerging nanotechnologies offer numerous opportunities in the field of regenerative medicine and have been widely explored to design novel scaffolds for the regeneration and stimulation of nerve tissue. In this review, we focus on peripheral nerve regeneration. First, we introduce the biomedical problem and the present status of nerve conduits that can be used to guide, fasten and enhance regeneration. Then, we thoroughly discuss graphene as an emerging candidate in nerve tissue engineering, in light of its chemical, tribological and electrical properties. We introduce the graphene forms commonly used as neural interfaces, briefly review their applications, and discuss their potential toxicity. We then focus on the adoption of graphene in peripheral nervous system applications, a research field that has gained in the last years ever-increasing attention. We discuss the potential integration of graphene in guidance conduits, and critically review graphene interaction not only with peripheral neurons, but also with non-neural cells involved in nerve regeneration; indeed, the latter have recently emerged as central players in modulating the immune and inflammatory response and accelerating the growth of new tissue.
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Affiliation(s)
- Domenica Convertino
- Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy
| | | | | | - Laura Marchetti
- Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Camilla Coletti
- Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy
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19
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Zheng S, Wei H, Cheng H, Qi Y, Gu Y, Ma X, Sun J, Ye F, Guo F, Cheng C. Advances in nerve guidance conduits for peripheral nerve repair and regeneration. AMERICAN JOURNAL OF STEM CELLS 2023; 12:112-123. [PMID: 38213640 PMCID: PMC10776341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/02/2023] [Indexed: 01/13/2024]
Abstract
Peripheral nerve injury (PNI) can cause partial or total motor and sensory nerve function, leading to physical disability and nerve pain that severely affects patients' quality of life. Autologous nerve transplantation is currently the clinically recognized gold standard, but due to its inherent limitations, researchers have been searching for alternative treatments. Nerve guidance conduits (NGCs) have attracted much attention as a favorable alternative to promote the repair and regeneration of damaged peripheral nerves. In this review, we provide an overview of the anatomy of peripheral nerves, peripheral nerve injury and repair, and current treatment methods. Importantly, different design strategies of NGCs used for the treatment of PNI and their applications in PNI repair are highlighted. Finally, an outlook on the future development and challenges of NGCs is presented.
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Affiliation(s)
- Shasha Zheng
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Hao Wei
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Hong Cheng
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Yanru Qi
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Yajun Gu
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Xiaofeng Ma
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
| | - Jiaqiang Sun
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaHefei 230001, Anhui, China
| | - Fanglei Ye
- Department of Otology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000, Henan, China
| | - Fangfang Guo
- Department of Plastic and Reconstruction Surgery, Zhongda Hospital, Southeast UniversityNanjing 210009, Jiangsu, China
| | - Cheng Cheng
- Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)Nanjing 210003, Jiangsu, China
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20
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Escobar A, Carvalho MR, Silva TH, Reis RL, Oliveira JM. Longitudinally aligned inner-patterned silk fibroin conduits for peripheral nerve regeneration. IN VITRO MODELS 2023; 2:195-205. [PMID: 39872172 PMCID: PMC11756464 DOI: 10.1007/s44164-023-00050-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 01/29/2025]
Abstract
Peripheral nerve injuries represent a major clinical challenge, if nerve ends retract, there is no spontaneous regeneration, and grafts are required to proximate the nerve ends and give continuity to the nerve. The nerve guidance conduits (NGCs) presented in this work are silk fibroin (SF)-based, which is biocompatible and very versatile. The formation of conduits is obtained by forming a covalently cross-linked hydrogel in two concentric moulds, and the inner longitudinally aligned pattern of the SF NGCs is obtained through the use of a patterned inner mould. SF NGCs with two wall thicknesses of ~ 200 to ~ 400 μm are synthesized. Their physicochemical and mechanical characteristics have shown improved properties when the wall thickness is thicker such as resistance to kinking, which is of special importance as conduits might also be used to substitute nerves in flexible body parts. The Young modulus is higher for conduits with inner pattern, and none of the conduits has shown any salt deposition in presence of simulated body fluid, meaning they do not calcify; thus, the regeneration does not get impaired when conduits have contact with body fluids. In vitro studies demonstrated the biocompatibility of the SF NGCs; proliferation is enhanced when iSCs are cultured on top of conduits with longitudinally aligned pattern. BJ fibroblasts cannot infiltrate through the SF wall, avoiding scar tissue formation on the lumen of the graft when used in vivo. These conduits have been demonstrated to be very versatile and fulfil with the requirements for their use in PNR. Supplementary Information The online version contains supplementary material available at 10.1007/s44164-023-00050-3.
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Affiliation(s)
- Ane Escobar
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Braga Portugal
- Centro de Física de Materiales (CSIC-UPV/EHU), Paseo Manuel de Lardizabal 5, 20018 Donostia-San Sebastián, Spain
| | - Mariana R. Carvalho
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Braga Portugal
| | - Tiago H. Silva
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Braga Portugal
| | - Rui L. Reis
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Braga Portugal
| | - J. Miguel Oliveira
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Braga Portugal
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21
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Han S, Cruz SH, Park S, Shin SR. Nano-biomaterials and advanced fabrication techniques for engineering skeletal muscle tissue constructs in regenerative medicine. NANO CONVERGENCE 2023; 10:48. [PMID: 37864632 PMCID: PMC10590364 DOI: 10.1186/s40580-023-00398-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/10/2023] [Indexed: 10/23/2023]
Abstract
Engineered three-dimensional (3D) tissue constructs have emerged as a promising solution for regenerating damaged muscle tissue resulting from traumatic or surgical events. 3D architecture and function of the muscle tissue constructs can be customized by selecting types of biomaterials and cells that can be engineered with desired shapes and sizes through various nano- and micro-fabrication techniques. Despite significant progress in this field, further research is needed to improve, in terms of biomaterials properties and fabrication techniques, the resemblance of function and complex architecture of engineered constructs to native muscle tissues, potentially enhancing muscle tissue regeneration and restoring muscle function. In this review, we discuss the latest trends in using nano-biomaterials and advanced nano-/micro-fabrication techniques for creating 3D muscle tissue constructs and their regeneration ability. Current challenges and potential solutions are highlighted, and we discuss the implications and opportunities of a future perspective in the field, including the possibility for creating personalized and biomanufacturable platforms.
