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Aldali F, Deng C, Nie M, Chen H. Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives. Neural Regen Res 2025; 20:3151-3171. [PMID: 39435603 PMCID: PMC11881730 DOI: 10.4103/nrr.nrr-d-24-00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/26/2024] [Accepted: 08/26/2024] [Indexed: 10/23/2024] Open
Abstract
"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.
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Affiliation(s)
- Fatima Aldali
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Chunchu Deng
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mingbo Nie
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hong Chen
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Ferreira LVDO, Amorim RM. Perspectives on Schwann-like cells derived from bone marrow-mesenchymal stem cells: Advancing peripheral nerve injury therapies. World J Stem Cells 2025; 17:102702. [DOI: 10.4252/wjsc.v17.i2.102702] [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: 10/25/2024] [Revised: 12/18/2024] [Accepted: 01/18/2025] [Indexed: 02/24/2025] Open
Abstract
Peripheral nerve injuries are clinical conditions that often result in functional deficits, compromising patient quality of life. Given the relevance of these injuries, new treatment strategies are constantly being investigated. Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action, the transdifferentiation of these cells into Schwann-like cells (SLCs) represents a significant advancement in nerve injury therapy. Recent studies indicate that SLCs can mimic the functions of Schwann cells, with promising results in animal models. However, challenges remain, such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications. A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries. Therefore, we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.
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Affiliation(s)
- Lucas Vinícius de Oliveira Ferreira
- Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, São Paulo, Brazil
| | - Rogério Martins Amorim
- Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, São Paulo, Brazil
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Tang Y, Li Y, Yang W, Tao Z, Shi W, Yu M, Xu B, Lu X. Nasal mucosal mesenchymal stem cells promote repair of sciatic nerve injury in rats by modulating the inflammatory microenvironment. Neurosci Lett 2025; 848:138112. [PMID: 39742941 DOI: 10.1016/j.neulet.2024.138112] [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: 08/29/2024] [Revised: 12/26/2024] [Accepted: 12/28/2024] [Indexed: 01/04/2025]
Abstract
Sciatic nerve injury (SNI) represents the most prevalent form of peripheral nerve damage, resulting in the rapid activation of macrophages into the M1 phenotype following injury. This activation induces an inflammatory microenvironment that negatively impacts nerve regeneration. Ectodermal mesenchymal stem cells (EMSCs), isolated from nasal mucosa, possess the capacity for multidirectional differentiation and exhibit immunomodulatory effects. Modulating macrophage polarization to create a favorable environment for nerve repair may represent a potential approach to facilitate nerve recovery. This investigation sought to explore the effects of EMSCs transplantation on macrophage polarization and nerve regeneration in SNI, as well as to identify the underlying mechanisms. An in vivo SNI model was established, and behavioral and histological analyses demonstrated that EMSCs transplantation facilitated nerve function recovery. Furthermore, immunofluorescence and Western blot assays revealed an increase in M2 macrophage presence and the secretion of anti-inflammatory cytokines following EMSCs transplantation, thereby promoting nerve regeneration. In vitro, EMSCs were found to enhance M2 macrophage polarization and the production of anti-inflammatory factors. Additionally, it was confirmed that EMSCs regulate macrophage polarization through the PI3K/AKT/NF-κB signaling pathway, thereby fostering an optimal inflammatory environment for nerve regeneration.
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Affiliation(s)
- Yushi Tang
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China; Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China
| | - Yilu Li
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China; Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China
| | - Wenhui Yang
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China; Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China
| | - Zhenxing Tao
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China
| | - Wentao Shi
- Department of Neurosurgery, Jiangnan University Medical Center ,Wuxi, Jiangsu Province, 214122, PR China; Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China
| | - Mengyuan Yu
- Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China
| | - Bai Xu
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China; Department of Neurosurgery, Jiangnan University Medical Center ,Wuxi, Jiangsu Province, 214122, PR China.
| | - Xiaojie Lu
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214122, PR China; Department of Neurosurgery, Jiangnan University Medical Center ,Wuxi, Jiangsu Province, 214122, PR China; Wuxi neurosurgical Institute, Wuxi, Jiangsu Province, 214122, PR China.
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Chang J, Yin XM, Zhang M, Liu JW, Zhao L. Bridging bioengineering and nanotechnology: Bone marrow derived mesenchymal stem cell-exosome solutions for peripheral nerve injury. World J Stem Cells 2025; 17:101161. [PMID: 39866899 PMCID: PMC11752453 DOI: 10.4252/wjsc.v17.i1.101161] [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: 09/05/2024] [Revised: 10/22/2024] [Accepted: 12/13/2024] [Indexed: 01/20/2025] Open
Abstract
Peripheral nerve injury (PNI) is a common disease that is difficult to nerve regeneration with current therapies. Fortunately, Zou et al demonstrated the role and mechanism of bone marrow derived mesenchymal stem cells (BMSCs) in promoting nerve regeneration, revealing broad prospects for BMSCs transplantation in alleviating PNI. We confirmed the fact that BMSCs significantly alleviate PNI, but there are shortcomings such as low cell survival rate and immune rejection, which limit the wide application of BMSCs. BMSCs-derived exosomes (Exos) are considered as a promising cell-free nanomedicine for PNI, avoiding the ethical issues of BMSCs. Exos in combination with bioengineering therapeutics (including extracellular matrix, hydrogel) brings new hope for PNI, provides a favorable microenvironment for neurological restoration and a therapeutic strategy with a favorable safety profile, significantly increases expression of neurotrophic factors, promotes axonal and myelin regeneration, and demonstrates a strong potential to enhance neurogenesis. Therefore, engineered Exos exhibit better properties, such as stronger targeting and more beneficial components. This article briefly describes the role of nanotechnology and bioengineering therapies for BMSCs in PNI, proposes clinical application prospects and challenges of nanotechnology and bioengineering BMSCs-derived Exos in PNI to improve the efficacy of BMSCs in the treatment of PNI.
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Affiliation(s)
- Jun Chang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Xiu-Mei Yin
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Man Zhang
- School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jian-Wei Liu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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Zhang WJ, Chen D. Mesenchymal stem cell transplantation plays a role in relieving cancer pain. Front Pharmacol 2024; 15:1483716. [PMID: 39679363 PMCID: PMC11637888 DOI: 10.3389/fphar.2024.1483716] [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: 08/20/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024] Open
Abstract
Tumors can invade, compress, and damage nerves, leading to persistent pain and seriously affecting the quality of life of patients. However, their treatment is challenging. Sensitization of peripheral receptors, abnormal activity of primary sensory neurons, activation of glial cells, enhanced inflammatory responses, and sensory information transmission contribute towards cancer pain. Therefore, considerable attention has been paid to exploring prospective methods to inhibit the occurrence of these factors and relieve cancer pain. Studies on different types of pains have revealed that the transplantation of functionally active cells into the host has the pharmacological effect of producing analgesia. Mesenchymal stem cells (MSCs) can act as small active pumps to reduce the expression of pain-related molecules and produce analgesic effects. Moreover, MSCs can establish complex communication networks with non-tumor and cancer cells in the microenvironment, interact with each other, and can be used as destinations for inflammation and tumor sites, affecting their potential for invasion and metastasis. This emphasizes the key role of MSCs in cancer and pain management. The pain relief mechanisms of MSCs include neuronutrition, neural protection, neural network reconstruction, immune regulation, and improvement of the inflammatory microenvironment around the nerve injury. All of these are beneficial for the recovery of injured or stimulated nerves and the reconstruction of neural function, and play a role in relieving pain. The pain treatment strategy of cell transplantation is to repair injured nerves and produce analgesic pharmacological properties that are different from those of painkillers and other physiotherapies. Although the therapeutic role of MSCs in cancer and pain is in its early stages, the therapeutic value of MSCs for cancer pain has great prospects. Therefore, in this study, we explored the possible mechanism between MSCs and cancer pain, the potential therapeutic role of therapeutic cells in cancer pain, and some problems and challenges.
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Affiliation(s)
- Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Jiangxi Medical college, Nanchang, China
| | - Dingyi Chen
- Emergency department, The Second Affiliated Hospital, Nanchang University, Jiangxi Medical college, Nanchang, China
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Bhatt A, Bhardwaj H, Srivastava P. Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases. Neuroscience 2024; 555:52-68. [PMID: 39032806 DOI: 10.1016/j.neuroscience.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.
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Affiliation(s)
- Aditya Bhatt
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Harshita Bhardwaj
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India.
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Bedar M, Pulos NA, Shin AY. Dynamic Seeding versus Microinjection of Adipose-Derived Mesenchymal Stem Cells to Acellular Nerve Allograft Reconstructions. Plast Reconstr Surg 2024; 154:114e-125e. [PMID: 37537724 PMCID: PMC10838349 DOI: 10.1097/prs.0000000000010970] [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] [Indexed: 08/05/2023]
Abstract
BACKGROUND Functional recovery after acellular nerve allograft (ANA) reconstruction remains inferior to that after autologous nerve grafting, but improved outcomes have been demonstrated with the addition of adipose-derived mesenchymal stem cells (MSCs). Controversy exists regarding the optimal cell-delivery method to enhance ANA reconstructions. The authors investigated the functional recovery of ANAs after dynamic seeding versus microinjection of MSCs. METHODS Forty Lewis rats underwent reconstruction of a 10-mm sciatic nerve defect. Animals were divided into 4 groups: reversed autograft, ANA alone, dynamically seeded ANA, or ANA injected with MSCs. During the survival period, ultrasound measurements of the tibialis anterior muscle cross-sectional area were performed. At 12 weeks, functional recovery was evaluated using measurements of ankle contracture, compound muscle action potential, maximum isometric tetanic force, muscle mass, histomorphometry, and immunofluorescence. RESULTS The dynamic seeding and microinjection groups demonstrated higher cross-sectional tibialis anterior muscle area recovery than autografts and ANAs alone at week 8 and weeks 4 and 8, respectively. The ankle contracture and compound muscle action potential amplitude recovery were superior in autografts and both seeding methods compared with ANAs alone. The microinjection group demonstrated significantly higher isometric tetanic force, muscle mass, and number of axons compared with ANAs alone. Both seeding methods showed higher CD34 densities compared with ANAs alone. No significant differences between dynamic seeding and microinjection were observed in functional or histologic outcomes. CONCLUSIONS The addition of MSCs to ANAs demonstrated earlier motor regeneration compared with autografts and ANAs alone. Both seeding methods improved functional outcomes in the rat sciatic nerve defect model.
