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Fan Z, Jia M, Zhou J, Zhu Z, Wu Y, Lin X, Qian Y, Lian J, Hua X, Dong J, Fang Z, Liu Y, Chen S, Xue X, Yue J, Zhu M, Wang Y, Huang Z, Teng H. Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury. Neural Regen Res 2025; 20:3287-3301. [PMID: 38993129 PMCID: PMC11881704 DOI: 10.4103/nrr.nrr-d-23-01256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 11/28/2023] [Accepted: 02/01/2024] [Indexed: 07/13/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202511000-00031/figure1/v/2024-12-20T164640Z/r/image-tiff The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury. Regulation of shifting microglia polarization from M1 (neurotoxic and proinflammatory type) to M2 (neuroprotective and anti-inflammatory type) after spinal cord injury appears to be crucial. Tryptanthrin possesses an anti-inflammatory biological function. However, its roles and the underlying molecular mechanisms in spinal cord injury remain unknown. In this study, we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro . Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway. Additionally, we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury, inhibited neuronal loss, and promoted tissue repair and functional recovery in a mouse model of spinal cord injury. Finally, using a conditional co-culture system, we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis. Taken together, these results suggest that by targeting the cGAS/STING/NF-κB axis, tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.
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Affiliation(s)
- Ziwei Fan
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Mengxian Jia
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Jian Zhou
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Zhoule Zhu
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Yumin Wu
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Xiaowu Lin
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Yiming Qian
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Jiashu Lian
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Xin Hua
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jianhong Dong
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Zheyu Fang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Yuqing Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Sibing Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Xiumin Xue
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Juanqing Yue
- Department of Pathology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China
| | - Minyu Zhu
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Ying Wang
- Department of Clinical Research Center, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China
| | - Zhihui Huang
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Honglin Teng
- Department of Orthopedics (Spine Surgery), the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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Naeimi A, Mousavi SF, Amini N, Golipoor M, Ghasemi Hamidabadi H. Therapeutic potential of melatonin-pretreated human dental pulp stem cells (hDPSCs) in an animal model of spinal cord injury. Sci Rep 2024; 14:28174. [PMID: 39548147 PMCID: PMC11568238 DOI: 10.1038/s41598-024-78077-z] [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: 08/22/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024] Open
Abstract
Dental pulp stem cells (DPSCs) show potential for treating neurodegenerative and traumatic diseases due to their neural crest origin. Melatonin (MT), an endogenous neurohormone with well-documented anti-inflammatory and antioxidant properties, has shown promising results with MSCs in terms of engraftment, proliferation, and neuronal differentiation in animal SCI models. However, the effects of melatonin preconditioning on human dental pulp stem cells (hDPSCs) for SCI treatment remain unclear. This study investigates the impact of melatonin preconditioning on hDPSCs engraftment, neural differentiation, and neurological function in rats with SCI. Forty-two male Sprague-Dawley rats were divided into six groups: Control, Sham, Model, Vehicle, Lesion Treatment A (SCI + hDPSCs), and Lesion Treatment B (SCI + MT-hDPSCs). After obtaining hDPSCs, stem cells were evaluated using flow cytometry. Cell viability was assessed using the MTT assay. SCI was induced in the Model, Vehicle, Lesion Treatment A, and Lesion Treatment B groups. The Lesion Treatment A and B groups received hDPSCs and hDPSCs pretreated with melatonin, respectively, 1 week after SCI, while the Vehicle group received only an intravenous injection of DMEM to simulate treatment. The other groups were used for behavioral testing. Immunohistochemistry (IHC) was employed to assess hDPSCs engraftment and differentiation at the SCI site. Motor function across the six groups was evaluated using the Basso, Beattie, and Bresnahan (BBB) score. Histological studies and cell counts confirmed hDPSCs implantation at the injury site, with a significantly higher presence in the MT-hDPSCs compared to hDPSCs (p < 0.01). IHC revealed that hDPSCs and MT-hDPSCs differentiated into neurons and astrocytes, with greater differentiation observed in the MT-hDPSCs compared to the hDPSCs (p < 0.01 and p < 0.05, respectively). Functional improvement was noted in both SCI + hDPSCs and SCI + MT-hDPSCs groups compared to SCI and Vehicle groups from Week 4 onward (p < 0.001). Significant differences were also observed between the SCI + hDPSCs and SCI + MT-hDPSCs groups starting from Week 7 (p < 0.01). Preconditioning hDPSCs with melatonin enhances engraftment, neuronal differentiation, and greater performance improvement compared to hDPSCs alone in the SCI animal model.
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Affiliation(s)
- Arvin Naeimi
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Seyedeh Fatemeh Mousavi
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Naser Amini
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mandana Golipoor
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Jenkner S, Clark JM, Gronthos S, O’Hare Doig RL. Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells. Cells 2024; 13:817. [PMID: 38786039 PMCID: PMC11119219 DOI: 10.3390/cells13100817] [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: 04/01/2024] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.
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Affiliation(s)
- Sandra Jenkner
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
| | - Jillian Mary Clark
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
| | - Stan Gronthos
- School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia; (S.J.); (S.G.)
- Mesenchymal Stem Cell Laboratory, Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia
| | - Ryan Louis O’Hare Doig
- Neil Sachse Centre for Spinal Cord Research, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide 5000, Australia;
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, Australia
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Fu J, Li W, Mao T, Chen Z, Lai L, Lin J, Nie Z, Sun Y, Chen Y, Zhang Q, Li X. The potential therapeutic roles of dental pulp stem cells in spinal cord injury. Front Mol Biosci 2024; 11:1363838. [PMID: 38741719 PMCID: PMC11089131 DOI: 10.3389/fmolb.2024.1363838] [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: 12/31/2023] [Accepted: 03/04/2024] [Indexed: 05/16/2024] Open
Abstract
Spinal cord injury (SCI) can lead to serious functional disorders, which have serious impacts on patients and society. The current traditional treatments of SCI are not effective the injured spinal cord is difficult to repair and regenerate. In recent years, stem cell transplantation for the treatment of SCI has been a hot research topic. Dental pulp stem cells have strong abilities of self-renewal and multi-directional differentiation, and have been applied for tissue engineering and regenerative medicine. And dental pulp stem cells have certain advantages in neuro-regenetation, bringing new hope to biotherapy for SCI. This article reviews the characteristics of dental pulp stem cells and their research progress in the treatment of SCI.
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Affiliation(s)
- Jing Fu
- Department of Stomatology, Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenjie Li
- Department of Anesthesiology and Surgery, Qingdao Municipal Hospital Group, Qingdao, China
| | - Tengfei Mao
- Yuncheng Central Hospital Affiliated to Shanxi Medical University, Yuncheng, China
| | - Zaipeng Chen
- College of Pharmacy, Guizhou Medical University, Guiyang, China
| | - Lili Lai
- Department of Orthopedics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiachen Lin
- Department of Orthopedics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhiqiang Nie
- College of Pharmacy, Guizhou Medical University, Guiyang, China
| | - Yunkai Sun
- The Eighth Clinical Medical College of Shanxi Medical University, Yuncheng, China
| | - Yanqin Chen
- College of Pharmacy, Guizhou Medical University, Guiyang, China
| | - Qin Zhang
- Yuncheng Central Hospital Affiliated to Shanxi Medical University, Yuncheng, China
| | - Xigong Li
- Department of Orthopedics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Li F, Wang X, Shi J, Wu S, Xing W, He Y. Anti-inflammatory effect of dental pulp stem cells. Front Immunol 2023; 14:1284868. [PMID: 38077342 PMCID: PMC10701738 DOI: 10.3389/fimmu.2023.1284868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Dental pulp stem cells (DPSCs) have received a lot of attention as a regenerative medicine tool with strong immunomodulatory capabilities. The excessive inflammatory response involves a variety of immune cells, cytokines, and has a considerable impact on tissue regeneration. The use of DPSCs for controlling inflammation for the purpose of treating inflammation-related diseases and autoimmune disorders such as supraspinal nerve inflammation, inflammation of the pulmonary airways, systemic lupus erythematosus, and diabetes mellitus is likely to be safer and more regenerative than traditional medicines. The mechanism of the anti-inflammatory and immunomodulatory effects of DPSCs is relatively complex, and it may be that they themselves or some of the substances they secrete regulate a variety of immune cells through inflammatory immune-related signaling pathways. Most of the current studies are still at the laboratory cellular level and animal model level, and it is believed that through the efforts of more researchers, DPSCs/SHED are expected to be transformed into excellent drugs for the clinical treatment of related diseases.