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Affiliation(s)
- Seokgyu Han
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Korea
| | - Sebastián Herrera Cruz
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
| | - Sungsu Park
- School of Mechanical Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Korea.
- Department of Biophysics, Institute of Quantum Biophysics (IQB), Sungkyunkwan University (SKKU), Suwon, 16419, Korea.
| | - Su Ryon Shin
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.
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22
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Tai Y, Tonmoy TI, Win S, Brinkley NT, Park BH, Nam J. Enhanced peripheral nerve regeneration by mechano-electrical stimulation. NPJ Regen Med 2023; 8:57. [PMID: 37848428 PMCID: PMC10582163 DOI: 10.1038/s41536-023-00334-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 09/29/2023] [Indexed: 10/19/2023] Open
Abstract
To address limitations in current approaches for treating large peripheral nerve defects, the presented study evaluated the feasibility of functional material-mediated physical stimuli on peripheral nerve regeneration. Electrospun piezoelectric poly(vinylidene fluoride-trifluoroethylene) nanofibers were utilized to deliver mechanical actuation-activated electrical stimulation to nerve cells/tissues in a non-invasive manner. Using morphologically and piezoelectrically optimized nanofibers for neurite extension and Schwann cell maturation based on in vitro experiments, piezoelectric nerve conduits were synthesized and implanted in a rat sciatic nerve transection model to bridge a critical-sized sciatic nerve defect (15 mm). A therapeutic shockwave system was utilized to periodically activate the piezoelectric effect of the implanted nerve conduit on demand. The piezoelectric nerve conduit-mediated mechano-electrical stimulation (MES) induced enhanced peripheral nerve regeneration, resulting in full axon reconnection with myelin regeneration from the proximal to the distal ends over the critical-sized nerve gap. In comparison, a control group, in which the implanted piezoelectric conduits were not activated in vivo, failed to exhibit such nerve regeneration. In addition, at both proximal and distal ends of the implanted conduits, a decreased number of damaged myelination (ovoids), an increased number of myelinated nerves, and a larger axonal diameter were observed under the MES condition as compared to the control condition. Furthermore, unlike the control group, the MES condition exhibited a superior functional nerve recovery, assessed by walking track analysis and polarization-sensitive optical coherence tomography, demonstrating the significant potential of the piezoelectric conduit-based physical stimulation approach for the treatment of peripheral nerve injury.
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Affiliation(s)
- Youyi Tai
- Department of Bioengineering, University of California, Riverside, CA, 92521, USA
| | | | - Shwe Win
- Department of Bioengineering, University of California, Riverside, CA, 92521, USA
| | - Natasha T Brinkley
- Department of Bioengineering, University of California, Riverside, CA, 92521, USA
| | - B Hyle Park
- Department of Bioengineering, University of California, Riverside, CA, 92521, USA
| | - Jin Nam
- Department of Bioengineering, University of California, Riverside, CA, 92521, USA.
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23
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Feng R, Zhang P. The significance of M1 macrophage should be highlighted in peripheral nerve regeneration. Histol Histopathol 2023; 38:975-987. [PMID: 36734334 DOI: 10.14670/hh-18-591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Macrophage influences peripheral nerve regeneration. According to the classical M1/M2 paradigm, the M1 macrophage is an inhibitor of regeneration, while the M2 macrophage is a promoter. However, several studies have shown that M1 macrophages are indispensable for peripheral nerve repair and facilitate many critical processes in axonal regeneration. In this review, we summarized the information on macrophage polarization and focused on the activities of M1 macrophages in regeneration. We also provided some examples where the macrophage phenotypes were regulated to help regeneration. We argued that the coordination of both macrophage phenotypes might be effective in peripheral nerve repair, and a more comprehensive view of macrophages might contribute to macrophage-based immunomodulatory therapies.
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Affiliation(s)
- Ruiqin Feng
- Department of Orthopedics and Trauma, Peking University People's Hospital, Key Laboratory of Trauma and Neural Regeneration, Ministry of Education and National Center for Trauma Medicine, Beijing, China
| | - Peixun Zhang
- Department of Orthopedics and Trauma, Peking University People's Hospital, Key Laboratory of Trauma and Neural Regeneration, Ministry of Education and National Center for Trauma Medicine, Beijing, China.