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Affiliation(s)
- Meiwand Bedar
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands
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Fujiwara S, Nakano-Doi A, Sawano T, Kubo S, Doe N, Nakagomi T. Administration of Human-Derived Mesenchymal Stem Cells Activates Locally Stimulated Endogenous Neural Progenitors and Reduces Neurological Dysfunction in Mice after Ischemic Stroke. Cells 2024; 13:939. [PMID: 38891071 PMCID: PMC11171641 DOI: 10.3390/cells13110939] [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: 04/22/2024] [Revised: 05/25/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Increasing evidence shows that the administration of mesenchymal stem cells (MSCs) is a promising option for various brain diseases, including ischemic stroke. Studies have demonstrated that MSC transplantation after ischemic stroke provides beneficial effects, such as neural regeneration, partially by activating endogenous neural stem/progenitor cells (NSPCs) in conventional neurogenic zones, such as the subventricular and subgranular zones. However, whether MSC transplantation regulates the fate of injury-induced NSPCs (iNSPCs) regionally activated at injured regions after ischemic stroke remains unclear. Therefore, mice were subjected to ischemic stroke, and mCherry-labeled human MSCs (h-MSCs) were transplanted around the injured sites of nestin-GFP transgenic mice. Immunohistochemistry of brain sections revealed that many GFP+ cells were observed around the grafted sites rather than in the regions in the subventricular zone, suggesting that transplanted mCherry+ h-MSCs stimulated GFP+ locally activated endogenous iNSPCs. In support of these findings, coculture studies have shown that h-MSCs promoted the proliferation and neural differentiation of iNSPCs extracted from ischemic areas. Furthermore, pathway analysis and gene ontology analysis using microarray data showed that the expression patterns of various genes related to self-renewal, neural differentiation, and synapse formation were changed in iNSPCs cocultured with h-MSCs. We also transplanted h-MSCs (5.0 × 104 cells/µL) transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion. Compared with phosphate-buffered saline-injected controls, h-MSC transplantation displayed significantly improved neurological functions. These results suggest that h-MSC transplantation improves neurological function after ischemic stroke in part by regulating the fate of iNSPCs.
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Affiliation(s)
- Shuichi Fujiwara
- Institute for Advanced Medical Sciences, Hyogo Medical University (Nishinomiya Campus), 1-1 Mukogawacho, Nishinomiya 663-8501, Japan; (S.F.); (A.N.-D.); (S.K.)
| | - Akiko Nakano-Doi
- Institute for Advanced Medical Sciences, Hyogo Medical University (Nishinomiya Campus), 1-1 Mukogawacho, Nishinomiya 663-8501, Japan; (S.F.); (A.N.-D.); (S.K.)
- Department of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan
| | - Toshinori Sawano
- Department of Biomedical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu 525-8577, Japan;
| | - Shuji Kubo
- Institute for Advanced Medical Sciences, Hyogo Medical University (Nishinomiya Campus), 1-1 Mukogawacho, Nishinomiya 663-8501, Japan; (S.F.); (A.N.-D.); (S.K.)
| | - Nobutaka Doe
- Department of Rehabilitation, Hyogo Medical University (Kobe Campus), 1-3-6 Minatojima, Chuo-ku, Kobe 650-8530, Japan;
| | - Takayuki Nakagomi
- Institute for Advanced Medical Sciences, Hyogo Medical University (Nishinomiya Campus), 1-1 Mukogawacho, Nishinomiya 663-8501, Japan; (S.F.); (A.N.-D.); (S.K.)
- Department of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawacho, Nishinomiya 663-8501, Japan
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Domingues RB, von Rautenfeld M, Kavalco CM, Caliari C, Dellagiustina C, da Fonseca LF, Costa FR, da Cruz Silva Reis A, Santos GS, Azzini G, de Faria APL, Santos N, Pires L, Huber SC, Mahmood A, Dallo I, Everts P, Lana JF. The role of orthobiologics in chronic wound healing. Int Wound J 2024; 21:e14854. [PMID: 38619232 PMCID: PMC11017856 DOI: 10.1111/iwj.14854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 03/13/2024] [Indexed: 04/16/2024] Open
Abstract
Chronic wounds, characterized by prolonged healing processes, pose a significant medical challenge with multifaceted aetiologies, including local and systemic factors. Here, it explores the complex pathogenesis of chronic wounds, emphasizing the disruption in the normal phases of wound healing, particularly the inflammatory phase, leading to an imbalance in extracellular matrix (ECM) dynamics and persistent inflammation. Senescent cell populations further contribute to impaired wound healing in chronic lesions. Traditional medical management focuses on addressing underlying causes, but many chronic wounds resist to conventional treatments, necessitating innovative approaches. Recent attention has turned to autologous orthobiologics, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF) and mesenchymal stem cells (MSCs), as potential regenerative interventions. These biologically derived materials, including bone marrow aspirate/concentrate (BMA/BMAC) and adipose tissue-derived stem cells (ADSCs), exhibit promising cytokine content and regenerative potential. MSCs, in particular, have emerged as key players in wound healing, influencing inflammation and promoting tissue regeneration. This paper reviews relevant scientific literature regarding basic science and brings real-world evidence regarding the use of orthobiologics in the treatment of chronic wounds, irrespective of aetiology. The discussion highlights the regenerative properties of PRP, PRF, BMA, BMAC and SVF, showcasing their potential to enhance wound healing. Despite advancements, further research is essential to elucidate the specific roles of each orthobiologic and determine optimal applications for different wound types. The conclusion underscores the evolving landscape in chronic wound management, with a call for more comprehensive studies to refine treatment strategies and maximize the benefits of regenerative medicine.
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Affiliation(s)
- Rafael Barnabé Domingues
- Clinical ResearchAnna Vitória Lana Institute (IAVL)SPBrazil
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
| | | | | | | | - Celso Dellagiustina
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | | | - Fabio Ramos Costa
- Department of Orthopedics, FC Sports Traumatology ClinicSalvadorBABrazil
| | | | - Gabriel Silva Santos
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | - Gabriel Azzini
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | | | - Napoliane Santos
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | - Luyddy Pires
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | - Stephany Cares Huber
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
| | - Ansar Mahmood
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Medical SchoolUniMAXIndaiatubaSPBrazil
| | - Ignacio Dallo
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Medical SchoolUniMAXIndaiatubaSPBrazil
| | - Peter Everts
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Medical SchoolUniMAXIndaiatubaSPBrazil
| | - José Fábio Lana
- Clinical ResearchAnna Vitória Lana Institute (IAVL)SPBrazil
- Regenerative Medicine, Orthoregen International CourseIndaiatubaSPBrazil
- Department of OrthopedicsBrazilian Institute of Regenerative Medicine (BIRM)SPBrazil
- Medical SchoolUniMAXIndaiatubaSPBrazil
- Medical SchoolUniFAJJaguariúnaSPBrazil
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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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11
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Hoveizi E. Enhancement of nerve regeneration through schwann cell-mediated healing in a 3D printed polyacrylonitrile conduit incorporating hydrogel and graphene quantum dots: a study on rat sciatic nerve injury model. Biomed Mater 2023; 19:015012. [PMID: 38091624 DOI: 10.1088/1748-605x/ad1576] [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: 09/09/2023] [Accepted: 12/13/2023] [Indexed: 12/22/2023]
Abstract
Despite recent technological advancements, effective healing from sciatic nerve damage remains inadequate. Cell-based therapies offer a promising alternative to autograft restoration for peripheral nerve injuries, and 3D printing techniques can be used to manufacture conduits with controlled diameter and size. In this study, we investigated the potential of Wharton's jelly-derived mesenchymal stem cells (WJMSCs) differentiated into schwann cells, using a polyacrylonitrile (PAN) conduit filled with fibrin hydrogel and graphene quantum dots (GQDs) to promote nerve regeneration in a rat sciatic nerve injury model. We investigated the potential of WJMSCs, extracted from the umbilical cord, to differentiate into schwann cells and promote nerve regeneration in a rat sciatic nerve injury model. WJMSCs were 3D cultured and differentiated into schwann cells within fibrin gel for two weeks. A 3 mm defect was created in the sciatic nerve of the rat model, which was then regenerated using a conduit/fibrin, conduit covered with schwann cells in fibrin/GQDs, GQDs in fibrin, and a control group without any treatment (n= 6/group). At 10 weeks after transplantation, motor and sensory functions and histological improvement were assessed. The WJMSCs were extracted, identified, and differentiated. The differentiated cells expressed typical schwann cell markers, S100 and P75.In vivoinvestigations established the durability and efficacy of the conduit to resist the pressures over two months of implantation. Histological measurements showed conduit efficiency, schwann cell infiltration, and association within the fibrin gel and lumen. Rats treated with the composite hydrogel-filled PAN conduit with GQDs showed significantly higher sensorial recovery than the other groups. Histological results showed that this group had significantly more axon numbers and remyelination than others. Our findings suggest that the conduit/schwann approach has the potential to improve nerve regeneration in peripheral nerve injuries, with future therapeutic implications.
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Affiliation(s)
- Elham Hoveizi
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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Joshi R, Missong H, Mishra J, Kaur S, Saini S, Kandimalla R, Reddy PH, Babu A, Bhatti GK, Bhatti JS. Nanotheranostics revolutionizing neurodegenerative diseases: From precision diagnosis to targeted therapies. J Drug Deliv Sci Technol 2023; 89:105067. [DOI: 10.1016/j.jddst.2023.105067] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Buccellato FR, D’Anca M, Tartaglia GM, Del Fabbro M, Scarpini E, Galimberti D. Treatment of Alzheimer's Disease: Beyond Symptomatic Therapies. Int J Mol Sci 2023; 24:13900. [PMID: 37762203 PMCID: PMC10531090 DOI: 10.3390/ijms241813900] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.
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Affiliation(s)
- Francesca R. Buccellato
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Marianna D’Anca
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Gianluca Martino Tartaglia
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Massimo Del Fabbro
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Elio Scarpini
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Daniela Galimberti
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Bhatti JS, Khullar N, Mishra J, Kaur S, Sehrawat A, Sharma E, Bhatti GK, Selman A, Reddy PH. Stem cells in the treatment of Alzheimer's disease - Promises and pitfalls. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166712. [PMID: 37030521 DOI: 10.1016/j.bbadis.2023.166712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 03/31/2023] [Indexed: 04/10/2023]
Abstract
Alzheimer's disease (AD) is the most widespread form of neurodegenerative disorder that causes memory loss and multiple cognitive issues. The underlying mechanisms of AD include the build-up of amyloid-β and phosphorylated tau, synaptic damage, elevated levels of microglia and astrocytes, abnormal microRNAs, mitochondrial dysfunction, hormonal imbalance, and age-related neuronal loss. However, the etiology of AD is complex and involves a multitude of environmental and genetic factors. Currently, available AD medications only alleviate symptoms and do not provide a permanent cure. Therefore, there is a need for therapies that can prevent or reverse cognitive decline, brain tissue loss, and neural instability. Stem cell therapy is a promising treatment for AD because stem cells possess the unique ability to differentiate into any type of cell and maintain their self-renewal. This article provides an overview of the pathophysiology of AD and existing pharmacological treatments. This review article focuses on the role of various types of stem cells in neuroregeneration, the potential challenges, and the future of stem cell-based therapies for AD, including nano delivery and gaps in stem cell technology.