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Affiliation(s)
- FenYao Li
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - XinXin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Jin Shi
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - ShuTing Wu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - WenBo Xing
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
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Li Y, Wu M, Xing X, Li X, Shi C. Effect of Wnt10a/β-catenin signaling pathway on promoting the repair of different types of dentin-pulp injury. In Vitro Cell Dev Biol Anim 2023; 59:486-504. [PMID: 37700204 PMCID: PMC10520212 DOI: 10.1007/s11626-023-00785-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/06/2023] [Indexed: 09/14/2023]
Abstract
How to repair dentin-pulp injury effectively has always been a clinical problem, and the comparative study of repair process between different injuries is unknown. Dental pulp stem cells (DPSCs) often are selected as seed cells for the study of dentin-pulp injury repair due to excellent advantages in odontogenesis and pulp differentiation. Although many previous researches have indicated that the Wnt protein and Wnt/β-catenin signaling pathway were crucial for dental growth, development, and injury repair, the specific mechanism remained unknown. In this study, different dentine-pulp injury models of adult mice were established successfully by abrasion and cutting methods. The gross morphology and micro-CT were used to observe the repair of injured mice incisor in different groups. We found that the repair time of each group was different. The repair time of the cutting group was longer than the abrasion group and the qRT-PCR detection showed that the expression of DSPP in the cutting group was higher than that in the abrasion group, but there was no significant difference in proliferation among the groups. In vivo and cell experiments showed that activation of Wnt/β-catenin signaling pathway can promote the proliferation and odontoblast differentiation of DPSCs. In addition, by using RNAscope staining, we observed that Wnt10a was mainly expressed in the proliferative region and partially expressed in the odontoblast region. The Western blotting results showed that in the early stage of repair, the expression of Wnt10a increased with the extension of days after injury in both abrasion and cutting group and the increase of Wnt10a was tested obviously on the 5th day after injury. But on the 7th day after injury, the expression of Wnt10a was still obvious in the cutting group, while the expression of Wnt10a was significantly reduced in the abrasion group, which was close to the control group. It is suggested that Wnt10a acts as a repair-related protein and has an important role in tooth injury repair. Wnt10a was activated by R-spondin and LiCl, and Wnt10a-siRNA DPSCs were constructed to inhibit Wnt10a. The results showed that Wnt10a/β-catenin signaling pathway promoted the proliferation and odontoblast differentiation of DPSCs. It plays a crucial role in the repair process of different injuries. This study enriched the mechanisms of Wnt10a /β-catenin signaling pathways in different types of dentin-pulp injury repair, which could provide experimental evidences for the target gene screening and also give some new ideas for the subsequent research on the molecular mechanisms of tooth regeneration.
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Affiliation(s)
- Yue Li
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China
| | - Meiying Wu
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China
| | - Xinyu Xing
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China
| | - Xingxing Li
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China
- Department of Prosthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China
| | - Congchong Shi
- Department of Orthodontics, Kunming Medical University School and Hospital of Stomatology, Kunming, 650106, China.
- Yunnan Key Laboratory of Stomatology, Kunming, 650106, China.
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Almeida F, Marques S, Santos A, Prins C, Cardoso F, Heringer L, Mendonça H, Martinez A. Molecular approaches for spinal cord injury treatment. Neural Regen Res 2023; 18:23-30. [PMID: 35799504 PMCID: PMC9241396 DOI: 10.4103/1673-5374.344830] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans.
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Wenceslau CV, de Souza DM, Mambelli-Lisboa NC, Ynoue LH, Araldi RP, da Silva JM, Pagani E, Haddad MS, Kerkis I. Restoration of BDNF, DARPP32, and D2R Expression Following Intravenous Infusion of Human Immature Dental Pulp Stem Cells in Huntington's Disease 3-NP Rat Model. Cells 2022; 11:1664. [PMID: 35626701 PMCID: PMC9139280 DOI: 10.3390/cells11101664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/25/2022] [Accepted: 04/29/2022] [Indexed: 02/04/2023] Open
Abstract
Huntington's disease (HD) is a neurodegenerative inherited genetic disorder, which leads to the onset of motor, neuropsychiatric and cognitive disturbances. HD is characterized by the loss of gamma-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs). To date, there is no treatment for HD. Mesenchymal stem cells (MSCs) provide a substantial therapeutic opportunity for the HD treatment. Herein, we investigated the therapeutic potential of human immature dental pulp stem cells (hIDPSC), a special type of MSC originated from the neural crest, for HD treatment. Two different doses of hIDPSC were intravenously administrated in a subacute 3-nitropropionic acid (3NP)-induced rat model. We demonstrated hIDPSC homing in the striatum, cortex and subventricular zone using specific markers for human cells. Thirty days after hIDPSC administration, the cells found in the brain are still express hallmarks of undifferentiated MSC. Immunohistochemistry quantities analysis revealed a significant increase in the number of BDNF, DARPP32 and D2R positive stained cells in the striatum and cortex in the groups that received hIDPSC. The differences were more expressive in animals that received only one administration of hIDPSC. Altogether, these data suggest that the intravenous administration of hIDPSCs can restore the BDNF, DARPP32 and D2R expression, promoting neuroprotection and neurogenesis.
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Affiliation(s)
| | - Dener Madeiro de Souza
- Genetics Laboratory, Instituto Butantan, São Paulo 05503-900, SP, Brazil; (D.M.d.S.); (N.C.M.-L.)
| | | | | | - Rodrigo Pinheiro Araldi
- Cellavita Pesquisas Científicas Ltda., Valinhos 13271-650, SP, Brazil;
- Genetics Laboratory, Instituto Butantan, São Paulo 05503-900, SP, Brazil; (D.M.d.S.); (N.C.M.-L.)
- Programa de Pós-graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil
| | | | - Eduardo Pagani
- Azidus Brasil, Valinhos 13271-130, SP, Brazil; (L.H.Y.); (J.M.d.S.); (E.P.)
| | - Monica Santoro Haddad
- Hospital das Clínicas, Faculdade de Medicina, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-872, SP, Brazil;
| | - Irina Kerkis
- Genetics Laboratory, Instituto Butantan, São Paulo 05503-900, SP, Brazil; (D.M.d.S.); (N.C.M.-L.)
- Programa de Pós-graduação em Biologia Estrutural e Funcional, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil
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Srikawnawan W, Songsaad A, Gonmanee T, Thonabulsombat C, Phruksaniyom C, White KL, Ruangsawasdi N. Rho kinase inhibitor induced human dental pulp stem cells to differentiate into neurons. Life Sci 2022; 300:120566. [DOI: 10.1016/j.lfs.2022.120566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/13/2022] [Accepted: 04/16/2022] [Indexed: 10/18/2022]
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Jure I, De Nicola AF, Encinas JM, Labombarda F. Spinal Cord Injury Leads to Hippocampal Glial Alterations and Neural Stem Cell Inactivation. Cell Mol Neurobiol 2022; 42:197-215. [PMID: 32537668 PMCID: PMC11441270 DOI: 10.1007/s10571-020-00900-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/06/2020] [Indexed: 12/12/2022]
Abstract
The hippocampus encodes spatial and contextual information involved in memory and learning. The incorporation of new neurons into hippocampal networks increases neuroplasticity and enhances hippocampal-dependent learning performances. Only few studies have described hippocampal abnormalities after spinal cord injury (SCI) although cognitive deficits related to hippocampal function have been reported in rodents and even humans. The aim of this study was to characterize in further detail hippocampal changes in the acute and chronic SCI. Our data suggested that neurogenesis reduction in the acute phase after SCI could be due to enhanced death of amplifying neural progenitors (ANPs). In addition, astrocytes became reactive and microglial cells increased their number in almost all hippocampal regions studied. Glial changes resulted in a non-inflammatory response as the mRNAs of the major pro-inflammatory cytokines (IL-1β, TNFα, IL-18) remained unaltered, but CD200R mRNA levels were downregulated. Long-term after SCI, astrocytes remained reactive but on the other hand, microglial cell density decreased. Also, glial cells induced a neuroinflammatory environment with the upregulation of IL-1β, TNFα and IL-18 mRNA expression and the decrease of CD200R mRNA. Neurogenesis reduction may be ascribed at later time points to inactivation of neural stem cells (NSCs) and inhibition of ANP proliferation. The number of granular cells and CA1 pyramidal neurons decreased only in the chronic phase. The release of pro-inflammatory cytokines at the chronic phase might involve neurogenesis reduction and neurodegeneration of hippocampal neurons. Therefore, SCI led to hippocampal changes that could be implicated in cognitive deficits observed in rodents and humans.
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Affiliation(s)
- Ignacio Jure
- Laboratory of Neuroendocrine Biochemistry, IBYME-CONICET., Instituto de Biologia Y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
| | - Alejandro F De Nicola
- Laboratory of Neuroendocrine Biochemistry, IBYME-CONICET., Instituto de Biologia Y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina
- Department of Human Biochemistry, School of Medicine, Buenos Aires University, Paraguay 2155, C1121A6B, Buenos Aires, Argentina
| | - Juan Manuel Encinas
- Laboratory of Neural Stem Cells and Neurogenesis, Achucarro Basque Center for Neuroscience. Sede Bldg. Campus, UPV/EHU, Barrio Sarriena S/N, 48940, Leioa, Spain
| | - Florencia Labombarda
- Laboratory of Neuroendocrine Biochemistry, IBYME-CONICET., Instituto de Biologia Y Medicina Experimental, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina.
- Department of Human Biochemistry, School of Medicine, Buenos Aires University, Paraguay 2155, C1121A6B, Buenos Aires, Argentina.