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24
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de Assis ACC, Reis ALS, Nunes LV, Ferreira LFR, Bilal M, Iqbal HMN, Soriano RN. Stem Cells and Tissue Engineering-Based Therapeutic Interventions: Promising Strategies to Improve Peripheral Nerve Regeneration. Cell Mol Neurobiol 2023; 43:433-454. [PMID: 35107689 PMCID: PMC11415205 DOI: 10.1007/s10571-022-01199-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/21/2022] [Indexed: 02/05/2023]
Abstract
Unlike the central nervous system, the peripheral one has the ability to regenerate itself after injury; however, this natural regeneration process is not always successful. In fact, even with some treatments, the prognosis is poor, and patients consequently suffer with the functional loss caused by injured nerves, generating several impacts on their quality of life. In the present review we aimed to address two strategies that may considerably potentiate peripheral nerve regeneration: stem cells and tissue engineering. In vitro studies have shown that pluripotent cells associated with neural scaffolds elaborated by tissue engineering can increase functional recovery, revascularization, remyelination, neurotrophin expression and reduce muscle atrophy. Although these results are very promising, it is important to note that there are some barriers to be circumvented: the host's immune response, the oncogenic properties attributed to stem cells and the duration of the pro-regenerative effects. After all, more studies are still needed to overcome the limitations of these treatments; those that address techniques for manipulating the lesion microenvironment combining different therapies seem to be the most promising and proactive ones.
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Affiliation(s)
- Ana Carolina Correa de Assis
- Department of Medicine, Federal University of Juiz de Fora (UFJF-GV), 241 Manoel Byrro St., Governador Valadares, MG, 35032-620, Brazil
| | - Amanda Luiza Silva Reis
- Department of Medicine, Federal University of Juiz de Fora (UFJF-GV), 241 Manoel Byrro St., Governador Valadares, MG, 35032-620, Brazil
| | - Leonardo Vieira Nunes
- School of Medicine, Federal University of Juiz de Fora (UFJF-JF), Eugênio do Nascimento Avenue, Juiz de Fora, MG, 36038-330, Brazil
| | - Luiz Fernando Romanholo Ferreira
- Graduate Program in Process Engineering, Tiradentes University (UNIT), 300 Murilo Dantas Ave., Aracaju, SE, 49032-490, Brazil
- Institute of Technology and Research (ITP), Tiradentes University (UNIT), 300 Murilo Dantas Ave., Aracaju, SE, 49032-490, Brazil
| | - Muhammad Bilal
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, 223003, China.
| | - Hafiz M N Iqbal
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Monterrey, Ave. Eugenio Garza Sada 2501, CP 64849, Monterrey, NL , Mexico
| | - Renato Nery Soriano
- Division of Physiology and Biophysics, Department of Basic Life Sciences, Federal University of Juiz de Fora (UFJF-GV), 1167 Moacir Paleta Ave., Governador Valadares, MG, 35020-360, Brazil.
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25
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Wang H, Wang F, Wang Y, Li X, Di C, Liang C, Mu Y, Zhou J. Study on the Mechanism of BMSCs in Regulating NF-κB Signal Pathway by Targeting miR-449a to Improve the Inflammatory Response to Peripheral Nerve Injury. JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS 2022; 22:546-561. [PMID: 36458392 PMCID: PMC9716300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 08/24/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To evaluate the mechanism of Bone Marrow Mesenchymal Stem Cells (BMSCs) in regulating NF-κB signal pathway by targeting miR-449a. METHODS Stem cells were transfected by over-expressing and inhibiting miR-449a to detect the levels and viability of miR-449a in stem cells after transfection. Stem cells and neurons were co-cultured in vitro to evaluate the in vitro mechanism of stem cells over-expressing miR-449a on neurons. RESULTS After the addition of neurons, the neuronal activity of miR-449a over-expression group increased significantly, the expression of NF-κB signal pathway proteins (IκBα, p50, and p65) decreased, and the inflammatory cytokines (TNF-α and IL-1β) decreased significantly (P<0.05). In vivo experiments in rats also showed that rats were unresponsive, did not chirp or elude after being stimulated. After stem cell therapy, the weight and response of rats gradually returned to normal levels. miR-449a expression significantly increased in the stem cell + miR-449a over-expression group, expression of NF-κB signal pathway proteins (IκBα, p50, and p65) decreased, inflammatory cytokines (TNF-α and IL-1β) significantly decreased, and cell activity significantly increased (P<0.05). CONCLUSIONS BMSCs can modulate NF-κB signaling pathway by targeting miR-449a, so as to reduce the inflammatory response to peripheral nerve injury and repair nerve injury.
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Affiliation(s)
- Hongjiao Wang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
| | - Fangyuan Wang
- Department of General Surgery, Qiqihar First Hospital, China
| | - Yuejing Wang
- Department of Histology and Embryology, Qiqihar Medical College, China
| | - Xiaonan Li
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
| | - Cihan Di
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
| | - Chunming Liang
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
| | - Yuyuan Mu
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
| | - Jiexin Zhou
- Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical College, China
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26
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Transcriptional Control of Peripheral Nerve Regeneration. Mol Neurobiol 2022; 60:329-341. [PMID: 36261692 DOI: 10.1007/s12035-022-03090-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/10/2022] [Indexed: 10/24/2022]
Abstract
Transcription factors are master regulators of various cellular processes under diverse physiological and pathological conditions. Many transcription factors that are differentially expressed after injury to peripheral nerves play important roles in nerve regeneration. Considering that rapid and timely regrowth of injured axons is a prerequisite for successful target reinnervation, here, we compile transcription factors that mediates axon elongation, including axon growth suppressor Klf4 and axon growth promoters c-Myc, Sox11, STAT3, Atf3, c-Jun, Smad1, C/EBPδ, and p53. Besides neuronal changes, Schwann cell phenotype modulation is also critical for nerve regeneration. The activation of Schwann cells at early time points post injury provides a permissive microenvironment whereas the re-differentiation of Schwann cells at later time points supports myelin sheath formation. Hence, c-Jun and Sox2, two critical drivers for Schwann cell reprogramming, as well as Krox-20 and Sox10, two essential regulators of Schwann cell myelination, are reviewed. These transcription factors may serve as promising targets for promoting the functional recovery of injured peripheral nerves.