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Affiliation(s)
- Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Jayapriya Mishra
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Satinder Kaur
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Abhishek Sehrawat
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Eva Sharma
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - Ashley Selman
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA.
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Zhu Z, Zhang Y, Huang Z, Hao H, Yan M. Hypoxic culture of umbilical cord mesenchymal stem cell-derived sEVs prompts peripheral nerve injury repair. Front Cell Neurosci 2023; 16:897224. [PMID: 36970310 PMCID: PMC10035596 DOI: 10.3389/fncel.2022.897224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 12/07/2022] [Indexed: 03/11/2023] Open
Abstract
IntroductionRepair and regeneration of the peripheral nerve are important for the treatment of peripheral nerve injury (PNI) caused by mechanical tears, external compression injuries and traction injuries. Pharmacological treatment can promote the proliferation of fibroblasts and Schwann cells (SCs), which longitudinally fill the endoneurial canal and form Bungner’s band, helping the repair of peripheral nerves. Therefore, the development of new drugs for the treatment of PNI has become a top priority in recent years.MethodsHere, we report that small extracellular vesicles (sEVs) produced from umbilical cord mesenchymal stem cells (MSC-sEVs) cultured under hypoxia promote repair and regeneration of the peripheral nerve in PNI and may be a new therapeutic drug candidate.ResultsThe results showed that the amount of secreted sEVs was significantly increased in UC-MSCs compared with control cells after 48 h of culture at 3% oxygen partial pressure in a serum-free culture system. The identified MSC-sEVs could be taken up by SCs in vitro, promoting the growth and migration of SCs. In a spared nerve injury (SNI) mouse model, MSC-sEVs accelerated the recruitment of SCs at the site of PNI and promoted peripheral nerve repair and regeneration. Notably, repair and regeneration in the SNI mouse model were enhanced by treatment with hypoxic cultured UC-MSC-derived sEVs.DiscussionTherefore, we conclude that hypoxic cultured UC-MSC-derived sEVs may be a promising candidate drug for repair and regeneration in PNI.
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Affiliation(s)
- Ziying Zhu
- The First Medical Center of Chinese PLA General Hospital, Beijing, China
- *Correspondence: Ziying Zhu,
| | - Yujun Zhang
- Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing, China
| | - Zhihua Huang
- Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing, China
| | - Haojie Hao
- The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Haojie Hao,
| | - Muyang Yan
- The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Muyang Yan,
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Wang M, Wu S, Wang J, Fan D, Li Z, Tian S, Yao S, Zhang H, Gao H. MiRNA-206 Affects the Recovery of Sciatic Function by Stimulating BDNF Activity through the Down-regulation of Notch3 Expression. JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS 2023; 23:109-121. [PMID: 36856106 PMCID: PMC9976182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
OBJECTIVE To investigate the effects and mechanisms of microRNA 206 (miRNA-206) on neurological recovery through Notch receptor 3 (Notch3). METHODS The sciatic functional index (SFI), nerve conduction velocity (NCV), tricipital muscle wet weight (TWW) and cross-sectional area of the muscular fiber, and grip strength of posterior limbs were detected by establishing a model of the sciatic nerve to evaluate the effect of sciatic nerve injury model. miRNA-206 expression in the model was detected by real-time quantitative polymerase chain reaction (qRT-PCR), to regulate the effects of miRNA-206 on the proliferation of gastrocnemius myocytes by Cell Counting Kit-8 (CCK-8). RESULTS SFI of the model established by immediate epineurium suture after sciatic nerve resection was in the range of -150% to -100% and TWW, the average area of gastrocnemius myocytes, the NCV, and the grasping power of the hind limbs in the model were all lower than those in the normal group. And in the model, TWW, the average area of gastrocnemius myocytes, NCV, and grip strength of posterior limbs were lower in the normal group, which verified the successful establishment of the model. CONCLUSION Over-expression of miRNA-206 can down-regulate Notch3 expression, and then stimulate brain-derived neurotrophic factor (BDNF) activity to promote the repair and functional recovery of sciatic nerve injury.
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Affiliation(s)
- Meng Wang
- Post-graduation Education Office, College of General Practice and Continuing Education, Qiqihar Medical University, Qiqihar, China
| | - Shuang Wu
- Ward 5, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Jun Wang
- Academic Affairs Office, Qiqihar Medical University, Qiqihar, China
| | - Dandan Fan
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Zhiyong Li
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Shaohua Tian
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Sining Yao
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Hongyu Zhang
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Hongwei Gao
- Ward 2, Department of Orthopedics, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
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Paes SM, Castro MVD, Barbosa RM, Politti Cartarozzi L, Coser LDO, Kempe PRG, Decarli MC, Moraes ÂM, Barraviera B, Ferreira Júnior RS, Oliveira ALRD. Human dental pulp stem cell monolayer and spheroid therapy after spinal motor root avulsion in adult rats. Brain Res 2023; 1802:148229. [PMID: 36592804 DOI: 10.1016/j.brainres.2022.148229] [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: 11/02/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
Spinal cord injuries result in severe neurological deficits and neuronal loss, with poor functional recovery. Mesenchymal stem cells have shown promising results; therefore the present objective of this work was to compare motor recovery after treatment with human dental pulp stem cells (hDPSC) cultivated in monolayer (2D) or as spheroids (3D), following avulsion and reimplantation of spinal motor roots in adult rats. Thus, 72 adult female Lewis rats were divided into 4 groups: avulsion (AV); avulsion followed by reimplantation (AR); avulsion associated with reimplant and 2D cell therapy (AR + 2D), and avulsion associated with reimplant and 3D cell therapy (AR + 3D). The application of the cells in 2D and 3D was performed by microsurgery, with subsequent functional assessment using a walking track test (Catwalk system), immunohistochemistry, neuronal survival, and qRT-PCR in 1-, 4-, and 12-weeks post-injury. The animals in the AR + 2D and AR + 3D groups showed the highest neuronal survival rates, and immunofluorescence revealed downregulation of GFAP, and Iba-1, with preservation of synaptophysin, indicating a reduction in glial reactivity, combined with the maintenance of pre-synaptic inputs. There was an increase in anti-inflammatory (IL-4, TGFβ) and a reduction of pro-inflammatory factors (IL-6, TNFα) in animals treated with reimplantation and hDPSC. As for the functional recovery, in all analyzed parameters, the AR + 2D group performed better and was superior to the avulsion alone. Overall, our results indicate that the 2D and 3D cell therapy approaches provide successful immunomodulation and motor recovery, consistent with advanced therapies after spinal cord injury.
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Affiliation(s)
- Sabrina Moreira Paes
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Mateus Vidigal de Castro
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Rafael Maza Barbosa
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil; School of Chemical Engineering, University of Campinas, UNICAMP, Av. Albert Einstein, 500, Brazil
| | - Luciana Politti Cartarozzi
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Lilian de Oliveira Coser
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Paula Regina Gelinski Kempe
- Laboratory of Nerve Regeneration, Institute of Biology (IB), State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Monize Caiado Decarli
- School of Chemical Engineering, University of Campinas, UNICAMP, Av. Albert Einstein, 500, Brazil
| | - Ângela Maria Moraes
- School of Chemical Engineering, University of Campinas, UNICAMP, Av. Albert Einstein, 500, Brazil
| | - Benedito Barraviera
- Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Rui Seabra Ferreira Júnior
- Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil
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Comprehensive dynamic and kinematic analysis of the rodent hindlimb during over ground walking. Sci Rep 2022; 12:19725. [PMID: 36385108 PMCID: PMC9668918 DOI: 10.1038/s41598-022-20288-3] [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: 12/03/2021] [Accepted: 09/12/2022] [Indexed: 11/18/2022] Open
Abstract
The rat hindlimb is a frequently utilized pre-clinical model system to evaluate injuries and pathologies impacting the hindlimbs. These studies have demonstrated the translational potential of this model but have typically focused on the force generating capacity of target muscles as the primary evaluative outcome. Historically, human studies investigating extremity injuries and pathologies have utilized biomechanical analysis to better understand the impact of injury and extent of recovery. In this study, we expand that full biomechanical workup to a rat model in order to characterize the spatiotemporal parameters, ground reaction forces, 3-D joint kinematics, 3-D joint kinetics, and energetics of gait in healthy rats. We report data on each of these metrics that meets or exceeds the standards set by the current literature and are the first to report on all these metrics in a single set of animals. The methodology and findings presented in this study have significant implications for the development and clinical application of the improved regenerative therapeutics and rehabilitative therapies required for durable and complete functional recovery from extremity traumas, as well as other musculoskeletal pathologies.
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Jiang Y, Tang X, Li T, Ling J, Yang Y. The success of biomaterial-based tissue engineering strategies for peripheral nerve regeneration. Front Bioeng Biotechnol 2022; 10:1039777. [PMID: 36329703 PMCID: PMC9622790 DOI: 10.3389/fbioe.2022.1039777] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 10/04/2022] [Indexed: 11/26/2022] Open
Abstract
Peripheral nerve injury is a clinically common injury that causes sensory dysfunction and locomotor system degeneration, which seriously affects the quality of the patients' daily life. Long gapped defects in large nerve are difficult to repair via surgery and limited donor source of autologous nerve greatly challenges the successful nerve repair by transplantation. Significantly, remarkable progress has been made in repairing the peripheral nerve injury using artificial nerve grafts and a variety of products for peripheral nerve repair have emerged been approved globally in recent years. The raw materials of these commercial products includes natural/synthetic polymers, extracellular matrix. Despite a lot of effort, the desirable functional recovery still remains great challenges in long gapped nerve defects. Thus this review discusses the recent development of tissue engineering products for peripheral nerve repair and the design of bionic grafts improving the local microenvironment for accelerating nerve regeneration against locomotor disorder, which may provide potential strategies for the repair of long gaps or thick nerve defects by multifunctional biomaterials.