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Turrioni AP, Oliveira Neto NFD, Xu Y, Morse L, Costa CADS, Battaglino R, Hebling J. Proliferation rate and expression of stem cells markers during expansion in primary culture of pulp cells. Braz Oral Res 2021; 35:e128. [PMID: 34878083 DOI: 10.1590/1807-3107bor-2021.vol35.0128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 05/03/2021] [Indexed: 11/22/2022] Open
Abstract
The aim of the present study was to evaluate the proliferation rate and the expression of stem cells markers during expansion in primary culture of dental pulp stem cells (DPSCs), comparing different techniques (explant and enzymatic digestion), subject ages (up to 40 and over 40) and cell passages (#2, #5 and #8). DPSCs were isolated using either the enzymatic digestion (ED) or explant (EX) technique. The number of days needed for the cells to reach confluence was determined. Immunophenotyping was performed by immunofluorescence and flow cytometry analysis using antibodies specific for nestin, vimentin, CD44, CD146, Oct3/4 and CD34. Data were subjected to three-way analysis of variance (n = 6/group). The ANOVA tests were complemented by Tukey's or t-tests (p < 0.05). The variables "donor age" and "technique" were analyzed to define the optimal desirability value using a response optimization. DPSCs presented a high proliferation rate from passages 2 to 5 while cells from passage 8 proliferated at a slower rate. For all markers, no significant difference was observed among passages, irrespective of the technique used or the donor's age. The mean fraction of specific antibodies was 73.7% (± 11.5), 49.0% (± 18.7), 80.1% (± 8.0), 45.2% (± 13.7), 64.7% (± 5.3) and 2.0% (± 1.5) for CD44, OCT, vimentin, nestin, CD146 and CD34, respectively. The highest optimal desirability value was obtained using the ED technique and cells from younger patients (d = 0.92). However, it was concluded that neither the isolation technique nor the donor age or cell passage significantly interfered with the stem cell phenotype and proliferation rate during cell expansion.
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Affiliation(s)
- Ana Paula Turrioni
- Universidade Federal de Uberlândia - UFU, School of Dentistry, Department of Pediatric Dentistry, Uberlandia, MG, Brazil
| | | | - Yan Xu
- The Forsyth Institute, Department of Mineralized Tissue Biology, Cambridge MA, USA
| | - Leslie Morse
- University of Minnesota, School of Medicine, Department of Rehabilitation Medicine, Minneapolis, MI, USA
| | - Carlos Alberto de Souza Costa
- Universidade Estadual Paulista - Unesp, School of Dentistry, Department of Physiology and Pathology, Araraquara, SP, Brazil
| | - Ricardo Battaglino
- University of Minnesota, School of Medicine, Department of Rehabilitation Medicine, Minneapolis, MI, USA
| | - Josimeri Hebling
- Universidade Estadual Paulista - Unesp, School of Dentistry, Department of Orthodontics and Pediatric Dentistry, Araraquara, Brazil
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12
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Al Madhoun A, Sindhu S, Haddad D, Atari M, Ahmad R, Al-Mulla F. Dental Pulp Stem Cells Derived From Adult Human Third Molar Tooth: A Brief Review. Front Cell Dev Biol 2021; 9:717624. [PMID: 34712658 PMCID: PMC8545885 DOI: 10.3389/fcell.2021.717624] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
The fields of regenerative medicine and stem cell-based tissue engineering have the potential of treating numerous tissue and organ defects. The use of adult stem cells is of particular interest when it comes to dynamic applications in translational medicine. Recently, dental pulp stem cells (DPSCs) have been traced in third molars of adult humans. DPSCs have been isolated and characterized by several groups. DPSCs have promising characteristics including self-renewal capacity, rapid proliferation, colony formation, multi-lineage differentiation, and pluripotent gene expression profile. Nevertheless, genotypic, and phenotypic heterogeneities have been reported for DPSCs subpopulations which may influence their therapeutic potentials. The underlying causes of DPSCs' heterogeneity remain poorly understood; however, their heterogeneity emerges as a consequence of an interplay between intrinsic and extrinsic cellular factors. The main objective of the manuscript is to review the current literature related to the human DPSCs derived from the third molar, with a focus on their physiological properties, isolation procedures, culture conditions, self-renewal, proliferation, lineage differentiation capacities and their prospective advances use in pre-clinical and clinical applications.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
| | - Sardar Sindhu
- Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | - Maher Atari
- Biointelligence Technology Systems S.L., Barcelona, Spain
| | - Rasheed Ahmad
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
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13
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Hayashi Y, Kato H, Nonaka K, Nakanishi H. Stem cells from human exfoliated deciduous teeth attenuate mechanical allodynia in mice through distinct from the siglec-9/MCP-1-mediated tissue-repairing mechanism. Sci Rep 2021; 11:20053. [PMID: 34625639 PMCID: PMC8501097 DOI: 10.1038/s41598-021-99585-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/27/2021] [Indexed: 12/30/2022] Open
Abstract
The effects of stem cells from human exfoliated deciduous teeth (SHED) on mechanical allodynia were examined in mice. A single intravenous injection of SHED and conditioned medium from SHED (SHED-CM) through the left external jugular vein significantly reversed the established mechanical allodynia induced by spinal nerve transection at 6 days after injection. SHED or SHED-CM significantly decreased the mean numbers of activating transcription factor 3-positive neurons and macrophages in the ipsilateral side of the dorsal root ganglion (DRG) at 20 days after spinal nerve transection. SHED or SHED-CM also suppressed activation of microglia and astrocytes in the ipsilateral side of the dorsal spinal cord. A single intravenous injection of secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 had no effect on the established mechanical allodynia, whereas a single intravenous injection of protein component(s) contained in SHED-CM with molecular weight of between 30 and 50 kDa reversed the pain. Therefore, it may be concluded that protein component(s) with molecular mass of 30–50 kDa secreted by SHED could protect and/or repair DRG neurons damaged by nerve transection, thereby ameliorating mechanical allodynia.
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Affiliation(s)
- Yoshinori Hayashi
- Department of Physiology, Nihon University School of Dentistry, Tokyo, 101-8310, Japan. .,Faculty of Dental Science, Department of Aging Science and Pharmacology, Kyushu University, Fukuoka, 812-8582, Japan.
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.,Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan
| | - Kazuaki Nonaka
- School of Health Sciences at Fukuoka, International University of Health and Welfare, Okawa, Fukuoka, 831-8501, Japan
| | - Hiroshi Nakanishi
- Department of Pharmacology, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, 731-0153, Japan.
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14
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Asadi-Golshan R, Razban V, Mirzaei E, Rahmanian A, Khajeh S, Mostafavi-Pour Z, Dehghani F. Efficacy of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in spinal cord injury in rats: Stereological evidence. J Chem Neuroanat 2021; 116:101978. [PMID: 34098013 DOI: 10.1016/j.jchemneu.2021.101978] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/30/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Spinal cord injury (SCI) causes histological alterations which in turn affects functional activity. Studies have demonstrated that dental pulp-derived stem cells conditioned medium has beneficial effects on the nervous system. Besides, collagen hydrogel acts as a drug releasing system in SCI investigations. This research aimed to evaluate effects of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in SCI. After culturing of Stem cells from human exfoliated deciduous teeth (SHEDs), SHED-conditioned medium (SHED-CM) was harvested and concentrated. Collagen hydrogel containing SHED-CM was prepared. The rats were divided into five groups receiving laminectomy, compressive SCI with or without intraspinal injection of biomaterials (SHED-CM and collagen hydrogel with or without SHED-CM). After 6 weeks, histological parameters were estimated using stereological methods. The total volume of preserved white matter and gray matter (p < 0.05) as well as the total number of neurons and oligodendrocytes in the rats received SHED-CM loaded in collagen hydrogel were significantly higher, and also lesion volume and lesion length were significantly lower (p < 0.05) compared to those of the other injured groups. In conclusion, intraspinal administration of SHED-CM loaded in collagen hydrogel leads to neuroprotection, proposing a cell-free therapeutic approach in SCI.
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Affiliation(s)
- Reza Asadi-Golshan
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Razban
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Esmaeil Mirzaei
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Sahar Khajeh
- Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zohreh Mostafavi-Pour
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Dehghani
- Histomorphometry and Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran.
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15
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Xiao Z, Lei T, Liu Y, Yang Y, Bi W, Du H. The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2021; 12:5. [PMID: 33407864 PMCID: PMC7789713 DOI: 10.1186/s13287-020-01957-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/27/2020] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, is caused by the loss of dopaminergic (DAergic) neurons in the substantia nigra resulting in a series of motor or non-motor disorders. Current treatment methods are unable to stop the progression of PD and may bring certain side effects. Cell replacement therapy has brought new hope for the treatment of PD. Recently, human dental tissue-derived mesenchymal stem cells have received extensive attention. Currently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are considered to have strong potential for the treatment of these neurodegenerative diseases. These cells are considered to be ideal cell sources for the treatment of PD on account of their unique characteristics, such as neural crest origin, immune rejection, and lack of ethical issues. In this review, we briefly describe the research investigating cell therapy for PD and discuss the application and progress of DPSCs and SHED in the treatment of PD. This review offers significant and comprehensive guidance for further clinical research on PD.