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27
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Saffari TM, Saffari S, Vyas KS, Mardini S, Shin AY. Role of adipose tissue grafting and adipose-derived stem cells in peripheral nerve surgery. Neural Regen Res 2022; 17:2179-2184. [PMID: 35259826 PMCID: PMC9083182 DOI: 10.4103/1673-5374.336870] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The application of autologous fat grafting in reconstructive surgery is commonly used to improve functional form. This review aims to provide an overview of the scientific evidence on the biology of adipose tissue, the role of adipose-derived stem cells, and the indications of adipose tissue grafting in peripheral nerve surgery. Adipose tissue is easily accessible through the lower abdomen and inner thighs. Non-vascularized adipose tissue grafting does not support oxidative and ischemic stress, resulting in variable survival of adipocytes within the first 24 hours. Enrichment of adipose tissue with a stromal vascular fraction is purported to increase the number of adipose-derived stem cells and is postulated to augment the long-term stability of adipose tissue grafts. Basic science nerve research suggests an increase in nerve regeneration and nerve revascularization, and a decrease in nerve fibrosis after the addition of adipose-derived stem cells or adipose tissue. In clinical studies, the use of autologous lipofilling is mostly applied to secondary carpal tunnel release revisions with promising results. Since the use of adipose-derived stem cells in peripheral nerve reconstruction is relatively new, more studies are needed to explore safety and long-term effects on peripheral nerve regeneration. The Food and Drug Administration stipulates that adipose-derived stem cell transplantation should be minimally manipulated, enzyme-free, and used in the same surgical procedure, e.g. adipose tissue grafts that contain native adipose-derived stem cells or stromal vascular fraction. Future research may be shifted towards the use of tissue-engineered adipose tissue to create a supportive microenvironment for autologous graft survival. Shelf-ready alternatives could be enhanced with adipose-derived stem cells or growth factors and eliminate the need for adipose tissue harvest.
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Affiliation(s)
- Tiam M Saffari
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA; Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands
| | - Sara Saffari
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA; Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands
| | - Krishna S Vyas
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN, USA
| | - Samir Mardini
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN, USA
| | - Alexander Y Shin
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA
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28
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Kaplan B, Levenberg S. The Role of Biomaterials in Peripheral Nerve and Spinal Cord Injury: A Review. Int J Mol Sci 2022; 23:ijms23031244. [PMID: 35163168 PMCID: PMC8835501 DOI: 10.3390/ijms23031244] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/18/2022] Open
Abstract
Peripheral nerve and spinal cord injuries are potentially devastating traumatic conditions with major consequences for patients’ lives. Severe cases of these conditions are currently incurable. In both the peripheral nerves and the spinal cord, disruption and degeneration of axons is the main cause of neurological deficits. Biomaterials offer experimental solutions to improve these conditions. They can be engineered as scaffolds that mimic the nerve tissue extracellular matrix and, upon implantation, encourage axonal regeneration. Furthermore, biomaterial scaffolds can be designed to deliver therapeutic agents to the lesion site. This article presents the principles and recent advances in the use of biomaterials for axonal regeneration and nervous system repair.
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Affiliation(s)
- Ben Kaplan
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
- Bruce Rapaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel
| | - Shulamit Levenberg
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
- Correspondence:
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Lopes B, Sousa P, Alvites R, Branquinho M, Sousa AC, Mendonça C, Atayde LM, Luís AL, Varejão ASP, Maurício AC. Peripheral Nerve Injury Treatments and Advances: One Health Perspective. Int J Mol Sci 2022; 23:ijms23020918. [PMID: 35055104 PMCID: PMC8779751 DOI: 10.3390/ijms23020918] [Citation(s) in RCA: 141] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 02/04/2023] Open
Abstract
Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions, that can lead to the loss of structure and/or function impairment. These changes can cause partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, which in turn can affect the quality of life. This review aims to revisit the concepts associated with the PNI and the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to enhance the importance of new therapies, especially in severe lesions, to overcome limitations and achieve better outcomes. The urge for new approaches and the understanding of the different methods to evaluate nerve regeneration is fundamental from a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine.
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Affiliation(s)
- Bruna Lopes
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Patrícia Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Rui Alvites
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Mariana Branquinho
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana Catarina Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Carla Mendonça
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Luís Miguel Atayde
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana Lúcia Luís
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Artur S. P. Varejão
- Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal;
- CECAV, Centre for Animal Sciences and Veterinary Studies, University of Trás-os-Montes e Alto Douro, Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Ana Colette Maurício
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (B.L.); (P.S.); (R.A.); (M.B.); (A.C.S.); (C.M.); (L.M.A.); (A.L.L.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
- Correspondence: ; Tel.: +351-91-9071286
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Podsednik A, Cabrejo R, Rosen J. Adipose Tissue Uses in Peripheral Nerve Surgery. Int J Mol Sci 2022; 23:ijms23020644. [PMID: 35054833 PMCID: PMC8776017 DOI: 10.3390/ijms23020644] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/30/2021] [Accepted: 01/02/2022] [Indexed: 12/15/2022] Open
Abstract
Currently, many different techniques exist for the surgical repair of peripheral nerves. The degree of injury dictates the repair and, depending on the defect or injury of the peripheral nerve, plastic surgeons can perform nerve repairs, grafts, and transfers. All the previously listed techniques are routinely performed in human patients, but a novel addition to these peripheral nerve surgeries involves concomitant fat grafting to the repair site at the time of surgery. Fat grafting provides adipose-derived stem cells to the injury site. Though fat grafting is performed as an adjunct to some peripheral nerve surgeries, there is no clear evidence as to which procedures have improved outcomes resultant from concomitant fat grafting. This review explores the evidence presented in various animal studies regarding outcomes of fat grafting at the time of various types of peripheral nerve surgery.