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Affiliation(s)
- Yuhui Jiang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Xiaoxuan Tang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Tao Li
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Jue Ling
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
| | - Yumin Yang
- Medical School of Nantong University, Nantong University, Nantong, China
- Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
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Trueman RP, Ahlawat AS, Phillips JB. A Shock to the (Nervous) System: Bioelectricity Within Peripheral Nerve Tissue Engineering. TISSUE ENGINEERING. PART B, REVIEWS 2022; 28:1137-1150. [PMID: 34806913 DOI: 10.1089/ten.teb.2021.0159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The peripheral nervous system has the remarkable ability to regenerate in response to injury. However, this is only successful over shorter nerve gaps and often provides poor outcomes for patients. Currently, the gold standard of treatment is the surgical intervention of an autograft, whereby patient tissue is harvested and transplanted to bridge the nerve gap. Despite being the gold standard, more than half of patients have dissatisfactory functional recovery after an autograft. Peripheral nerve tissue engineering aims to create biomaterials that can therapeutically surpass the autograft. Current tissue-engineered constructs are designed to deliver a combination of therapeutic benefits to the regenerating nerve, such as supportive cells, alignment, extracellular matrix, soluble factors, immunosuppressants, and other therapies. An emerging therapeutic opportunity in nerve tissue engineering is the use of electrical stimulation (ES) to modify and enhance cell function. ES has been shown to positively affect four key cell types, such as neurons, endothelial cells, macrophages, and Schwann cells, involved in peripheral nerve repair. Changes elicited include faster neurite extension, cellular alignment, and changes in cell phenotype associated with improved regeneration and functional recovery. This review considers the relevant modes of administration and cellular responses that could underpin incorporation of ES into nerve tissue engineering strategies. Impact Statement Tissue engineering is becoming increasingly complex, with multiple therapeutic modalities often included within the final tissue-engineered construct. Electrical stimulation (ES) is emerging as a viable therapeutic intervention to be included within peripheral nerve tissue engineering strategies; however, to date, there have been no review articles that collate the information regarding the effects of ES on key cell within peripheral nerve injury. This review article aims to inform the field on the different therapeutic effects that may be achieved by using ES and how they may become incorporated into existing strategies.
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Affiliation(s)
- Ryan P Trueman
- Center for Nerve Engineering, Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
- Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
| | - Ananya S Ahlawat
- Center for Nerve Engineering, Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
- Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
| | - James B Phillips
- Center for Nerve Engineering, Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
- Department of Pharmacology, UCL School of Pharmacy, University College London, London, United Kingdom
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Guo J, Hai H, Ma Y. Application of extracorporeal shock wave therapy in nervous system diseases: A review. Front Neurol 2022; 13:963849. [PMID: 36062022 PMCID: PMC9428455 DOI: 10.3389/fneur.2022.963849] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022] Open
Abstract
Neurological disorders are one of the leading causes of morbidity and mortality worldwide, and their therapeutic options remain limited. Recent animal and clinical studies have shown the potential of extracorporeal shock wave therapy (ESWT) as an innovative, safe, and cost-effective option to treat neurological disorders. Moreover, the cellular and molecular mechanism of ESWT has been proposed to better understand the regeneration and repairment of neurological disorders by ESWT. In this review, we discuss the principles of ESWT, the animal and clinical studies involving the use of ESWT to treat central and peripheral nervous system diseases, and the proposed cellular and molecular mechanism of ESWT. We also discuss the challenges encountered when applying ESWT to the human brain and spinal cord and the new potential applications of ESWT in treating neurological disorders.
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22
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Targosinski S, Henzi A, Engmann AK, Rushing EJ, Barth AA, Klein HJ, Kim BS, Giovanoli P, Schwab ME, Plock JA, Schweizer R. A swim test for functional assessment of rodent peripheral nerve regeneration. J Neurosci Methods 2022; 379:109663. [PMID: 35809863 DOI: 10.1016/j.jneumeth.2022.109663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 06/08/2022] [Accepted: 07/04/2022] [Indexed: 10/17/2022]
Affiliation(s)
- Stefan Targosinski
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Anna Henzi
- Institute of Neuropathology, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Anne K Engmann
- Department of Health Sciences and Technology, ETH Zurich, Switzerland; Brain Research Institute, University of Zurich, Zurich, Switzerland
| | | | - André A Barth
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Holger J Klein
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland; Department of Plastic Surgery and Hand Surgery, Kantonsspital Aarau, Aarau, Switzerland
| | - Bong-Sung Kim
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Pietro Giovanoli
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Martin E Schwab
- Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
| | - Jan A Plock
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland; Department of Plastic Surgery and Hand Surgery, Kantonsspital Aarau, Aarau, Switzerland
| | - Riccardo Schweizer
- Department of Plastic Surgery and Hand Surgery, UniversitätsSpital Zürich, Zurich, Switzerland.
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Mohebichamkhorami F, Fattahi R, Niknam Z, Aliashrafi M, Khakpour Naeimi S, Gilanchi S, Zali H. Periodontal ligament stem cells as a promising therapeutic target for neural damage. Stem Cell Res Ther 2022; 13:273. [PMID: 35729595 PMCID: PMC9210648 DOI: 10.1186/s13287-022-02942-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 06/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The damaged neuronal cells of adult mammalian lack the regenerative ability to replace the neuronal connections. Periodontal ligament stem cells (PDLSCs) are the promising source for neuroregenerative applications that can improve the injured microenvironment of the damaged neural system. They provide neuronal progenitors and neurotrophic, anti-apoptotic and anti-inflammatory factors. In this study, we aimed to comprehensively explore the various neuronal differentiation potentials of PDLSCs for application in neural regeneration therapy. MAIN TEXT PDLSCs have superior potential to differentiate into various neural-like cells through a dedifferentiation stage followed by differentiation process without need for cell division. Diverse combination of nutritional factors can be used to induce the PDLSCs toward neural lineage. PDLSCs when coupled with biomaterials could have significant implications for neural tissue repair. PDLSCs can be a new clinical research target for Alzheimer's disease treatment, multiple sclerosis and cerebral ischemia. Moreover, PDLSCs have beneficial effects on retinal ganglion cell regeneration and photoreceptor survival. PDLSCs can be a great source for the repair of injured peripheral nerve through the expression of several neural growth factors and differentiation into Schwann cells. CONCLUSION In conclusion, these cells are an appealing source for utilizing in clinical treatment of the neuropathological disorders. Although significant in vitro and in vivo investigations were carried out in order for neural differentiation evaluation of these cells into diverse types of neurons, more preclinical and clinical studies are needed to elucidate their therapeutic potential for neural diseases.
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Affiliation(s)
- Fariba Mohebichamkhorami
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roya Fattahi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Niknam
- Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morteza Aliashrafi
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran
| | | | - Samira Gilanchi
- Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abdelrahman SA, Abdelrahman AA, Samy W, Dessouky AA, Ahmed SM. Hypoxia pretreatment enhances the therapeutic potential of mesenchymal stem cells (BMSCs) on ozone-induced lung injury in rats. Cell Tissue Res 2022; 389:201-217. [PMID: 35551479 PMCID: PMC9287250 DOI: 10.1007/s00441-022-03627-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 04/16/2022] [Indexed: 11/26/2022]
Abstract
Ozone (O3) gas is a double-sided weapon. It provides a shield that protects life on earth from the harmful ultraviolet (UV) rays, but ground-level O3 is considered an urban air pollutant. So, a rat model of chronic O3 inhalation was established to assess the biochemical and morphological alterations in the lung tissue and to investigate the ameliorative effects of bone marrow-derived mesenchymal stem cells (BMSCs) with or without hypoxia pre-treatment. Forty-two adult male albino rats were divided into four groups: control, ozone-exposed, normoxic BMSC-treated, and hypoxic BMSC-treated groups. Lung tissue sections were processed for light and electron microscope examination, immunohistochemical staining for caspase 3, and iNOS. Quantitative real-time PCR for IL-1α, IL-17, TNF-α, and Nrf2 mRNA gene expression were also performed. Chronic O3 exposure caused elevated inflammatory cytokines and decreased antioxidant Nrf2 mRNA expression. Marked morphological alterations with increased collagen deposition and elevated apoptotic markers and iNOS were evident. BMSC treatment showed immunomodulatory (decreased inflammatory cytokine gene expression), antioxidant (increased Nrf2 expression and decreased iNOS), and anti-apoptotic (decreased caspase3 expression) effects. Consequently, ameliorated lung morphology with diminished collagen deposition was observed. Hypoxia pretreatment enhanced BMSC survival by MTT assay. It also augmented the previously mentioned effects of BMSCs on the lung tissue as proved by statistical analysis. Lung morphology was similar to that of control group. In conclusion, hypoxia pretreatment represents a valuable intervention to enhance the effects of MSCs on chronic lung injury.
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Affiliation(s)
- Shaimaa A Abdelrahman
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Abeer A Abdelrahman
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Walaa Samy
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Arigue A Dessouky
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samah M Ahmed
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Alipour H, Alizadeh A, Azarpira N, Saudi A, Alavi O, Tanideh N, Dehghani F. Incorporating fingolimod through poly(lactic‐co‐glycolic acid) nanoparticles in electrospun polyurethane/polycaprolactone/gelatin scaffold: An in vitro study for nerve tissue engineering. POLYM ADVAN TECHNOL 2022. [DOI: 10.1002/pat.5715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Hamed Alipour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences Shiraz Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences Shiraz Iran
| | - Negar Azarpira
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences Shiraz Iran
- Transplant Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Ahmad Saudi
- Department of Biomaterials, Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine Isfahan University of Medical Sciences Isfahan Iran
| | - Omid Alavi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies Shiraz University of Medical Sciences Shiraz Iran
| | - Nader Tanideh
- Stem Cells Technology Research Center Shiraz University of Medical Sciences Shiraz Iran
- Department of Pharmacology, School of Medicine Shiraz University of Medical Sciences Shiraz Iran
| | - Farzaneh Dehghani
- Department of Anatomical Sciences, School of Medicine Shiraz University of Medical Sciences Shiraz Iran
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Sanchez Rezza A, Kulahci Y, Gorantla VS, Zor F, Drzeniek NM. Implantable Biomaterials for Peripheral Nerve Regeneration-Technology Trends and Translational Tribulations. Front Bioeng Biotechnol 2022; 10:863969. [PMID: 35573254 PMCID: PMC9092979 DOI: 10.3389/fbioe.2022.863969] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 04/05/2022] [Indexed: 02/01/2023] Open
Abstract
The use of autografted nerve in surgical repair of peripheral nerve injuries (PNI) is severely limited due to donor site morbidity and restricted tissue availability. As an alternative, synthetic nerve guidance channels (NGCs) are available on the market for surgical nerve repair, but they fail to promote nerve regeneration across larger critical gap nerve injuries. Therefore, such injuries remain unaddressed, result in poor healing outcomes and are a limiting factor in limb reconstruction and transplantation. On the other hand, a myriad of advanced biomaterial strategies to address critical nerve injuries are proposed in preclinical literature but only few of those have found their way into clinical practice. The design of synthetic nerve grafts should follow rational criteria and make use of a combination of bioinstructive cues to actively promote nerve regeneration. To identify the most promising NGC designs for translation into applicable products, thorough mode of action studies, standardized readouts and validation in large animals are needed. We identify design criteria for NGC fabrication according to the current state of research, give a broad overview of bioactive and functionalized biomaterials and highlight emerging composite implant strategies using therapeutic cells, soluble factors, structural features and intrinsically conductive substrates. Finally, we discuss translational progress in bioartificial conduits for nerve repair from the surgeon's perspective and give an outlook toward future challenges in the field.