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Affiliation(s)
- Zhuangzhuang Xiao
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Tong Lei
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Yanyan Liu
- Kangyanbao (Beijing) Stem Cell Technology Co., Ltd, Beijing, 102600, China
| | - Yanjie Yang
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Wangyu Bi
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Hongwu Du
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China.
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16
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Eskandari N, Boroujeni ME, Abdollahifar MA, Piryaei A, Khodagholi F, Mirbehbahani SH, Siroosi S, Moghaddam MH, Aliaghaei A, Sadeghi Y. Transplantation of human dental pulp stem cells compensates for striatal atrophy and modulates neuro-inflammation in 3-nitropropionic acid rat model of Huntington's disease. Neurosci Res 2020; 170:133-144. [PMID: 33359180 DOI: 10.1016/j.neures.2020.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/09/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023]
Abstract
Stem cell-based therapy has recently offered a promising alternative for the remedy of neurodegenerative disorders like Huntington's disease (HD). Herein, we investigated the potential ameliorative effects of implantation of dental pulp stem cells (DPSCs) in 3-nitropropionic acid (3-NP) rat models of HD. In this regard, human DPSCs were isolated, culture-expanded and implanted in rats lesioned with 3-NP. Post-transplantation examinations revealed that DPSCs were able to survive and augment motor skills and muscle activity. Histological analysis showed DPSCs treatment hampered the shrinkage of the striatum along with the inhibition of gliosis and microgliosis in the striatum of 3-NP rat models. We also detected the downregulation of Caspase-3 and pro-inflammatory cytokines such as TNF and IL-1β upon DPSCs grafting. Overall, these findings imply that the grafting of DPSCs could repair motor-skill impairment and induce neurogenesis, probably through the secretion of neurotrophic factors and the modulation of neuroinflammatory response in HD animal models.
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Affiliation(s)
- Neda Eskandari
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Eskandarian Boroujeni
- Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Mohammad Amin Abdollahifar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shokoofeh Siroosi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Yousef Sadeghi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Anatomy & Neuroscience, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
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17
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Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury. J Neurosci 2020; 40:2644-2662. [PMID: 32066583 DOI: 10.1523/jneurosci.2229-19.2020] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 02/03/2020] [Accepted: 02/05/2020] [Indexed: 12/15/2022] Open
Abstract
Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Conditional knockout (KO) of yap in astrocytes significantly inhibited astrocytic proliferation, impaired the formation of glial scars, inhibited the axonal regeneration, and impaired the behavioral recovery of C57BL/6 male mice after SCI. Mechanistically, the bFGF was upregulated after SCI and induced the activation of YAP through RhoA pathways, thereby promoting the formation of glial scars. Additionally, YAP promoted bFGF-induced proliferation by negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Finally, bFGF or XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) injection indeed activated YAP signaling and promoted the formation of glial scars and the functional recovery of mice after SCI. These findings suggest that YAP promotes the formation of glial scars and neural regeneration of mice after SCI, and that the bFGF-RhoA-YAP-p27Kip1 pathway positively regulates astrocytic proliferation after SCI.SIGNIFICANCE STATEMENT Glial scars play critical roles in neuronal regeneration of CNS injury diseases, such as spinal cord injury (SCI). Here, we provide evidence for the function of Yes-associated protein (YAP) in the formation of glial scars after SCI through regulation of astrocyte proliferation. As a downstream of bFGF (which is upregulated after SCI), YAP promotes the proliferation of astrocytes through negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Activation of YAP by bFGF or XMU-MP-1 injection promotes the formation of glial scar and the functional recovery of mice after SCI. These results suggest that the bFGF-RhoA-YAP-p27Kip1 axis for the formation of glial scars may be a potential therapeutic strategy for SCI patients.
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18
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Looking into dental pulp stem cells in the therapy of photoreceptors and retinal degenerative disorders. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2019; 203:111727. [PMID: 31862637 DOI: 10.1016/j.jphotobiol.2019.111727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/13/2019] [Accepted: 12/02/2019] [Indexed: 01/09/2023]
Abstract
Blindness and vision impairment are caused by irremediable retinal degeneration in affected individuals worldwide. Cell therapy for a retinal replacement can potentially rescue their vision, specifically for those who lost the light sensing photoreceptors in the eye. As such, well-characterized retinal cells are required for the replacement purposes. Stem cell-based therapy in photoreceptor and retinal pigment epithelium transplantation is well received, however, the drawbacks of retinal transplantation is the limited clinical protocols development, insufficient number of transplanted cells for recovery, the selection of potential stem cell sources that can be differentiated into the target cells, and the ability of cells to migrate to the host tissue. Dental pulp stem cells (DPSC) belong to a subset of mesenchymal stem cells, and are recently being studied due to its high capability of differentiating into cells of the neuronal lineage. In this review, we look into the potential uses of DPSC in treating retinal degeneration, and also the current data supporting its application.
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19
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Darabi S, Tiraihi T, Nazm Bojnordi M, Ghasemi Hamidabadi H, Rezaei N, Zahiri M, Alizadeh R. Trans-Differentiation of Human Dental Pulp Stem Cells Into Cholinergic-Like Neurons Via Nerve Growth Factor. Basic Clin Neurosci 2019; 10:609-617. [PMID: 32477478 PMCID: PMC7253808 DOI: 10.32598/bcn.10.6.609] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/10/2018] [Accepted: 07/13/2019] [Indexed: 01/09/2023] Open
Abstract
Introduction: Cell therapy has been widely considered as a therapeutic approach for neurodegenerative diseases and nervous system damage. Cholinergic neurons as one of the most important neurons that play a significant role in controlling emotions, mobility, and autonomic systems. In this study, Human Dental Pulp Stem Cells (hDPSCs) were differentiated into the cholinergic neurons by β-mercaptoethanol in the preinduction phase and also by the nerve growth factor (NGF) in the induction phase. Methods: The hDPSCs were evaluated for CD73, CD31, CD34, and Oct-4. Concentration-time relationships for NGF were assessed by evaluating the viability rate of cells and the immune response to nestin, neurofilament 160, microtubule-associated protein-2, and choline acetyltransferase. Results: The hDPSCs had a negative response to CD34 and CD31. The optimal dose for the NGF was 50 ng/mL seven days after the induction when the highest percentage of expressing markers for the Cholinergic neurons (ChAT) was detected. Conclusion: The results of this study provided a method for producing cholinergic neurons by hDPSCs, which can be used in cytotherapy for degenerative diseases of the nervous system and also spinal cord injury.
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Affiliation(s)
- Shahram Darabi
- Cellular and Molecular Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Taki Tiraihi
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran
| | - Maryam Nazm Bojnordi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nourollah Rezaei
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maria Zahiri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran.,Department of Anatomical Sciences, School of Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Rafieh Alizadeh
- ENT and Head & Neck Research Center and Department, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
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20
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Massoto TB, Santos ACR, Ramalho BS, Almeida FM, Martinez AMB, Marques SA. Mesenchymal stem cells and treadmill training enhance function and promote tissue preservation after spinal cord injury. Brain Res 2019; 1726:146494. [PMID: 31586628 DOI: 10.1016/j.brainres.2019.146494] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 09/14/2019] [Accepted: 10/02/2019] [Indexed: 01/01/2023]
Abstract
Spinal cord injury (SCI) is considered a serious neurological disorder that can lead to severe sensory, motor and autonomic deficits. In this work, we investigated whether cell therapy associated with physical activity after mouse SCI could promote morphological and functional outcomes, using a lesion model established by our group. Mesenchymal stem cells (8 × 105 cells/2 µL) or DMEM (2 µL), were injected in the epicenter of the lesion at 7 days after SCI, and the mice started a moderate treadmill training 14 days after injury. Functional assessments were performed weekly up to 8 weeks after injury when the morphological analyses were also performed. Four injured groups were analyzed: DMEM (SCI plus DMEM injection), MSCT (SCI plus MSC injection), DMEM + TMT (SCI plus DMEM injection and treadmill training) and MSCT + TMT (SCI plus MSC injection and treadmill training). The animals that received the combined therapy (MSCT + TMT) were able to recover and maintained the better functional results throughout the analyzed period. The morphometric analysis from MSCT + TMT group evidenced a larger spared white matter area and a higher number of preserved myelinated fibers with the majority of them reaching the ideal G-ratio values, when compared to other groups. Ultrastructural analysis from this group, using transmission electron microscopy, showed better tissue preservation with few microcavitations and degenerating nerve fibers. Also, this group exhibited a significantly higher neurotrophin 4 (NT4) expression as compared to the other groups. The results provided by this study support the conclusion that the association of strategies is a potential therapeutic approach to treat SCI, with the possibility of translation into the clinical practice.