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Affiliation(s)
- Allison Podsednik
- The University of Texas Rio Grande Valley School of Medicine, Edinburg, TX 78541, USA;
| | - Raysa Cabrejo
- Section of Plastic Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA;
| | - Joseph Rosen
- Section of Plastic Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA;
- Correspondence:
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Mirancea N, Mirancea GV, Moroşanu AM, Moroşanu AM, Department of General Surgery, St. Pantelimon Emergency Clinical Hospital, Bucharest, Romania, Department of Developmental Biology, Institute of Biology Bucharest of Romanian Academy, Bucharest, Romania. Telocytes inside of the peripheral nervous system - a 3D endoneurial network and putative role in cell communication. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2022; 63:335-347. [PMID: 36374139 PMCID: PMC9804078 DOI: 10.47162/rjme.63.2.05] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In this paper, we developed the hypothesis concerning the reasons to assimilate endoneurial fibroblast-like dendritic phenotype [shortly termed endoneurial dendritic cells (EDCs)] to the endoneurial telocytes (TCs). We reviewed the literature concerning EDCs status and report our observations on ultrastructure and some immune electron microscopic aspects of the cutaneous peripheral nerves. Our data demonstrate that EDCs long time considered as fibroblasts or fibroblast-like, with an ovoidal nucleus and one or more moniliform cell extensions [telopodes (Tps)], which perform homocellular junctions, also able to shed extracellular microvesicles can be assimilated to TC phenotype. Sometimes, small profiles of basement membrane accompany to some extent Tps. Altogether data resulted from scientific literature and our results strength the conclusion EDCs are really TCs inside of the peripheral nervous system. The inner three-dimensional (3D) network of endoneurial TCs by their homo- and heterocellular communications appears as a genuine cell-to-cell communication system inside of each peripheral nerve.
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Affiliation(s)
- Nicolae Mirancea
- Department of Developmental Biology, Institute of Biology Bucharest of Romanian Academy, Bucharest, Romania;
| | | | - Ana-Maria Moroşanu
- Department of Developmental Biology, Institute of
Biology Bucharest of Romanian Academy, Bucharest, Romania
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Li Y, Ma Z, Ren Y, Lu D, Li T, Li W, Wang J, Ma H, Zhao J. Tissue Engineering Strategies for Peripheral Nerve Regeneration. Front Neurol 2021; 12:768267. [PMID: 34867754 PMCID: PMC8635143 DOI: 10.3389/fneur.2021.768267] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/15/2021] [Indexed: 11/13/2022] Open
Abstract
A peripheral nerve injury (PNI) has severe and profound effects on the life of a patient. The therapeutic approach remains one of the most challenging clinical problems. In recent years, many constructive nerve regeneration schemes are proposed at home and abroad. Nerve tissue engineering plays an important role. It develops an ideal nerve substitute called artificial nerve. Given the complexity of nerve regeneration, this review summarizes the pathophysiology and tissue-engineered repairing strategies of the PNI. Moreover, we discussed the scaffolds and seed cells for neural tissue engineering. Furthermore, we have emphasized the role of 3D printing in tissue engineering.
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Affiliation(s)
- Yin Li
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenjiang Ma
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya Ren
- Southwest JiaoTong University College of Medicine, Chengdu, China
| | - Dezhi Lu
- School of Medicine, Shanghai University, Shanghai, China
| | - Tao Li
- Department of Orthopaedics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wentao Li
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinwu Wang
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Ma
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zhao
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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33
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Maugeri G, D'Agata V, Trovato B, Roggio F, Castorina A, Vecchio M, Di Rosa M, Musumeci G. The role of exercise on peripheral nerve regeneration: from animal model to clinical application. Heliyon 2021; 7:e08281. [PMID: 34765794 PMCID: PMC8571504 DOI: 10.1016/j.heliyon.2021.e08281] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 06/26/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
Peripheral nerve injury is a complex condition with a variety of signs and symptoms depending on the severity and nerves involved. Peripheral nerve damage may lead to sensory and motor functions deficits and even lifelong disability, causing important socioeconomic costs worldwide. Despite the increase in knowledge of the mechanisms of injury and regeneration, a full functional recovery is still unsatisfying in the majority of patients. It is well known that exercise promotes physical and psychological well-being, by ameliorating general health. In the last years, there has been a growing interest in evaluating the effects of exercise on the peripheral nervous system. Experimental works with rodent models showed the potential utility of exercise following peripheral nerve injuries, as evinced by increasing axon regeneration, muscle reinnervation, better recovery of strength, muscle mass and higher expression of neurotrophic factors. Moreover, clinical evidence showed positive trends in favour of physical therapy following peripheral nerve damage based on the improvement of range of motion (ROM), muscle power grade and pain. After a brief overview of peripheral nerve anatomy and the different types of nerve injury, the present review aims to summarize the impact of exercise on peripheral nerve regeneration. Some clinical evidence regarding the effect of exercise after peripheral nerve injury will also be discussed.