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Affiliation(s)
- Angela Sanchez Rezza
- Charité— Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany
| | - Yalcin Kulahci
- Wake Forest School of Medicine, Department of Surgery, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States
| | - Vijay S. Gorantla
- Wake Forest School of Medicine, Department of Surgery, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States
| | - Fatih Zor
- Wake Forest School of Medicine, Department of Surgery, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States
| | - Norman M. Drzeniek
- Charité— Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
- Charité — Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
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Dynamic seeding versus microinjection of mesenchymal stem cells for acellular nerve allograft: an in vitro comparison. J Plast Reconstr Aesthet Surg 2022; 75:2821-2830. [PMID: 35570113 PMCID: PMC9391259 DOI: 10.1016/j.bjps.2022.04.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/17/2022] [Accepted: 04/12/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-supplemented acellular nerve allografts (ANA) are a potential strategy to improve the treatment of segmental nerve defects. Prior to clinical translation, optimal cell delivery methods must be defined. While two techniques, dynamic seeding and microinjection, have been described, the seeding efficiency, cell viability, and distribution of MSCs in ANAs are yet to be compared. METHODS Sciatic nerve segments of Sprague-Dawley rats were decellularized, and MSCs were harvested from the adipose tissue of Lewis rats. Cell viability was evaluated after injection of MSCs through a 27-gauge needle at different flow rates (10, 5, and 1 µL/min). MSCs were dynamically seeded or longitudinally injected into ANAs. Cell viability, seeding efficiency, and distribution were evaluated using LIVE/DEAD and MTS assays, scanning electron microscopy, and Hoechst staining. RESULTS No statistically significant difference in cell viability after injection at different flow rates was seen. After cell delivery, 84.1 ± 3.7% and 87.8 ± 2.8% of MSCs remained viable in the dynamic seeding and microinjection group, respectively (p = 0.41). The seeding efficiency of microinjection (100.4%±5.6) was significantly higher than dynamic seeding (48.1%±8.6) on day 1 (p = 0.001). Dynamic seeding demonstrated a significantly more uniform cell distribution over the course of the ANA compared to microinjection (p = 0.02). CONCLUSION MSCs remain viable after both dynamic seeding and microinjection in ANAs. Higher seeding efficiency was observed with microinjection, but dynamic seeding resulted in a more uniform distribution. In vivo studies are required to assess the effect on gene expression profiles and functional motor outcomes.
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Alvites R, Branquinho M, Sousa AC, Lopes B, Sousa P, Maurício AC. Mesenchymal Stem/Stromal Cells and Their Paracrine Activity-Immunomodulation Mechanisms and How to Influence the Therapeutic Potential. Pharmaceutics 2022; 14:381. [PMID: 35214113 PMCID: PMC8875256 DOI: 10.3390/pharmaceutics14020381] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration.
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Affiliation(s)
- 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana C. 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, 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; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
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Entezari M, Mozafari M, Bakhtiyari M, Moradi F, Bagher Z, Soleimani M. Three-dimensional-printed polycaprolactone/polypyrrole conducting scaffolds for differentiation of human olfactory ecto-mesenchymal stem cells into Schwann cell-like phenotypes and promotion of neurite outgrowth. J Biomed Mater Res A 2022; 110:1134-1146. [PMID: 35075781 DOI: 10.1002/jbm.a.37361] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/25/2021] [Accepted: 01/05/2022] [Indexed: 12/14/2022]
Abstract
Implantation of a suitable nerve guide conduit (NGC) seeded with sufficient Schwann cells (SCs) is required to improve peripheral nerve regeneration efficiently. Given the limitations of isolating and culturing SCs, using various sources of stem cells, including mesenchymal stem cells (MSCs) obtained from nasal olfactory mucosa, can be desirable. Olfactory ecto-MSCs (OE-MSCs) are a new population of neural crest-derived stem cells that can proliferate and differentiate into SCs and can be considered a promising autologous alternative to produce SCs. Regardless, a biomimetic physicochemical microenvironment in NGC such as electroconductive substrate can affect the fate of transplanted stem cells, including differentiation toward SCs and nerve regeneration. Therefore, in this study, the effect of 3D printed polycaprolactone (PCL)/polypyrrole (PPy) conductive scaffolds on differentiation of human OE-MSCS into functional SC-like phenotypes was investigated. Biological evaluation of 3D printed scaffolds was examined by in vitro culturing the OE-MSCs on samples surfaces, and conductivity showed no effect on increased cell attachment, proliferation rate, viability, and distribution. In contrast, immunocytochemical staining and real-time polymerase chain reaction analysis indicated that 3D structures coated with PPy could provide a favorable microenvironment for OE-MSCs differentiation. In addition, it was found that differentiated OE-MSCs within PCL/PPy could secrete the highest amounts of nerve growth factor and brain-derived neurotrophic factor neurotrophic factors compared to pure PCL and 2D culture. After co-culturing with PC12 cells, a significant increase in neurite outgrowth on PCL/PPy conductive scaffold seeded with differentiated OE-MSCs. These findings indicated that 3D printed PCL/PPy conductive scaffold could support differentiation of OE-MSCs into SC-like phenotypes to promote neurite outgrowth, suggesting their potential for neural tissue engineering applications.
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Affiliation(s)
- Maedeh Entezari
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,ENT and Head & Neck Research Center and Department, The Five Senses Health Institute, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Bakhtiyari
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Moradi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zohreh Bagher
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,ENT and Head & Neck Research Center and Department, The Five Senses Health Institute, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mansoureh Soleimani
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Adamowicz J, Kluth LA, Pokrywczynska M, Drewa T. Tissue Engineering and Its Potential to Reduce Prostate Cancer Treatment Sequelae-Narrative Review. Front Surg 2021; 8:644057. [PMID: 34722618 PMCID: PMC8551715 DOI: 10.3389/fsurg.2021.644057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 07/19/2021] [Indexed: 01/08/2023] Open
Abstract
Tissue engineering offers the possibility to overcome limitations of current management for postprostatectomy incontinence and ED. Developed in recent years biotechnological feasibility of mesenchymal stem cell isolation, in vitro cultivation and implantation became the basis for new cell-based therapies oriented to induce regeneration of adult tissue. The perspective to offer patients suffering from post-prostatectomy incontinence or erectile dysfunction minimal invasive one-time procedure utilizing autologous stem cell transplantation is desired management.
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Affiliation(s)
- Jan Adamowicz
- Chair of Urology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Luis Alex Kluth
- Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Marta Pokrywczynska
- Chair of Urology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Tomasz Drewa
- Chair of Urology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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Saffari S, Saffari TM, Chan K, Borschel GH, Shin AY. Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension. Biotechnol Bioeng 2021; 118:4477-4487. [PMID: 34396506 PMCID: PMC8744499 DOI: 10.1002/bit.27916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/04/2021] [Accepted: 08/12/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts. METHODS A three-dimensional in vitro compartmented cell culture system consisting of a neonatal dorsal root ganglion adjacent to a nerve graft was used to evaluate the regenerating neurites into the peripheral nerve scaffold. Nerve autografts and allografts were treated with (i) undifferentiated MSCs, (ii) FK506 (100 ng/mL) or (iii) both (N = 9/group). After 48 hours, neurite extension was measured to quantify nerve regeneration and stem cell viability was evaluated. RESULTS Stem cell viability was confirmed in all MSC-treated grafts. Neurite extension was superior in autografts treated with FK506, and MSCs and FK506 combined (p < 0.001 and p = 0.0001, respectively), and autografts treated with MSCs (p = 0.12) were comparable to untreated autografts. In allografts, FK506 treatment and combined treatment were superior to controls (p < 0.001 and p = 0.0001, respectively), and treatment with MSCs (p = 0.09) was comparable to controls. All autograft groups were superior compared to their respective allograft treatment group (p < 0.05) in neurite extension. CONCLUSIONS Alone, either MSC or FK506 treatment improved neurite outgrowth, and combined they further enhanced neurite extension in both autografts and allografts.
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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-, Reconstructive- and Hand Surgery, Radboud University, Nijmegen, the Netherlands
| | - Tiam M. Saffari
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Plastic-, Reconstructive- and Hand Surgery, Radboud University, Nijmegen, the Netherlands
| | - Katelyn Chan
- Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Gregory H. Borschel
- Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Neurosciences and Mental Health, SickKids Research Institute, Hospital for Sick Children, Toronto, ON, Canada
- Division of Plastic & Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Division of Plastic Surgery, Indiana University and Riley Hospital for Children, Indianapolis, IN, USA
| | - Alexander Y. Shin
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
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Daradka MH, Bani Ismail ZA, Irsheid MA. Peripheral nerve regeneration: A comparative study of the effects of autologous bone marrow-derived mesenchymal stem cells, platelet-rich plasma, and lateral saphenous vein graft as a conduit in a dog model. Open Vet J 2021; 11:686-694. [PMID: 35070865 PMCID: PMC8770172 DOI: 10.5455/ovj.2021.v11.i4.20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/11/2021] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The quality of healing of peripheral nerve injuries remains a common challenge causing pain and poor quality of life for millions of people and animals annually. AIMS The objectives of this study were to evaluate the healing quality of facial nerve injury in a dog model following local treatment using an autologous injection of platelet-rich plasma (PRP) or bone marrow-derived mesenchymal stem cells (BM-MSCs) at the injury site in combination with the application of an autologous saphenous vein graft as a conduit. METHODS 20 apparently healthy adult Mongrel dogs were randomly divided into 4 equal groups. Dogs in groups 1, 2, and 3 were subjected to facial nerve neurectomy and saphenous vein conduit graft implantation at the site of facial nerve injury. Dogs in groups 2 and 3 received 1 ml of autologous PRP and BM-MSCs, respectively. Injections were administered directly in the vein conduit immediately after nerve injury. Dogs in group 1 (grafted but not treated; control) received only an autologous vein graft, and those in group 4 (normal control) received no graft and no PRP or BM-MSCs treatment. The dogs were monitored daily for 8 weeks after surgery. Clinical evaluation of the facial nerve, including lower eyelid, ear drooping, upper lip, and tongue functions, was carried out once per week using a numerical scoring system of 0-3. At the end of the study period (week 8), the facial nerve injury site was evaluated grossly for the presence of adhesions using a numerical scoring system of 0-3. The facial nerve injury site was histopathologically assessed for the existence of perivascular mononuclear cell infiltration, fibrous tissue deposition, and axonal injury using H&E-stained tissue sections. RESULTS Clinically, BM-MSCs treated dogs experienced significant (p < 0.05) improvement in the lower eyelid, ear, lip, and tongue functions 4 weeks postoperatively compared to other groups. Grossly, the facial nerve graft site in the BM-MSCs treated group showed significantly (p < 0.05) lesser adhesion scores than the other groups. Histopathologically, there was significantly (p < 0.05) less perivascular mononuclear cell infiltration, less collagen deposition, and more normal axons at the facial nerve injury site in the BM-MSCs treated group compared to the other groups. CONCLUSION This study showed clinically significant enhancement of nerve regeneration by applying autologous BM-MSCs and autologous vein grafting at the site of facial nerve injury. However, further clinical trials are warranted before this application can be recommended to treat traumatic nerve injuries in the field.