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Affiliation(s)
- Tamires Braga Massoto
- Laboratory of Neural Regeneration and Function - Department of Neurobiology, Institute of Biology, Federal Fluminense University, Rio de Janeiro, Brazil
| | - Anne Caroline Rodrigues Santos
- Laboratory of Neural Regeneration and Function - Department of Neurobiology, Institute of Biology, Federal Fluminense University, Rio de Janeiro, Brazil; Laboratory of Neurodegeneration and Repair, Clementino Fraga Filho Hospital, Medical School, Departament of Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bruna S Ramalho
- Laboratory of Neurodegeneration and Repair, Clementino Fraga Filho Hospital, Medical School, Departament of Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Martins Almeida
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Maria Blanco Martinez
- Laboratory of Neurodegeneration and Repair, Clementino Fraga Filho Hospital, Medical School, Departament of Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Suelen Adriani Marques
- Laboratory of Neural Regeneration and Function - Department of Neurobiology, Institute of Biology, Federal Fluminense University, Rio de Janeiro, Brazil; Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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21
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Okuwa Y, Toriumi T, Nakayama H, Ito T, Otake K, Kurita K, Nakashima M, Honda M. Transplantation effects of dental pulp-derived cells on peripheral nerve regeneration in crushed sciatic nerve injury. J Oral Sci 2019; 60:526-535. [PMID: 30587687 DOI: 10.2334/josnusd.17-0462] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
The effects of transplanted human dental pulp-derived cells (DPCs) on peripheral nerve regeneration were studied in a rat model of sciatic nerve crush injury. In one group, DPCs were transplanted into the compression site (cell transplantation group); the control group underwent no transplantation (crushed group). Sciatic nerve regeneration was determined based on the recovery of motor function and histological and immunohistochemical analyses. The cell transplantation group showed improved motor function compared with the crushed group using the CatWalk XT system, which corresponded to a higher ratio of tibialis to anterior muscle weight 14 days after surgery. Histological analysis revealed a smaller interspace area and few vacuoles in the sciatic nerve after cell transplantation compared with the crushed group. The myelin sheath was visualized with Luxol Fast Blue (LFB) staining and anti-myelin basic protein (anti-MBP) antibody labeling; the percentages of LFB- and MBP-positive areas were higher in the cell transplantation group than in the crushed group. Human mitochondria-positive cells were also identified in the sciatic nerve at the transplantation site 14 days after surgery. Taken together, the observed correlation between morphological findings and functional outcomes following DPC transplantation indicates that DPCs promote peripheral nerve regeneration in rats.
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Affiliation(s)
- Yuta Okuwa
- Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry.,Department of Oral Anatomy, Aichi-Gakuin University School of Dentistry
| | - Taku Toriumi
- Department of Oral Anatomy, Aichi-Gakuin University School of Dentistry
| | - Hidenori Nakayama
- Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry
| | - Tatsuaki Ito
- Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry
| | - Keita Otake
- Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry
| | - Kenichi Kurita
- Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry
| | - Misako Nakashima
- Department of Stem Cell Biology and Regenerative Medicine,National Center for Geriatrics and Gerontology
| | - Masaki Honda
- Department of Oral Anatomy, Aichi-Gakuin University School of Dentistry
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22
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Aliaghaei A, Boroujeni ME, Ahmadi H, Bayat AH, Tavirani MR, Abdollahifar MA, Pooyafar MH, Mansouri V. Dental pulp stem cell transplantation ameliorates motor function and prevents cerebellar atrophy in rat model of cerebellar ataxia. Cell Tissue Res 2019; 376:179-187. [PMID: 30635776 DOI: 10.1007/s00441-018-02980-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/13/2018] [Indexed: 02/07/2023]
Abstract
Cerebellar ataxias (CA) include a range of neurodegenerative disorders hallmarked by deterioration of the cerebellum. Cell replacement therapy (CRT) offers a potential remedy for the diseases associated with the central nervous system (CNS). This study was designed to assess the neurorestorative/protective effects of dental pulp stem cell (DPSC) implantation on a rat model of CA induced by 3-acetylpyridine (3-AP) as a neurotoxin. To begin, human DPSCs were extracted, cultured and phenotypically characterized. Then, experimental ataxia was induced in 20 male adult rats by a single injection of 3-AP and bilateral DPSC transplantation was performed 3 days after 3-AP administration, followed by stereological analysis of cerebellar layers along with assessment of motor skills and inflammatory response. The findings showed that transplantation of DPSCs in a 3-AP model of ataxia ameliorated motor coordination and muscle activity, increased cerebellar volumes of molecular and granular layers plus white matter, reduced the levels of inflammatory cytokines and thwarted the degeneration of Purkinje cells against 3-AP toxicity. Taken together, human DPSCs could be considered as a suitable candidate for CRT-based therapies with a specific focus on CA.
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Affiliation(s)
- Abbas Aliaghaei
- Cell Biology & Anatomical Sciences Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Eskandarian Boroujeni
- Department of Stem Cells & Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering & Biotechnology, Tehran, Iran
| | - Houssein Ahmadi
- Cell Biology & Anatomical Sciences Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir-Hossein Bayat
- Department of Neurobiology and Neuropsychology, Saveh University of Medical Sciences, Saveh, Iran
| | | | - Mohammad Amin Abdollahifar
- Cell Biology & Anatomical Sciences Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad H Pooyafar
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Mansouri
- Faculty of Paramedical Science, Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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23
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Effects of Different Doses of Mesenchymal Stem Cells on Functional Recovery After Compressive Spinal-Cord Injury in Mice. Neuroscience 2019; 400:17-32. [DOI: 10.1016/j.neuroscience.2018.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 12/03/2018] [Accepted: 12/04/2018] [Indexed: 02/07/2023]
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24
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Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice. Int J Mol Sci 2019; 20:ijms20030568. [PMID: 30699944 PMCID: PMC6387212 DOI: 10.3390/ijms20030568] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 01/20/2019] [Accepted: 01/23/2019] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration.
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25
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Tosic J, Stanojevic Z, Vidicevic S, Isakovic A, Ciric D, Martinovic T, Kravic-Stevovic T, Bumbasirevic V, Paunovic V, Jovanovic S, Todorovic-Markovic B, Markovic Z, Danko M, Micusik M, Spitalsky Z, Trajkovic V. Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats. Neuropharmacology 2018; 146:95-108. [PMID: 30471296 DOI: 10.1016/j.neuropharm.2018.11.030] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 11/15/2018] [Accepted: 11/20/2018] [Indexed: 12/13/2022]
Abstract
We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0-32), while the protection was less pronounced if the treatment was limited to the induction (day 0-7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-γ-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response.
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Affiliation(s)
- Jelena Tosic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia
| | - Zeljka Stanojevic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia
| | - Sasenka Vidicevic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia
| | - Aleksandra Isakovic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia
| | - Darko Ciric
- Institute of Histology and Embryology, School of Medicine, University of Belgrade, Visegradska 26, 11000, Belgrade, Serbia
| | - Tamara Martinovic
- Institute of Histology and Embryology, School of Medicine, University of Belgrade, Visegradska 26, 11000, Belgrade, Serbia
| | - Tamara Kravic-Stevovic
- Institute of Histology and Embryology, School of Medicine, University of Belgrade, Visegradska 26, 11000, Belgrade, Serbia
| | - Vladimir Bumbasirevic
- Institute of Histology and Embryology, School of Medicine, University of Belgrade, Visegradska 26, 11000, Belgrade, Serbia
| | - Verica Paunovic
- Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 1, 11000, Belgrade, Serbia
| | - Svetlana Jovanovic
- Vinca Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, 11000, Belgrade, Serbia
| | | | - Zoran Markovic
- Polymer Institute, Slovak Academy of Sciences, Dubravska Cesta 9, 84541, Bratislava, Slovakia
| | - Martin Danko
- Polymer Institute, Slovak Academy of Sciences, Dubravska Cesta 9, 84541, Bratislava, Slovakia
| | - Matej Micusik
- Polymer Institute, Slovak Academy of Sciences, Dubravska Cesta 9, 84541, Bratislava, Slovakia
| | - Zdenko Spitalsky
- Polymer Institute, Slovak Academy of Sciences, Dubravska Cesta 9, 84541, Bratislava, Slovakia
| | - Vladimir Trajkovic
- Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 1, 11000, Belgrade, Serbia.
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26
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Dos Santos FP, Peruch T, Katami SJV, Martini APR, Crestani TA, Quintiliano K, Maurmann N, Sanches EF, Netto CA, Pranke P, de Souza Pagnussat A. Poly (lactide-co-glycolide) (PLGA) Scaffold Induces Short-term Nerve Regeneration and Functional Recovery Following Sciatic Nerve Transection in Rats. Neuroscience 2018; 396:94-107. [PMID: 30452974 DOI: 10.1016/j.neuroscience.2018.11.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 01/27/2023]
Abstract
Peripheral nerve injury is an important cause of incapability and has limited available treatment. Autologous donor nerve implant is the golden standard treatment, however, may cause secondary deficits. Stem cells show positive results in preclinical settings, preserving tissue and function. We tested the efficacy of stem cells derived from human exfoliated deciduous teeth seeded in poly (lactide-co-glycolide) scaffolds in sciatic nerve transection model. Seventy-two adult male Wistar rats had 7-mm nerve gap bridge using scaffolds with (or without) stem cells. Animals were randomly divided into: sham-operated; sham-operated without scaffold; sham-operated + scaffold + stem cells; sciatic transection + no treatment; sciatic transection + acellular scaffolds; sciatic transection + scaffold + stem cells. Sciatic Functional Index and Ladder Rung Walking tests were performed before (-1), 14 and 28 days after surgery. Morphometric nerve measurement and muscle weights were assessed. Scaffolds with stem cells improved function in Sciatic Functional Index. Acellular scaffold was effective, promoting functional recovery and nerve regeneration following nerve injury. Scaffolds provide better nerve regeneration and functional recovery after sciatic transection. Despite cell therapy promoting faster recovery after sciatic transection in the Sciatic Index Score, stem cells did not improve functional and morphological recovery after nerve injury. This is the first study testing the potential use of scaffolds combined with stem cells in the early stages after injury. Scaffolds with stem cells could accelerate nerve recovery and favor adjuvant therapies, evidencing the need for further studies to increase the knowledge about stem cells' mechanisms.