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Affiliation(s)
- Grazia Maugeri
- Department of Biomedical and Biotechnological Sciences, Human, Histology and Movement Science Section, University of Catania, Via S. Sofia n°87, 95123, Catania, Italy
| | - Velia D'Agata
- Department of Biomedical and Biotechnological Sciences, Human, Histology and Movement Science Section, University of Catania, Via S. Sofia n°87, 95123, Catania, Italy
| | - Bruno Trovato
- Research Center on Motor Activities (CRAM), University of Catania, Via S. Sofia n°97, 95123, Catania, Italy
| | - Federico Roggio
- Research Center on Motor Activities (CRAM), University of Catania, Via S. Sofia n°97, 95123, Catania, Italy
| | - Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, PO Box 123, Broadway, NSW, 2007, Australia.,Laboratory of Neural Structure and Function (LNSF), School of Medical Sciences, (Anatomy & Histology), Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia
| | - Michele Vecchio
- Unit of Rehabilitation, Vittorio Emanuele University Hospital, Catania, Italy
| | - Michelino Di Rosa
- Department of Biomedical and Biotechnological Sciences, Human, Histology and Movement Science Section, University of Catania, Via S. Sofia n°87, 95123, Catania, Italy
| | - Giuseppe Musumeci
- Department of Biomedical and Biotechnological Sciences, Human, Histology and Movement Science Section, University of Catania, Via S. Sofia n°87, 95123, Catania, Italy.,Research Center on Motor Activities (CRAM), University of Catania, Via S. Sofia n°97, 95123, Catania, Italy.,Department of Biology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA
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Adipose Mesenchymal Stem Cell-Derived Exosomes Enhance PC12 Cell Function through the Activation of the PI3K/AKT Pathway. Stem Cells Int 2021; 2021:2229477. [PMID: 34691190 PMCID: PMC8536463 DOI: 10.1155/2021/2229477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/20/2021] [Accepted: 09/09/2021] [Indexed: 11/18/2022] Open
Abstract
Transplantation of mesenchymal stem cells has been considered as an auspicious treatment for repairing nerve injuries. The rat adrenal pheochromocytoma cell line (PC12) is one of the traditional models for the study of neuronal differentiation and neuroregeneration in vitro. However, the effects of adipose mesenchymal stem cell-derived exosomes (ADSC-exo) on PC12 cells remain unclear and to be elucidated. In our study, the effects of ADSC-exo on PC12 cells were investigated. ADSC-exo were isolated by ultracentrifugation and characterized by transmission electron microscopy, flow nanoanalysis, and western blot. The effects of ADSC-exo on PC12 cell proliferation, migration, apoptosis, and the protein levels were analyzed using CCK-8 assay and EdU incorporation assay, transwell migration assay and scratch wound assay, flow cytometry, and western blot, respectively. We successfully isolated and purified exosomes from ADSC supernatant and found that ADSC-exo treatment significantly promoted PC12 cell proliferation and migration, inhibited their apoptosis, and activated the PI3K/AKT pathway, while PI3K/AKT signaling repression using LY294002 exhibited the opposite effects. The results showed that ADSC-exo promoted proliferation and migration and inhibited apoptosis of PC12 through the activation of the PI3K/AKT pathway. Thus, the effect of ADSC-exo on PC12 cells may suggest ADSC-exo may be a promising therapeutic for nerve damage.
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Chen F, Liu W, Zhang Q, Wu P, Xiao A, Zhao Y, Zhou Y, Wang Q, Chen Y, Tong Z. IL-17F depletion accelerates chitosan conduit guided peripheral nerve regeneration. Acta Neuropathol Commun 2021; 9:125. [PMID: 34274026 PMCID: PMC8285852 DOI: 10.1186/s40478-021-01227-1] [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: 01/18/2021] [Accepted: 07/08/2021] [Indexed: 12/24/2022] Open
Abstract
Peripheral nerve injury is a serious health problem and repairing long nerve deficits remains a clinical challenge nowadays. Nerve guidance conduit (NGC) serves as the most promising alternative therapy strategy to autografts but its repairing efficiency needs improvement. In this study, we investigated whether modulating the immune microenvironment by Interleukin-17F (IL-17F) could promote NGC mediated peripheral nerve repair. Chitosan conduits were used to bridge sciatic nerve defect in IL-17F knockout mice and wild-type mice with autografts as controls. Our data revealed that IL-17F knockout mice had improved functional recovery and axonal regeneration of sciatic nerve bridged by chitosan conduits comparing to the wild-type mice. Notably, IL-17F knockout mice had enhanced anti-inflammatory macrophages in the NGC repairing microenvironment. In vitro data revealed that IL-17F knockout peritoneal and bone marrow derived macrophages had increased anti-inflammatory markers after treatment with the extracts from chitosan conduits, while higher pro-inflammatory markers were detected in the Raw264.7 macrophage cell line, wild-type peritoneal and bone marrow derived macrophages after the same treatment. The biased anti-inflammatory phenotype of macrophages by IL-17F knockout probably contributed to the improved chitosan conduit guided sciatic nerve regeneration. Additionally, IL-17F could enhance pro-inflammatory factors production in Raw264.7 cells and wild-type peritoneal macrophages. Altogether, IL-17F may partially mediate chitosan conduit induced pro-inflammatory polarization of macrophages during nerve repair. These results not only revealed a role of IL-17F in macrophage function, but also provided a unique and promising target, IL-17F, to modulate the microenvironment and enhance the peripheral nerve regeneration.