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Affiliation(s)
- Mousa H Daradka
- Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Zuhair A Bani Ismail
- Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Mohammad A Irsheid
- Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Peripheral Nerve Regeneration Using Different Germ Layer-Derived Adult Stem Cells in the Past Decade. Behav Neurol 2021; 2021:5586523. [PMID: 34539934 PMCID: PMC8448597 DOI: 10.1155/2021/5586523] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 07/27/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022] Open
Abstract
Peripheral nerve injuries (PNIs) are some of the most common types of traumatic lesions affecting the nervous system. Although the peripheral nervous system has a higher regenerative ability than the central nervous system, delayed treatment is associated with disturbances in both distal sensory and functional abilities. Over the past decades, adult stem cell-based therapies for peripheral nerve injuries have drawn attention from researchers. This is because various stem cells can promote regeneration after peripheral nerve injuries by differentiating into neural-line cells, secreting various neurotrophic factors, and regulating the activity of in situ Schwann cells (SCs). This article reviewed research from the past 10 years on the role of stem cells in the repair of PNIs. We concluded that adult stem cell-based therapies promote the regeneration of PNI in various ways.
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Mesenchymal Stem Cell Therapy for Alzheimer's Disease. Stem Cells Int 2021; 2021:7834421. [PMID: 34512767 PMCID: PMC8426054 DOI: 10.1155/2021/7834421] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/09/2021] [Indexed: 12/17/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease responsible for 60-70% of the 50 million cases of dementia worldwide. It is characterized by neuronal cell death, shrinkage of brain tissue, and progressive cognitive, motor, and behavioral impairment, which often leads to death. Although current treatment has helped improve the patient's quality of life, it has not been able to alter the underlying disease pathology of AD. Studies have shown that mesenchymal stem cells (MSCs)—a group of multipotent stem cells—have the ability to stimulate neuroregeneration and inhibit disease progression. More recently, extracellular vesicles (EVs) from cytokine-preconditioned MSCs have also shown to induce immunomodulatory and neuroprotective effects in AD models. This review will aim to compile pertinent preclinical AD research on transgenic mice as well as clinical trials on MSC-based therapy from diverse sources.
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Evidence-Based Approach to Nerve Gap Repair in the Upper Extremity: A Review of the Literature and Current Algorithm for Surgical Management. Ann Plast Surg 2021; 84:S369-S374. [PMID: 32039999 DOI: 10.1097/sap.0000000000002278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The upper extremity is the most common site for nerve injuries. In most cases, direct repair can be performed, but when a critical gap occurs, special techniques must be used to enhance nerve regeneration and allow recovery of sensory and motor functions. These techniques include the use of autografts, processed nerve allografts, and conduits. However, surprisingly few studies have compared outcomes from the different methods of nerve gap repair in a rigorous fashion. There is a lack of evidence-based guidelines for the management of digital and motor and mixed nerve injuries with a nerve gap. The purpose of this study is to perform a comprehensive literature review and propose a rational algorithm for management of nerve injuries with a critical gap.
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Saffari TM, Chan K, Saffari S, Zuo KJ, McGovern RM, Reid JM, Borschel GH, Shin AY. Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration. Biotechnol Bioeng 2021; 118:2804-2814. [PMID: 33913523 DOI: 10.1002/bit.27799] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/19/2022]
Abstract
The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.
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Affiliation(s)
- Tiam M Saffari
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.,Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Katelyn Chan
- Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Engineering, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Sara Saffari
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.,Department of Plastic and Reconstructive Surgery, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Kevin J Zuo
- Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Division of Neurosciences and Mental Health, SickKids Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.,Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Renee M McGovern
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Joel M Reid
- Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Gregory H Borschel
- Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.,Division of Plastic Surgery, Riley Hospital for Children, Indiana University, Indianapolis, Indiana, USA
| | - Alexander Y Shin
- Division of Hand and Microvascular Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
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Schwann-like cell conditioned medium promotes angiogenesis and nerve regeneration. Cell Tissue Bank 2021; 23:101-118. [PMID: 33837877 DOI: 10.1007/s10561-021-09920-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 03/27/2021] [Indexed: 12/29/2022]
Abstract
Vascular network reconstruction plays a pivotal role in the axonal regeneration and nerve function recovery after peripheral nerve injury. Increasing evidence indicates that Schwann cells (SCs) can promote nerve function repair, and the beneficial effects attributed to SCs therapy may exert their therapeutic effects through paracrine mechanisms. Recently, the previous research of our group demonstrated the promising neuroregenerative capacity of Schwann-like cells (SCLCs) derived from differentiated human embryonic stem cell-derived neural stem cells (hESC-NSCs) in vitro. Herein, the effects of SC-like cell conditioned medium (SCLC-CM) on angiogenesis and nerve regeneration were further explored. The assays were performed to show the pro-angiogenic effects of SCLC-CM, such as promoted endothelial cell proliferation, migration and tube formation in vitro. In addition, Sprague-Dawley rats were treated with SCLC-CM after sciatic nerve crush injury, SCLC-CM was conducive for the recovery of sciatic nerve function, which was mainly manifested in the SFI increase, the wet weight ratio of gastrocnemius muscle, as well as the number and thickness of myelin. The SCLC-CM treatment reduced the Evans blue leakage and increased the expression of CD34 microvessels. Furthermore, SCLC-CM upregulated the expressions of p-Akt and p-mTOR in endothelial cells. In conclusion, SCLC-CM promotes angiogenesis and nerve regeneration, it is expected to become a new treatment strategy for peripheral nerve injury.
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Applications of Mesenchymal Stem Cells in Skin Regeneration and Rejuvenation. Int J Mol Sci 2021; 22:ijms22052410. [PMID: 33673711 PMCID: PMC7957487 DOI: 10.3390/ijms22052410] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells derived from adult stem cells. Primary MSCs can be obtained from diverse sources, including bone marrow, adipose tissue, and umbilical cord blood. Recently, MSCs have been recognized as therapeutic agents for skin regeneration and rejuvenation. The skin can be damaged by wounds, caused by cutting or breaking of the tissue, and burns. Moreover, skin aging is a process that occurs naturally but can be worsened by environmental pollution, exposure to ultraviolet radiation, alcohol consumption, tobacco use, and undernourishment. MSCs have healing capacities that can be applied in damaged and aged skin. In skin regeneration, MSCs increase cell proliferation and neovascularization, and decrease inflammation in skin injury lesions. In skin rejuvenation, MSCs lead to production of collagen and elastic fibers, inhibition of metalloproteinase activation, and promote protection from ultraviolet radiation-induced senescence. In this review, we focus on how MSCs and MSC-derived molecules improve diseased and aged skin. Additionally, we emphasize that induced pluripotent stem cell (iPSC)-derived MSCs are potentially advanced MSCs, which are suitable for cell therapy.
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Li L, Zhang Y, Wang M, Zhou J, Zhang Q, Yang W, Li Y, Yan F. Gold Nanoparticles Combined Human β-Defensin 3 Gene-Modified Human Periodontal Ligament Cells Alleviate Periodontal Destruction via the p38 MAPK Pathway. Front Bioeng Biotechnol 2021; 9:631191. [PMID: 33585435 PMCID: PMC7876295 DOI: 10.3389/fbioe.2021.631191] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/11/2021] [Indexed: 02/05/2023] Open
Abstract
Periodontitis is a chronic inflammatory disease with plaques as the initiating factor, which will induce the destruction of periodontal tissues. Numerous studies focused on how to obtain periodontal tissue regeneration in inflammatory environments. Previous studies have reported adenovirus-mediated human β-defensin 3 (hBD3) gene transfer could potentially enhance the osteogenic differentiation of human periodontal ligament cells (hPDLCs) and bone repair in periodontitis. Gold nanoparticles (AuNPs), the ideal inorganic nanomaterials in biomedicine applications, were proved to have synergetic effects with gene transfection. To further observe the potential promoting effects, AuNPs were added to the transfected cells. The results showed the positive effects of osteogenic differentiation while applying AuNPs into hPDLCs transfected by adenovirus encoding hBD3 gene. In vivo, after rat periodontal ligament cell (rPDLC) transplantation into SD rats with periodontitis, AuNPs combined hBD3 gene modification could also promote periodontal regeneration. The p38 mitogen-activated protein kinase (MAPK) pathway was demonstrated to potentially regulate both the in vitro and in vivo processes. In conclusion, AuNPs can promote the osteogenic differentiation of hBD3 gene-modified hPDLCs and periodontal regeneration via the p38 MAPK pathway.
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Affiliation(s)
- Lingjun Li
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yangheng Zhang
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Min Wang
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jing Zhou
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, The Affiliated Stomatological Hospital, Zhejiang University School of Medicine, Zhejiang University School of Stomatology, Hangzhou, China
| | - Qian Zhang
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenrong Yang
- School of Life and Environmental Science, Centre for Chemistry and Biotechnology, Deakin University, Geelong, VIC, Australia
| | - Yanfen Li
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Fuhua Yan
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Choi SJ, Park SY, Shin YH, Heo SH, Kim KH, Lee HI, Kim JK. Mesenchymal Stem Cells Derived from Wharton's Jelly Can Differentiate into Schwann Cell-Like Cells and Promote Peripheral Nerve Regeneration in Acellular Nerve Grafts. Tissue Eng Regen Med 2021; 18:467-478. [PMID: 33515168 DOI: 10.1007/s13770-020-00329-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 12/08/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Schwann cells (SCs) secrete neurotrophic factors and provide structural support and guidance during axonal regeneration. However, nearby nerves may be damaged to obtain primary SCs, and there is a lack of nervous tissue donors. We investigated the potential of Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) in differentiating into Schwann cell-like cells (WJ-SCLCs) as an alternative to SCs. We also examined whether implantation of WJ-SCLCs-laden acellular nerve grafts (ANGs) are effective in inducing functional recovery and nerve regeneration in an animal model of peripheral nerve injury. METHODS The differentiation of WJ-MSCs into WJ-SCLCs was determined by analyzing SC-specific markers. The secretion of neurotrophic factors was assessed by the Neuro Discovery antibody array. Neurite outgrowth and myelination of axons were found in a co-culture system involving motor neuron cell lines. The effects of ANGs on repairing sciatic nerves were evaluated using video gait angle test, isometric tetanic force analysis, and toluidine blue staining. RESULTS Compared with undifferentiated WJ-MSCs, WJ-SCLCs showed higher expression levels of SC-specific markers such as S100β, GFAP, KROX20, and NGFR. WJ-SCLCs also showed higher secreted amounts of brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and granulocyte-colony stimulating factor than did WJ-MSCs. WJ-SCLCs effectively promoted the outgrowth and myelination of neurites in motor neuron cells, and WJ-SCLCs laden ANGs significantly facilitated peripheral nerve regeneration in an animal model of sciatic nerve injury. CONCLUSION WJ-MSCs were readily differentiated into WJ-SCLCs, which effectively promoted the regeneration of peripheral nerves. Transplantation of WJ-SCLCs with ANGs might be useful for assisting peripheral nerve regeneration.