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Affiliation(s)
- Franciele Pereira Dos Santos
- Post-graduation Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | - Thais Peruch
- Department of Physical Therapy, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
| | | | - Ana Paula Rodrigues Martini
- Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Thayane Antoniolli Crestani
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Kerlin Quintiliano
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Natasha Maurmann
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Eduardo Farias Sanches
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Post-graduation Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Carlos Alexandre Netto
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patricia Pranke
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-graduation Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Stem Cell Research Institute (SCRI), Porto Alegre, RS, Brazil
| | - Aline de Souza Pagnussat
- Post-graduation Program in Rehabilitation Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil; Department of Physical Therapy, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil; Post-graduation Program in Health Sciences, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil
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27
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Baniebrahimi G, Khanmohammadi R, Mir F. Teeth-derived stem cells: A source for cell therapy. J Cell Physiol 2018; 234:2426-2435. [PMID: 30238990 DOI: 10.1002/jcp.27270] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022]
Abstract
Cell therapy is one of the important therapeutic approaches in the treatment of many diseases such as cancer, degenerative diseases, and cardiovascular diseases. Among various cell types, which could be used as cell therapies, stem cell therapy has emerged as powerful tools in the treatment of several diseases. Multipotent stem cells are one of the main classes of stem cells that could originate from different parts of the body such as bone marrow, adipose, placenta, and tooth. Among several types of multipotent stem cells, tooth-derived stem cells (TDSCs) are associated with special properties such as accessible, easy isolation, and low invasive, which have introduced them as a good source for using in the treatment of several diseases such as neural injuries, liver fibrosis, and Cohrn's disease. Here, we provided an overview of TDSCs particular stem cells from human exfoliated deciduous teeth and clinical application of them. Moreover, we highlighted molecular mechanisms involved in the regulation of dental stem cells fate.
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Affiliation(s)
- Ghazaleh Baniebrahimi
- Department of Pediatric Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Razieh Khanmohammadi
- Department of Pediatric Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mir
- Department of Pediatric Dentistry, School of Dentistry, Zahedan University of Medical Sciences, Zahedan, Iran
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28
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Nicola F, Marques MR, Odorcyk F, Petenuzzo L, Aristimunha D, Vizuete A, Sanches EF, Pereira DP, Maurmann N, Gonçalves CA, Pranke P, Netto CA. Stem Cells from Human Exfoliated Deciduous Teeth Modulate Early Astrocyte Response after Spinal Cord Contusion. Mol Neurobiol 2018; 56:748-760. [PMID: 29796991 DOI: 10.1007/s12035-018-1127-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 05/11/2018] [Indexed: 12/19/2022]
Abstract
The transplantation of stem cells from human exfoliated deciduous teeth (SHED) has been studied as a possible treatment strategy for spinal cord injuries (SCIs) due to its potential for promoting tissue protection and functional recovery. The aim of the present study was to investigate the effects of the early transplantation of SHED on glial scar formation and astrocytic reaction after an experimental model of SCI. Wistar rats were spinalized using the NYU Impactor. Animals were randomly distributed into three groups: control (naive) (animal with no manipulation); SCI (receiving laminectomy followed by SCI and treated with vehicle), and SHED (SCI rat treated with intraspinal SHED transplantation, 1 h after SCI). In vitro investigation demonstrated that SHED were able to express mesenchymal stem cells, vimentin and S100B markers, related with neural progenitor and glial cells, respectively. The acute SHED transplantation promoted functional recovery, measured as from the first week after spinal cord contusion by Basso, Beattie, and Bresnahan scale. Twenty-four and 48 h after lesion, flow cytometry revealed a spinal cord vimentin+ cells increment in the SHED group. The increase of vimentin+ cells was confirmed by immunofluorescence. Moreover, the bioavailability of astrocytic proteins such as S100B and Kir4.1 shown to be increased in the spinal cord of SHED group, whereas there was a glial scar reduction, as indicated by ELISA and Western blot techniques. The presented results support that SHED act as a neuroprotector agent after transplantation, probably through paracrine signaling to reduce glial scar formation, inducing tissue plasticity and functional recovery.
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Affiliation(s)
- Fabrício Nicola
- Post Graduate Program in Neuroscience, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. .,Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
| | - Marília Rossato Marques
- Post Graduate Program in Neuroscience, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Felipe Odorcyk
- Post Graduate Program in Neuroscience, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Letícia Petenuzzo
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Dirceu Aristimunha
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Adriana Vizuete
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Eduardo Farias Sanches
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Daniela Pavulack Pereira
- Hematology and Stem Cell Laboratory, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Natasha Maurmann
- Hematology and Stem Cell Laboratory, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Post Graduate Program in Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Patricia Pranke
- Hematology and Stem Cell Laboratory, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Post Graduate Program in Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Stem Cell Research Institute, Porto Alegre, Brazil
| | - Carlos Alexandre Netto
- Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
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29
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Ramalho BDS, Almeida FMD, Sales CM, de Lima S, Martinez AMB. Injection of bone marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative to spinal cord injury treatment in mice. Neural Regen Res 2018; 13:1046-1053. [PMID: 29926832 PMCID: PMC6022457 DOI: 10.4103/1673-5374.233448] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In spite of advances in surgical care and rehabilitation, the consequences of spinal cord injury (SCI) are still challenging. Several experimental therapeutic strategies have been studied in the SCI field, and recent advances have led to the development of therapies that may act on the inhibitory microenvironment. Assorted lineages of stem cells are considered a good treatment for SCI. This study investigated the effect of systemic transplantation of mesenchymal stem cells (MSCs) in a compressive SCI model. Here we present results of the intraperitoneal route, which has not been used previously for MSC administration after compressive SCI. We used adult female C57BL/6 mice that underwent laminectomy at the T9 level, followed by spinal cord compression for 1 minute with a 30-g vascular clip. The animals were divided into five groups: sham (anesthesia and laminectomy but without compression injury induction), MSC i.p. (intraperitoneal injection of 8 × 105 MSCs in 500 µL of DMEM at 7 days after SCI), MSC i.v. (intravenous injection of 8 × 105 MSCs in 500 µL of DMEM at 7 days after SCI), DMEM i.p. (intraperitoneal injection of 500 µL of DMEM at 7 days after SCI), DMEM i.v. (intravenous injection of 500 µL of DMEM at 7 days after SCI). The effects of MSCs transplantation in white matter sparing were analyzed by luxol fast blue staining. The number of preserved fibers was counted in semithin sections stained with toluidine blue and the presence of trophic factors was analyzed by immunohistochemistry. In addition, we analyzed the locomotor performance with Basso Mouse Scale and Global Mobility Test. Our results showed white matter preservation and a larger number of preserved fibers in the MSC groups than in the DMEM groups. Furthermore, the MSC groups had higher levels of trophic factors (brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and neurotrophin-4) in the spinal cord and improved locomotor performance. Our results indicate that injection of MSCs by either intraperitoneal or intravenous routes results in beneficial outcomes and can be elected as a choice for SCI treatment.
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Affiliation(s)
- Bruna Dos Santos Ramalho
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia - Faculdade de Medicina, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Martins de Almeida
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia - Faculdade de Medicina, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Conrado Mendonça Sales
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia - Faculdade de Medicina, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Silmara de Lima
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia - Faculdade de Medicina, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Maria Blanco Martinez
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia - Faculdade de Medicina, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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30
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Mortada I, Mortada R, Al Bazzal M. Dental pulp stem cells and the management of neurological diseases: An update. J Neurosci Res 2017; 96:265-272. [PMID: 28736906 DOI: 10.1002/jnr.24122] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/05/2017] [Accepted: 07/05/2017] [Indexed: 01/08/2023]
Abstract
Medical research in regenerative medicine has brought promising perspectives for the use of stem cells in clinical trials. Stem cells are undifferentiated cells capable of multilineage differentiation and available in numerous sources in the human body. Dental pulp constitutes an attractive source of these cells since collecting mesenchymal stem cells from this site is a noninvasive practice that can be performed after a common surgical extraction of supernumerary or wisdom teeth. Thus, tissue sacrifice is very low and several cytotypes can be obtained owing to these cells' multipotency, in addition to the fact that they can be cryopreserved and stored for long periods. Mesenchymal stem cells have high proliferation rates, making them favorable for clinical application. These multipotent cells, present in biological waste, constitute an appropriate resource in the treatment of many neurological diseases.