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36
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Huang Y, Wu W, Liu H, Chen Y, Li B, Gou Z, Li X, Gou M. 3D printing of functional nerve guide conduits. BURNS & TRAUMA 2021; 9:tkab011. [PMID: 34212061 PMCID: PMC8240533 DOI: 10.1093/burnst/tkab011] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Nerve guide conduits (NGCs), as alternatives to nerve autografts and allografts, have been widely explored as an advanced tool for the treatment of peripheral nerve injury. However, the repairing efficiency of NGCs still needs significant improvements. Functional NGCs that provide a more favorable microenvironment for promoting axonal elongation and myelination are of great importance. In recent years, 3D printing technologies have been widely applied in the fabrication of customized and complex constructs, exhibiting great potential for tissue engineering applications, especially for the construction of functional NGCs. In this review, we introduce the 3D printing technologies for manufacturing functional NGCs, including inkjet printing, extrusion printing, stereolithography-based printing and indirect printing. Further, we summarize the current methods and strategies for constructing functional NGCs, such as designing special conduit architectures, using appropriate materials and co-printing with different biological cues. Finally, the challenges and prospects for construction of functional NGCs are also presented.
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Affiliation(s)
- Yulan Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenbi Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haofan Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuwen Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bo Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhiyuan Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xun Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.,Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Maling Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
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Lomboni DJ, Steeves A, Schock S, Bonetti L, De Nardo L, Variola F. Compounded topographical and physicochemical cueing by micro-engineered chitosan substrates on rat dorsal root ganglion neurons and human mesenchymal stem cells. SOFT MATTER 2021; 17:5284-5302. [PMID: 34075927 DOI: 10.1039/d0sm02170a] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Given the intertwined physicochemical effects exerted in vivo by both natural and synthetic (e.g., biomaterial) interfaces on adhering cells, the evaluation of structure-function relationships governing cellular response to micro-engineered surfaces for applications in neuronal tissue engineering requires the use of in vitro testing platforms which consist of a clinically translatable material with tunable physiochemical properties. In this work, we micro-engineered chitosan substrates with arrays of parallel channels with variable width (20 and 60 μm). A citric acid (CA)-based crosslinking approach was used to provide an additional level of synergistic cueing on adhering cells by regulating the chitosan substrate's stiffness. Morphological and physicochemical characterization was conducted to unveil the structure-function relationships which govern the activity of rat dorsal root ganglion neurons (DRGs) and human mesenchymal stem cells (hMSCs), ultimately singling out the key role of microtopography, roughness and substrate's stiffness. While substrate's stiffness predominantly affected hMSC spreading, the modulation of the channels' design affected the neuronal architecture's complexity and guided the morphological transition of hMSCs. Finally, the combined analysis of tubulin expression and cell morphology allowed us to cast new light on the predominant role of the microtopography over substrate's stiffness in the process of hMSCs neurogenic differentiation.
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Affiliation(s)
- David J Lomboni
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - Alexander Steeves
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada
| | - Sarah Schock
- Department of Cellular and Molecular Medicine, University of Ottawa, Canada and The Children's Hospital of Eastern Ontario (CHEO) Research Institute, Canada
| | - Lorenzo Bonetti
- Department of Chemistry, Materials and Chemical Engineering, "G. Natta", Politecnico di Milano, Italy
| | - Luigi De Nardo
- Department of Chemistry, Materials and Chemical Engineering, "G. Natta", Politecnico di Milano, Italy
| | - Fabio Variola
- Department of Mechanical Engineering, University of Ottawa, K1N 6N5 Canada. and Ottawa-Carleton Institute for Biomedical Engineering (OCIBME), Ottawa, Canada and Department of Cellular and Molecular Medicine, University of Ottawa, Canada and The Children's Hospital of Eastern Ontario (CHEO) Research Institute, Canada
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38
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Chen S, Carlson MA, Li X, Siddique A, Zhu W, Xie J. Minimally Invasive Delivery of 3D Shape Recoverable Constructs with Ordered Structures for Tissue Repair. ACS Biomater Sci Eng 2021; 7:2204-2211. [PMID: 33929841 DOI: 10.1021/acsbiomaterials.1c00344] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Minimally invasive procedures are becoming increasingly more common in surgery. However, the biomaterials capable of delivering biomimetic, three-dimensional (3D) functional tissues in a minimally invasive manner and exhibiting ordered structures after delivery are lacking. Herein, we reported the fabrication of gelatin methacryloyl (GelMA)-coated, 3D expanded nanofiber scaffolds, and their potential applications in minimally invasive delivery of 3D functional tissue constructs with ordered structures and clinically appropriate sizes (4 cm × 2 cm × 1.5 mm). GelMA-coated, expanded 3D nanofiber scaffolds produced by combining electrospinning, gas-foaming expansion, hydrogel coating, and cross-linking are extremely shape recoverable after release of compressive strain, displaying a superelastic property. Such scaffolds can be seeded with various types of cells, including dermal fibroblasts, bone marrow-derived mesenchymal stem cells, and human neural stem/precursor cells to form 3D complex tissue constructs. Importantly, the developed 3D tissue constructs can be compressed and loaded into a 4 mm diameter glass tube for minimally invasive delivery without compromising the cell viability. Taken together, the method developed in this study could hold great promise for transplantation of biomimetic, 3D functional tissue constructs with well-organized structures for tissue repair and regeneration using minimally invasive procedures like laparoscopy and thoracoscopy.