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Affiliation(s)
- Soon Jin Choi
- Asan Peripheral Nerve Regeneration Lab Institute for Life Sciences, Seoul, South Korea
| | - Suk Young Park
- Asan Peripheral Nerve Regeneration Lab Institute for Life Sciences, Seoul, South Korea
| | - Young Ho Shin
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Seung-Ho Heo
- Convergence Medicine Research Center, Asan Medical Center, Seoul, South Korea
| | - Kang-Hyun Kim
- Convergence Medicine Research Center, Asan Medical Center, Seoul, South Korea
| | - Hyo In Lee
- Convergence Medicine Research Center, Asan Medical Center, Seoul, South Korea
| | - Jae Kwang Kim
- Asan Peripheral Nerve Regeneration Lab Institute for Life Sciences, Seoul, South Korea. .,Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic Road 43-gil, Songpa-gu, Seoul, 05505, South Korea.
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Zhang RC, Du WQ, Zhang JY, Yu SX, Lu FZ, Ding HM, Cheng YB, Ren C, Geng DQ. Mesenchymal stem cell treatment for peripheral nerve injury: a narrative review. Neural Regen Res 2021; 16:2170-2176. [PMID: 33818489 PMCID: PMC8354135 DOI: 10.4103/1673-5374.310941] [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] [Indexed: 12/20/2022] Open
Abstract
Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life. The peripheral nervous system has an inherent capability to regenerate axons. However, peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy. Although conventional surgical procedures for peripheral nerve injuries present many benefits, there are still several limitations including scarring, difficult accessibility to donor nerve, neuroma formation and a need to sacrifice the autologous nerve. For many years, other therapeutic approaches for peripheral nerve injuries have been explored, the most notable being the replacement of Schwann cells, the glial cells responsible for clearing out debris from the site of injury. Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery. However, there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro. Therefore, novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated. This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells, nerve engineering using the nerve guidance conduits containing mesenchymal stem cells, and genetically engineered mesenchymal stem cells. We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries.
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Affiliation(s)
- Rui-Cheng Zhang
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Wen-Qi Du
- Department of Human Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Jing-Yuan Zhang
- Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Shao-Xia Yu
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Fang-Zhi Lu
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Hong-Mei Ding
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yan-Bo Cheng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Chao Ren
- Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - De-Qin Geng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
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Dagnino APA, Chagastelles PC, Medeiros RP, Estrázulas M, Kist LW, Bogo MR, Weber JBB, Campos MM, Silva JB. Neural Regenerative Potential of Stem Cells Derived from the Tooth Apical Papilla. Stem Cells Dev 2020; 29:1479-1496. [PMID: 32988295 DOI: 10.1089/scd.2020.0121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The regenerative effects of stem cells derived from dental tissues have been previously investigated. This study assessed the potential of human tooth stem cells from apical papilla (SCAP) on nerve regeneration. The SCAP collected from nine individuals were characterized and polarized by exposure to interferon-γ (IFN-γ). IFN-γ increased kynurenine and interleukin-6 (IL-6) production by SCAP, without affecting the cell viability. IFN-γ-primed SCAP exhibited a decrease of brain-derived neurotrophic factor (BDNF) mRNA levels, followed by an upregulation of glial cell-derived neurotrophic factor mRNA. Ex vivo, the co-culture of SCAP with neurons isolated from the rat dorsal root ganglion induced neurite outgrowth, accompanied by increased BDNF secretion, irrespective of IFN-γ priming. In vivo, the local application of SCAP reduced the mechanical and thermal hypersensitivity in Wistar rats that had been submitted to sciatic chronic constriction injury. The SCAP also reduced the pain scores, according to the evaluation of the Grimace scale, partially restoring the myelin damage and BDNF immunopositivity secondary to nerve lesion. Altogether, our results provide novel evidence about the regenerative effects of human SCAP, indicating their potential to handle nerve injury-related complications.
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Affiliation(s)
- Ana Paula Aquistapase Dagnino
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Pedro Cesar Chagastelles
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Renata Priscila Medeiros
- Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Marina Estrázulas
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Luiza Wilges Kist
- Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Laboratório de Biologia Genômica e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Maurício Reis Bogo
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Laboratório de Biologia Genômica e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - João Batista Blessmann Weber
- Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Maria Martha Campos
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Centro de Pesquisa em Toxicologia e Farmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Odontologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Jefferson Braga Silva
- Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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Highly elastic, electroconductive, immunomodulatory graphene crosslinked collagen cryogel for spinal cord regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 118:111518. [PMID: 33255073 DOI: 10.1016/j.msec.2020.111518] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 07/31/2020] [Accepted: 08/12/2020] [Indexed: 12/22/2022]
Abstract
Novel amino-functionalized graphene crosslinked collagen based nerve conduit having appropriate electric (3.8 ± 0.2 mSiemens/cm) and mechanical cues (having young modulus value of 100-347 kPa) for stem cell transplantation and neural tissue regeneration was fabricated using cryogelation. The developed conduit has shown sufficiently high porosity with interconnectivity between the pores. Raman spectroscopy analysis revealed the increase in orderliness and crosslinking of collagen molecules in the developed cryogel due to the incorporation of amino-functionalized graphene. BM-MSCs grown on graphene collagen cryogels have shown enhanced expression of CD90 and CD73 gene upon electric stimulation (100 mV/mm) contributing towards maintaining their stemness. Furthermore, an increased secretion of ATP from BM-MSCs grown on graphene collagen cryogel was also observed upon electric stimulation that may help in regeneration of neurons and immuno-modulation. Neuronal differentiation of BM-MSCs on graphene collagen cryogel in the presence of electric stimulus showed an enhanced expression of MAP-2 kinase and β-tubulin III. Immunohistochemistry studies have also demonstrated the improved neuronal differentiation of BM-MSCs. BM-MSCs grown on electro-conductive collagen cryogels under inflammatory microenvironment in vitro showed high indoleamine 2,3 dioxygenase activity. Moreover, macrophages cells grown on graphene collagen cryogels have shown high CD206 (M2 polarization marker) and CD163 (M2 polarization marker) and low CD86 (M1 polarization marker) gene expression demonstrating M2 polarization of macrophages, which may aid in tissue repair. In an organotypic culture, the developed cryogel conduit has supported cellular growth and migration from adult rat spinal cord. Thus, this novel electro-conductive graphene collagen cryogels have potential for suppressing the neuro-inflammation and promoting the neuronal cellular migration and proliferation, which is a major barrier during the spinal cord regeneration.
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Colazo JM, Evans BC, Farinas AF, Al-Kassis S, Duvall CL, Thayer WP. Applied Bioengineering in Tissue Reconstruction, Replacement, and Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2020; 25:259-290. [PMID: 30896342 DOI: 10.1089/ten.teb.2018.0325] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPACT STATEMENT The use of autologous tissue in the reconstruction of tissue defects has been the gold standard. However, current standards still face many limitations and complications. Improving patient outcomes and quality of life by addressing these barriers remain imperative. This article provides historical perspective, covers the major limitations of current standards of care, and reviews recent advances and future prospects in applied bioengineering in the context of tissue reconstruction, replacement, and regeneration.
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Affiliation(s)
- Juan M Colazo
- 1Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.,2Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brian C Evans
- 3Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Angel F Farinas
- 4Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Salam Al-Kassis
- 4Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Craig L Duvall
- 3Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Wesley P Thayer
- 3Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.,4Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
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高 海, 王 波, 曹 家, 李 秀, 黄 陈, 吴 佳, 刘 宗. [Experimental study on autologous injectable platelets rich fibrin combined with bone mesenchymal stem cells in treating sciatic nerve injury in rats]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2020; 34:637-642. [PMID: 32410433 PMCID: PMC8171844 DOI: 10.7507/1002-1892.201909061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 03/03/2020] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To investigate the effectiveness of autologous injectable platelet rich fibrin (i-PRF) combined with bone marrow mesenchymal stem cells (BMSCs) for sciatic nerve injury in rats. METHODS BMSCs were isolated and cultured from tibial bone marrow of Sprague Dawley (SD) neonatal rats aged 10-15 days and passaged to the 4th generation. i-PRF was prepared from posterior orbital venous blood of adult SD rats by improved low-speed centrifugation. Twenty-four adult SD rats were selected and randomly divided into 4 groups with 6 rats in each group after the sciatic nerve Ⅲ degree injury model was established by modified crush injury method. Groups A, B, C, and D were injected with BMSCs suspension+autologous i-PRF, autologous i-PRF, BMSCs suspension, and normal saline, respectively. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate the recovery of neurological function of the affected limb of rats every week from 1 to 8 weeks after operation. At 2 months after operation, the rats were sacrificed and the histological changes of sciatic nerve were observed by HE staining. The microstructural changes of nerve fibers, myelin sheath, and nucleus were observed by transmission electron microscope. The expressions of N-cadherin, Nestin, and glial fibrillary acidic protein (GFAP) were detected by Western blot. RESULTS No immune rejection or death occurred in the rats after operation. There was no significant difference in BBB scores between groups at 1 week after operation ( P>0.05); at 2-8 weeks after operation, BBB scores in group A were significantly higher than those in groups B, C, and D, and in groups B, C than in group D ( P<0.05), there was no significant difference between groups B and C ( P>0.05). HE staining showed that the nerve fibers in group A arranged in order, without defect or demyelination; the nerve fibers in group B were not clear and slightly swollen; some of the nerve fibers in group C were disordered and demyelinated; the nerve fibers in group D were not continuous, obviously demyelinated, and some of the nerve adventitia damaged. Transmission electron microscope showed that the structure of nerve fibers in group A was clear, myelin sheath was complete, and nucleus was dense; group B was slightly less than group A; group C had fuzzy structure, demyelination, and hollowing out; group D had disorder structure, demyelination, and hollowing out, and the middle part of nerve adventitia continuity. Western blot detection results showed that there was no significant difference in the relative expression of Nestin between groups ( P>0.05). The relative expression of N-cadherin was significantly lower in groups B, C, and D than in group A, in groups C and D than in group B, and in group D than in group C ( P<0.05). The relative expression of GFAP was significantly lower in groups B, C, and D than in group A, in group D than in groups B and C ( P<0.05); there was no significant difference between groups B and C ( P>0.05). CONCLUSION Autologous i-PRF combined with BMSCs can effectively treat sciatic nerve tissue injury in rats.