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Affiliation(s)
- Ibrahim Mortada
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rola Mortada
- Lebanese University School of Dentistry, Beirut, Lebanon
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31
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Wang F, Jia Y, Liu J, Zhai J, Cao N, Yue W, He H, Pei X. Dental pulp stem cells promote regeneration of damaged neuron cells on the cellular model of Alzheimer's disease. Cell Biol Int 2017; 41:639-650. [PMID: 28328017 DOI: 10.1002/cbin.10767] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 03/19/2017] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is an incurable neurodegenerative disease and many types of stem cells have been used in AD therapy with some favorable effects. In this study, we investigated the potential therapeutical effects of human dental pulp stem cells (hDPSCs) on AD cellular model which established by okadaic acid (OA)-induced damage to human neuroblastoma cell line, SH-SY5Y, in vitro for 24 h. After confirmed the AD cellular model, the cells were co-culture with hDPSCs by transwell co-culture system till 24 h for treatment. Then the cytomorphology of the hDPSCs-treated cells were found to restore gradually with re-elongation of retracted dendrites. Meanwhile, Cell Counting Kit-8 assay and Hoechst 33258 staining showed that hDPSCs caused significant increase in the viability and decrease in apoptosis of the model cells, respectively. Observation of DiI labeling also exhibited the prolongation dendrites in hDPSCs-treated cells which were obviously different from the retraction dendrites in AD model cells. Furthermore, specific staining of α-tubulin and F-actin demonstrated that the hDPSCs-treated cells had the morphology of restored neurons, with elongated dendrites, densely arranged microfilaments, and thickened microtubular fibrils. In addition, results from western blotting revealed that phosphorylation at Ser 396 of Tau protein was significantly suppressed by adding of hDPSCs. These results indicate that hDPSCs may promote regeneration of damaged neuron cells in vitro model of AD and may serve as a useful cell source for treatment of AD.
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Affiliation(s)
- Feixiang Wang
- Department of Stomatology, Chinese PLA General Hospital and Chinese PLA Medical School, 28, Fuxing Road, Beijing, 100853, China
| | - Yali Jia
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
| | - Jiajing Liu
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
| | - Jinglei Zhai
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
| | - Ning Cao
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
| | - Huixia He
- Department of Stomatology, Chinese PLA General Hospital and Chinese PLA Medical School, 28, Fuxing Road, Beijing, 100853, China
| | - Xuetao Pei
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Academy of Military Medical Sciences, 27, Taiping Road, Beijing, 100850, China
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Neuroprotector effect of stem cells from human exfoliated deciduous teeth transplanted after traumatic spinal cord injury involves inhibition of early neuronal apoptosis. Brain Res 2017; 1663:95-105. [PMID: 28322752 DOI: 10.1016/j.brainres.2017.03.015] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/12/2017] [Accepted: 03/13/2017] [Indexed: 12/20/2022]
Abstract
Stem cells from human exfoliated deciduous teeth (SHED) transplants have been investigated as a possible treatment strategy for spinal cord injuries (SCI) due to their potential for promoting functional recovery. The aim of present study was to investigate the effects of SHED on neuronal death after an experimental model of SCI. METHODS Wistar rats were spinalized using NYU impactor®. Animals were randomly distributed into 4 groups: Control (Naive) or Surgical control, Sham (laminectomy with no SCI); SCI (laminectomy followed by SCI, treated with vehicle); SHED (SCI treated with intraspinal transplantation of 3×105 SHED, 1h after SCI). Functional evaluations and morphological analysis were performed to confirm the spinal injury and the benefit of SHED transplantation on behavior, tissue protection and motor neuron survival. Flow cytometry of neurons, astrocytes, macrophages/microglia and T cells of spinal cord tissue were run at six, twenty-four, forty-eight and seventy-two hours after lesion. Six hours after SCI, ELISA and Western Blot were run to assess pro- and anti-apoptotic factors. The SHED group showed a significant functional improvement in comparison to the SCI animals, as from the first week until the end of the experiment. This behavioral protection was associated with less tissue impairment and greater motor neuron preservation. SHED reduced neuronal loss over time, as well as the overexpression of pro-apoptotic factor TNF-α, while maintained basal levels of the anti-apoptotic BCL-XL six hours after lesion. Data here presented show that SHED transplantation one hour after SCI interferes with the balance between pro- and anti-apoptotic factors and reduces early neuronal apoptosis, what contributes to tissue and motor neuron preservation and hind limbs functional recovery.
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Carnevale G, Pisciotta A, Riccio M, Bertoni L, De Biasi S, Gibellini L, Zordani A, Cavallini GM, La Sala GB, Bruzzesi G, Ferrari A, Cossarizza A, de Pol A. Human dental pulp stem cells expressing STRO-1, c-kit and CD34 markers in peripheral nerve regeneration. J Tissue Eng Regen Med 2017; 12:e774-e785. [PMID: 27943583 DOI: 10.1002/term.2378] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 10/10/2016] [Accepted: 12/06/2016] [Indexed: 12/16/2022]
Abstract
Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional defects. The application of stem cells able to differentiate in Schwann cell-like cells in vitro and in vivo, could represent an attractive therapeutic approach for the treatment of nerve injuries. Further, stem cells sources sharing the same embryological origin as Schwann cells might be considered a suitable tool. The aim of this study was to demonstrate the ability of a neuroectodermal subpopulation of human STRO-1+ /c-Kit+ /CD34+ DPSCs, expressing P75NTR , nestin and SOX-10, to differentiate into Schwann cell-like cells in vitro and to promote axonal regeneration in vivo, which led to functional recovery as measured by sustained gait improvement, in animal rat model of peripheral nerve injury. Transplanted human dental pulp stem cells (hDPSCs) engrafted into sciatic nerve defect, as revealed by the positive staining against human nuclei, showed the expression of typical Schwann cells markers, S100b and, noteworthy, a significant number of myelinated axons was detected. Moreover, hDPSCs promoted axonal regeneration from proximal to distal stumps 1 month after transplantation. This study demonstrates that STRO-1+ /c-Kit+ /CD34+ hDPSCs, associated with neural crest derivation, represent a promising source of stem cells for the treatment of demyelinating disorders and might provide a valid alternative tool for future clinical applications to achieve functional recovery after injury or peripheral neuropathies besides minimizing ethical issues. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Riccio
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bertoni
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Sara De Biasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Lara Gibellini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessio Zordani
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gian Maria Cavallini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Giacomo Bruzzesi
- Oro-Maxillo-Facial Department, AUSL Baggiovara, Baggiovara, Modena, Italy
| | - Adriano Ferrari
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.,Children Rehabilitation Special Unit, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
| | - Andrea Cossarizza
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Anto de Pol
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
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Surgical Procedure for Extracting Pig Teeth for Isolation and Cultivation of Mesenchymal Stem Cells from Dental Pulp for Regenerative Therapy Applications. BIONANOSCIENCE 2017. [DOI: 10.1007/s12668-016-0297-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Zhang J, Lian M, Cao P, Bao G, Xu G, Sun Y, Wang L, Chen J, Wang Y, Feng G, Cui Z. Effects of Nerve Growth Factor and Basic Fibroblast Growth Factor Promote Human Dental Pulp Stem Cells to Neural Differentiation. Neurochem Res 2016; 42:1015-1025. [PMID: 28005222 DOI: 10.1007/s11064-016-2134-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 10/14/2016] [Accepted: 12/03/2016] [Indexed: 02/08/2023]
Abstract
Dental pulp stem cells (DPSCs) were the most widely used seed cells in the field of neural regeneration and bone tissue engineering, due to their easily isolation, lack of ethical controversy, low immunogenicity and low rates of transplantation rejection. The purpose of this study was to investigate the role of basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) on neural differentiation of DPSCs in vitro. DPSCs were cultured in neural differentiation medium containing NGF and bFGF alone or combination for 7 days. Then neural genes and protein markers were analyzed using western blot and RT-PCR. Our study revealed that bFGF and NGF increased neural differentiation of DPSCs synergistically, compared with bFGF and NGF alone. The levels of Nestin, MAP-2, βIII-tubulin and GFAP were the most highest in the DPSCs + bFGF + NGF group. Our results suggested that bFGF and NGF signifiantly up-regulated the levels of Sirt1. After treatment with Sirt1 inhibitor, western blot, RT-PCR and immunofluorescence staining showed that neural genes and protein markers had markedly decreased. Additionally, the ERK and AKT signaling pathway played a key role in the neural differentiation of DPSCs stimulated with bFGF + NGF. These results suggested that manipulation of the ERK and AKT signaling pathway may be associated with the differentiation of bFGF and NGF treated DPSCs. Our date provided theoretical basis for DPSCs to treat neurological diseases and repair neuronal damage.