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Affiliation(s)
- Shixuan Chen
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Mark Alan Carlson
- Department of Surgery-General Surgery, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Xiaowei Li
- Department of Neurological Sciences and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Aleem Siddique
- Department of Surgery-Cardiothoracic Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Wuqiang Zhu
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center of Regenerative Medicine, Mayo Clinic, Scottsdale, Arizona 85259, United States
| | - Jingwei Xie
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.,Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, United States
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Wang Y, Zhang F, Zhang Y, Shan Q, Liu W, Zhang F, Zhang F, Yi S. Betacellulin regulates peripheral nerve regeneration by affecting Schwann cell migration and axon elongation. Mol Med 2021; 27:27. [PMID: 33794764 PMCID: PMC8015203 DOI: 10.1186/s10020-021-00292-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/16/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve repair and regeneration. Our previous sequencing data showed that the mRNA coding for betacellulin (Btc), an epidermal growth factor protein family member, was up-regulated in rat sciatic nerve segment after nerve injury, implying the potential involvement of Btc during peripheral nerve regeneration. METHODS Expression of Btc was examined in Schwann cells by immunostaining. The function of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or treating cells with Btc recombinant protein. The influence of Schwann cell-secreted Btc on neurons was determined using a co-culture assay. The in vivo effects of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated. RESULTS Immunostaining images and ELISA outcomes indicated that Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that transfection with siRNA against Btc impeded Schwann cell migration while application of exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells influenced neuron behavior and increased neurite length. In vivo evidence supported the promoting role of Btc in nerve regeneration after both rat sciatic nerve crush injury and transection injury. CONCLUSION Our findings demonstrate the essential roles of Btc on Schwann cell migration and axon elongation and imply the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.
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Affiliation(s)
- Yaxian Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China
| | - Fuchao Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China
| | - Yunsong Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China
| | - Qi Shan
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China
| | - Wei Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China
| | - Fengyuan Zhang
- Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Feiyu Zhang
- Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Sheng Yi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, China.
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Saffari S, Saffari TM, Ulrich DJO, Hovius SER, Shin AY. The interaction of stem cells and vascularity in peripheral nerve regeneration. Neural Regen Res 2021; 16:1510-1517. [PMID: 33433464 PMCID: PMC8323682 DOI: 10.4103/1673-5374.303009] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The degree of nerve regeneration after peripheral nerve injury can be altered by the microenvironment at the site of injury. Stem cells and vascularity are postulated to be a part of a complex pathway that enhances peripheral nerve regeneration; however, their interaction remains unexplored. This review aims to summarize current knowledge on this interaction, including various mechanisms through which trophic factors are promoted by stem cells and angiogenesis. Angiogenesis after nerve injury is stimulated by hypoxia, mediated by vascular endothelial growth factor, resulting in the growth of pre-existing vessels into new areas. Modulation of distinct signaling pathways in stem cells can promote angiogenesis by the secretion of various angiogenic factors. Simultaneously, the importance of stem cells in peripheral nerve regeneration relies on their ability to promote myelin formation and their capacity to be influenced by the microenvironment to differentiate into Schwann-like cells. Stem cells can be acquired through various sources that correlate to their differentiation potential, including embryonic stem cells, neural stem cells, and mesenchymal stem cells. Each source of stem cells serves its particular differentiation potential and properties associated with the promotion of revascularization and nerve regeneration. Exosomes are a subtype of extracellular vesicles released from cell types and play an important role in cell-to-cell communication. Exosomes hold promise for future transplantation applications, as these vesicles contain fewer membrane-bound proteins, resulting in lower immunogenicity. This review presents pre-clinical and clinical studies that focus on selecting the ideal type of stem cell and optimizing stem cell delivery methods for potential translation to clinical practice. Future studies integrating stem cell-based therapies with the promotion of angiogenesis may elucidate the synergistic pathways and ultimately enhance nerve regeneration.
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Affiliation(s)
- Sara Saffari
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Tiam M Saffari
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Dietmar J O Ulrich
- Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Steven E R Hovius
- Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Alexander Y Shin
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
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Wei Z, Shu S, Zhang M, Xie S, Tang S, Nie K, Li H. A Subpopulation of Schwann Cell-Like Cells With Nerve Regeneration Signatures Is Identified Through Single-Cell RNA Sequencing. Front Physiol 2021; 12:637924. [PMID: 34093220 PMCID: PMC8171402 DOI: 10.3389/fphys.2021.637924] [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: 12/07/2020] [Accepted: 02/15/2021] [Indexed: 02/05/2023] Open
Abstract
Schwann cell-like cells (SCLCs) derived from human amniotic mesenchymal stem cells (hAMSCs) have been shown to promote peripheral nerve regeneration, but the underlying molecular mechanism was still poorly understood. In order to investigate the heterogeneity and potential molecular mechanism of SCLCs in the treatment of peripheral nerve regeneration at a single cell level, single-cell RNA sequencing was applied to profile single cell populations of hAMSCs and SCLCs. We profiled 6,008 and 5,140 single cells from hAMSCs and SCLCs, respectively. Based on bioinformatics analysis, pathways associated with proliferation, ECM organization, and tissue repair were enriched within both populations. Cell cycle analysis indicated that single cells within these two populations remained mostly in the G0/G1 phase. The transformation of single cells from hAMSCs to SCLCs was characterized by pseudotime analysis. Furthermore, we identified a subpopulation of SCLCs that highly expressed genes associated with Schwann cell proliferation, migration, and survival, such as JUN, JUND, and NRG1., Genes such as PTGS2, PITX1, VEGFA, and FGF2 that promote nerve regeneration were also highly expressed in single cells within this subpopulation, and terms associated with inflammatory and tissue repair were enriched in this subpopulation by pathway enrichment analysis. Our results indicate that a subpopulation of SCLCs with nerve regeneration signatures may be the key populations that promote nerve regeneration.
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Affiliation(s)
- Zairong Wei
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Shenyou Shu
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Mingjun Zhang
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Sitian Xie
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Shijie Tang
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Kaiyu Nie
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Haihong Li
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
- Department of Wound Repair and Dermatologic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Haihong Li,
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