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Affiliation(s)
- 海明 高
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 波 王
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 家全 曹
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 秀军 李
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 陈翼 黄
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 佳奇 吴
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
| | - 宗超 刘
- 西南医科大学附属中医医院骨科（四川泸州 646000）Department of Orthopedics, the Traditional Chinese Medicine Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China
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Bojanic C, To K, Zhang B, Mak C, Khan WS. Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration. World J Stem Cells 2020; 12:288-302. [PMID: 32399137 PMCID: PMC7202926 DOI: 10.4252/wjsc.v12.i4.288] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/15/2020] [Accepted: 03/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Peripheral nerve injury can occur as a result of trauma or disease and carries significant morbidity including sensory and motor loss. The body has limited ability for nerve regeneration and functional recovery. Left untreated, nerve lesions can cause lifelong disability. Traditional treatment options such as neurorrhaphy and neurolysis have high failure rates. Surgical reconstruction with autograft carries donor site morbidity and often provide suboptimal results. Mesenchymal stem cells (MSCs) are known to have promising regenerative potential and have gained attention as a treatment option for nerve lesions. It is however, unclear whether it can be effectively used for nerve regeneration.
AIM To evaluate the evidence for the use of human umbilical cord derived MSCs (UCMSCs) in peripheral nerve regeneration.
METHODS We carried out a systematic literature review in accordance with the PRISMA protocol. A literature search was performed from conception to September 2019 using PubMed, EMBASE and Web of Science. The results of eligible studies were appraised. A risk of bias analysis was carried out using Cochrane’s RoB 2.0 tool.
RESULTS Fourteen studies were included in this review. A total of 279 subjects, including both human and animal were treated with UCMSCs. Four studies obtained UCMSCs from a third-party source and the remainder were harvested by the investigators. Out of the 14 studies, thirteen conducted xenogenic transplantation into nerve injury models. All studies reported significant improvement in nerve regeneration in the UCMSC treated groups compared with the various different controls and untreated groups.
CONCLUSION The evidence summarised in this PRISMA systematic review of in vivo studies supports the notion that human UCMSC transplantation is an effective treatment option for peripheral nerve injury.
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Affiliation(s)
- Christine Bojanic
- Department of Plastic and Reconstructive Surgery, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom
| | - Kendrick To
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Bridget Zhang
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Christopher Mak
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
| | - Wasim S Khan
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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Wilcox M, Gregory H, Powell R, Quick TJ, Phillips JB. Strategies for Peripheral Nerve Repair. CURRENT TISSUE MICROENVIRONMENT REPORTS 2020; 1:49-59. [PMID: 33381765 PMCID: PMC7749870 DOI: 10.1007/s43152-020-00002-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW This review focuses on biomechanical and cellular considerations required for development of biomaterials and engineered tissues suitable for implantation following PNI, as well as translational requirements relating to outcome measurements for testing success in patients. RECENT FINDINGS Therapies that incorporate multiple aspects of the regenerative environment are likely to be key to improving therapies for nerve regeneration. This represents a complex challenge when considering the diversity of biological, chemical and mechanical factors involved. In addition, clinical outcome measures following peripheral nerve repair which are sensitive and responsive to changes in the tissue microenvironment following neural injury and regeneration are required. SUMMARY Effective new therapies for the treatment of PNI are likely to include engineered tissues and biomaterials able to evoke a tissue microenvironment that incorporates both biochemical and mechanical features supportive to regeneration. Translational development of these technologies towards clinical use in humans drives a concomitant need for improved clinical measures to quantify nerve regeneration.
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Affiliation(s)
- Matthew Wilcox
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK
- UCL Centre for Nerve Engineering, University College London, London, UK
- Peripheral Nerve Injury Research Unit, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Holly Gregory
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK
- UCL Centre for Nerve Engineering, University College London, London, UK
| | - Rebecca Powell
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK
- UCL Centre for Nerve Engineering, University College London, London, UK
| | - Tom J. Quick
- Peripheral Nerve Injury Research Unit, Royal National Orthopaedic Hospital, Stanmore, UK
| | - James B. Phillips
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX UK
- UCL Centre for Nerve Engineering, University College London, London, UK
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Yao S, He F, Cao Z, Sun Z, Chen Y, Zhao H, Yu X, Wang X, Yang Y, Rosei F, Wang LN. Mesenchymal Stem Cell-Laden Hydrogel Microfibers for Promoting Nerve Fiber Regeneration in Long-Distance Spinal Cord Transection Injury. ACS Biomater Sci Eng 2020; 6:1165-1175. [PMID: 33464837 DOI: 10.1021/acsbiomaterials.9b01557] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Mesenchymal stem cell (MSC)-based regenerative medicine is widely considered as a promising approach for repairing tissue and re-establishing function in spinal cord injury (SCI). However, low survival rate, uncontrollable migration, and differentiation of stem cells after implantation represent major challenges toward the clinical deployment of this approach. In this study, we fabricated three-dimensional MSC-laden microfibers via electrospinning in a rotating cell culture to mimic nerve tissue, control stem cell behavior, and promote integration with the host tissue. The hierarchically aligned fibrin hydrogel was used as the MSC carrier though a rotating method and the aligned fiber structure induced the MSC-aligned adhesion on the surface of the hydrogel to form microscale cell fibers. The MSC-laden microfiber implantation enhanced the donor MSC neural differentiation, encouraged the migration of host neurons into the injury gap and significantly promoted nerve fiber regeneration across the injury site. Abundant GAP-43- and NF-positive nerve fibers were observed to regenerate in the caudal, rostral, and middle sites of the injury position 8 weeks after the surgery. The NF fiber density reached to 29 ± 6 per 0.25 mm2 at the middle site, 82 ± 13 per 0.25 mm2 at the adjacent caudal site, and 70 ± 23 at the adjacent rostral site. Similarly, motor axons labeled with 5-hydroxytryptamine were significantly regenerated in the injury gap, which was 122 ± 22 at the middle injury site that was beneficial for motor function recovery. Most remarkably, the transplantation of MSC-laden microfibers significantly improved electrophysiological expression and re-established limb motor function. These findings highlight the combination of MSCs with microhydrogel fibers, the use of which may become a promising method for MSC implantation and SCI repair.
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Affiliation(s)
- Shenglian Yao
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.,Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Feng He
- Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Zheng Cao
- Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Zhenxing Sun
- Department of Neurosurgery, Beijing Tsinghua Changgeng Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China
| | - Yingzhi Chen
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - He Zhao
- Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China.,Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xing Yu
- Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xiumei Wang
- Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Yongdong Yang
- Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Federico Rosei
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.,INRS Centre for Energy, Materials and Telecommunications, 1650 Boul. Lionel Boulet, Varennes J3X 1S2, Canada
| | - Lu-Ning Wang
- Beijing Advanced Innovation Center for Materials Genome Engineering, School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China
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Raza C, Riaz HA, Anjum R, Shakeel NUA. Repair strategies for injured peripheral nerve: Review. Life Sci 2020; 243:117308. [PMID: 31954163 DOI: 10.1016/j.lfs.2020.117308] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/27/2022]
Abstract
Compromised functional regains in about half of the patients following surgical nerve repair pose a serious socioeconomic burden to the society. Although surgical strategies such as end-to-end neurorrhaphy, nerve grafting and nerve transfer are widely applied in distal injuries leading to optimal recovery; however in proximal nerve defects functional outcomes remain unsatisfactory. Biomedical engineering approaches unite the efforts of the surgeons, engineers and biologists to develop regeneration facilitating structures such as extracellular matrix based supportive polymers and tubular nerve guidance channels. Such polymeric structures provide neurotrophic support from injured nerve stumps, retard the fibrous tissue infiltration and guide regenerating axons to appropriate targets. The development and application of nerve guidance conduits (NGCs) to treat nerve gap injuries offer clinically relevant and feasible solutions. Enhanced understanding of the nerve regeneration processes and advances in NGCs design, polymers and fabrication strategies have led to developing modern NGCs with superior regeneration-conducive capacities. Current review focuses on the advances in surgical and engineering approaches to treat peripheral nerve injuries. We suggest the incorporation of endothelial cell growth promoting cues and factors into the NGC interior for its possible enhancement effects on the axonal regeneration process that may result in substantial functional outcomes.
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Affiliation(s)
- Chand Raza
- Department of Zoology, Government College University, Lahore 54000, Pakistan.
| | - Hasib Aamir Riaz
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Rabia Anjum
- Department of Zoology, Government College University, Lahore 54000, Pakistan
| | - Noor Ul Ain Shakeel
- Department of Zoology, Government College University, Lahore 54000, Pakistan
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Ashraf R, Sofi HS, Sheikh FA. Experimental Protocol of MSC Differentiation into Neural Lineage for Nerve Tissue Regeneration Using Polymeric Scaffolds. Methods Mol Biol 2020; 2125:109-117. [PMID: 31020638 DOI: 10.1007/7651_2019_229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The treatment of neurodegenerative diseases is still a challenging grindstone in reconstructive surgeries and regenerative medicine. The retention of mesenchymal stem cells (MSCs) to retain remarkable properties of differentiating into motor neuron-like cells and Schwann cells can prove to be effective in repairing disorders. Moreover, the ultrafine electrospun nanofibers provide a favorable and conducive platform for proliferation and differentiation of MSCs. The development of new 3D culture methods with electrospun scaffolds that closely mimic the physiological niche of cells will help us to understand the functional benefits of MSCs in regeneration process. This article highlights the protocols for isolation of MSCs from rat bone marrow and their subsequent culture on nanofiber scaffolds. Furthermore, this chapter summarizes the various procedures including isolation of the MSCs, their seeding on electrospun nanofibrous scaffolds, and their proliferation and differentiation into neural lineage upon appropriate induction. The materials and preparation of various reagents used at different steps of the protocol are also summarized in detail.
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Affiliation(s)
- Roqia Ashraf
- Department of Nanotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Hasham S Sofi
- Department of Nanotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Faheem A Sheikh
- Department of Nanotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India.
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