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Affiliation(s)
- Jinlong Zhang
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Min Lian
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Peipei Cao
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Guofeng Bao
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Guanhua Xu
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuyu Sun
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Lingling Wang
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Jiajia Chen
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yi Wang
- Department of Stomatology, Wang Yi Dental Clinic of Mudu Town, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Guijuan Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Zhiming Cui
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
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Therapeutic Potential of Dental Pulp Stem Cell Secretome for Alzheimer's Disease Treatment: An In Vitro Study. Stem Cells Int 2016; 2016:8102478. [PMID: 27403169 PMCID: PMC4923581 DOI: 10.1155/2016/8102478] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 04/25/2016] [Accepted: 05/16/2016] [Indexed: 12/15/2022] Open
Abstract
The secretome obtained from stem cell cultures contains an array of neurotrophic factors and cytokines that might have the potential to treat neurodegenerative conditions. Alzheimer's disease (AD) is one of the most common human late onset and sporadic neurodegenerative disorders. Here, we investigated the therapeutic potential of secretome derived from dental pulp stem cells (DPSCs) to reduce cytotoxicity and apoptosis caused by amyloid beta (Aβ) peptide. We determined whether DPSCs can secrete the Aβ-degrading enzyme, neprilysin (NEP), and evaluated the effects of NEP expression in vitro by quantitating Aβ-degrading activity. The results showed that DPSC secretome contains higher concentrations of VEGF, Fractalkine, RANTES, MCP-1, and GM-CSF compared to those of bone marrow and adipose stem cells. Moreover, treatment with DPSC secretome significantly decreased the cytotoxicity of Aβ peptide by increasing cell viability compared to nontreated cells. In addition, DPSC secretome stimulated the endogenous survival factor Bcl-2 and decreased the apoptotic regulator Bax. Furthermore, neprilysin enzyme was detected in DPSC secretome and succeeded in degrading Aβ 1-42 in vitro in 12 hours. In conclusion, our study demonstrates that DPSCs may serve as a promising source for secretome-based treatment of Alzheimer's disease.
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Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells. Stem Cells Int 2016; 2016:1290561. [PMID: 27313623 PMCID: PMC4899607 DOI: 10.1155/2016/1290561] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/24/2016] [Accepted: 05/08/2016] [Indexed: 12/22/2022] Open
Abstract
Cellular heterogeneity presents an important challenge to the development of cell-based therapies where there is a fundamental requirement for predictable and reproducible outcomes. Transplanted Dental Pulp Stem/Progenitor Cells (DPSCs) have demonstrated early promise in experimental models of spinal cord injury and stroke, despite limited evidence of neuronal and glial-like differentiation after transplantation. Here, we report, for the first time, on the ability of single cell-derived clonal cultures of murine DPSCs to differentiate in vitro into immature neuronal-like and oligodendrocyte-like cells. Importantly, only DPSC clones with high nestin mRNA expression levels were found to successfully differentiate into Map2 and NF-positive neuronal-like cells. Neuronally differentiated DPSCs possessed a membrane capacitance comparable with primary cultured striatal neurons and small inward voltage-activated K(+) but not outward Na(+) currents were recorded suggesting a functionally immature phenotype. Similarly, only high nestin-expressing clones demonstrated the ability to adopt Olig1, Olig2, and MBP-positive immature oligodendrocyte-like phenotype. Together, these results demonstrate that appropriate markers may be used to provide an early indication of the suitability of a cell population for purposes where differentiation into a specific lineage may be beneficial and highlight that further understanding of heterogeneity within mixed cellular populations is required.
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Bianco J, De Berdt P, Deumens R, des Rieux A. Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it? Cell Mol Life Sci 2016; 73:1413-37. [PMID: 26768693 PMCID: PMC11108394 DOI: 10.1007/s00018-015-2126-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 12/15/2022]
Abstract
Dental stem cells are an emerging star on a stage that is already quite populated. Recently, there has been a lot of hype concerning these cells in dental therapies, especially in regenerative endodontics. It is fitting that most research is concentrated on dental regeneration, although other uses for these cells need to be explored in more detail. Being a true mesenchymal stem cell, their capacities could also prove beneficial in areas outside their natural environment. One such field is the central nervous system, and in particular, repairing the injured spinal cord. One of the most formidable challenges in regenerative medicine is to restore function to the injured spinal cord, and as yet, a cure for paralysis remains to be discovered. A variety of approaches have already been tested, with graft-based strategies utilising cells harbouring appropriate properties for neural regeneration showing encouraging results. Here we present a review focusing on properties of dental stem cells that endorse their use in regenerative medicine, with particular emphasis on repairing the damaged spinal cord.
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Affiliation(s)
- John Bianco
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium.
- Integrated Center for Cell Therapy and Regenerative Medicine, International Clinical Research Center (FNUSA-ICRC), St. Anne's University Hospital Brno, Pekařská 53, 656 91, Brno, Czech Republic.
| | - Pauline De Berdt
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
| | - Ronald Deumens
- Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, 1200, Brussels, Belgium
| | - Anne des Rieux
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
- Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348, Louvain-La-Neuve, Belgium
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Ishikawa J, Takahashi N, Matsumoto T, Yoshioka Y, Yamamoto N, Nishikawa M, Hibi H, Ishigro N, Ueda M, Furukawa K, Yamamoto A. Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis. Bone 2016; 83:210-219. [PMID: 26603475 DOI: 10.1016/j.bone.2015.11.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 11/02/2015] [Accepted: 11/17/2015] [Indexed: 12/17/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti-inflammatory and reparative therapy for RA.
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Affiliation(s)
- Jun Ishikawa
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Nobunori Takahashi
- Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Takuya Matsumoto
- Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Yutaka Yoshioka
- Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Noriyuki Yamamoto
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Masaya Nishikawa
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Naoki Ishigro
- Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Minoru Ueda
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Koichi Furukawa
- Biochemistry II of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Akihito Yamamoto
- Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
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Neuromuscular Regeneration: Perspective on the Application of Mesenchymal Stem Cells and Their Secretion Products. Stem Cells Int 2016; 2016:9756973. [PMID: 26880998 PMCID: PMC4736584 DOI: 10.1155/2016/9756973] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 10/12/2015] [Accepted: 11/16/2015] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stem cells are posing as a promising character in the most recent therapeutic strategies and, since their discovery, extensive knowledge on their features and functions has been gained. In recent years, innovative sources have been disclosed in alternative to the bone marrow, conveying their associated ethical concerns and ease of harvest, such as the umbilical cord tissue and the dental pulp. These are also amenable of cryopreservation and thawing for desired purposes, in benefit of the donor itself or other patients in pressing need. These sources present promising possibilities in becoming useful cell sources for therapeutic applications in the forthcoming years. Effective and potential applications of these cellular-based strategies for the regeneration of peripheral nerve are overviewed, documenting recent advances and identified issues for this research area in the near future. Finally, besides the differentiation capacities attributed to mesenchymal stem cells, advances in the recognition of their effective mode of action in the regenerative theatre have led to a new area of interest: the mesenchymal stem cells' secretome. The paracrine modulatory pathway appears to be a major mechanism by which these are beneficial to nerve regeneration and comprehension on the specific growth factors, cytokine, and extracellular molecules secretion profiles is therefore of great interest.
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Abstract
Within the nervous system, regeneration is limited, and this is due to the small amount of neural stem cells, the inhibitory origin of the stem cell niche and often to the development of a scar which constitutes a mechanical barrier for the regeneration. Regarding these aspects, many efforts have been done in the research of a cell component that combined with scaffolds and growth factors could be suitable for nervous regeneration in regenerative medicine approaches. Autologous mesenchymal stem cells represent nowadays the ideal candidate for this aim, thank to their multipotency and to their amount inside adult tissues. However, issues in their harvesting, through the use of invasive techniques, and problems involved in their ageing, require the research of new autologous sources. To this purpose, the recent discovery of a stem cells component in teeth, and which derive from neural crest cells, has came to the light the possibility of using dental stem cells in nervous system regeneration. In this work, in order to give guidelines on the use of dental stem cells for neural regeneration, we briefly introduce the concepts of regeneration and regenerative medicine, we then focus the attention on odontogenesis, which involves the formation and the presence of a stem component in different parts of teeth, and finally we describe some experimental approaches which are exploiting dental stem cells for neural studies.
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Affiliation(s)
- Ludovica Parisi
- Centro Universitario di Odontoiatria, University of Parma, Parma, Italy; Dip. Scienze Biomediche, Biotecnologiche e Traslazionali, University of Parma, Parma, Italy
| | - Edoardo Manfredi
- Centro Universitario di Odontoiatria, University of Parma, Parma, Italy; Dip. Scienze Biomediche, Biotecnologiche e Traslazionali, University of Parma, Parma, Italy
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Regenerative Applications Using Tooth Derived Stem Cells in Other Than Tooth Regeneration: A Literature Review. Stem Cells Int 2015; 2016:9305986. [PMID: 26798366 PMCID: PMC4699044 DOI: 10.1155/2016/9305986] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 09/03/2015] [Accepted: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Tooth derived stem cells or dental stem cells are categorized according to the location from which they are isolated and represent a promising source of cells for regenerative medicine. Originally, as one kind of mesenchymal stem cells, they are considered an alternative of bone marrow stromal cells. They share many commonalties but maintain differences. Considering their original function in development and the homeostasis of tooth structures, many applications of these cells in dentistry have aimed at tooth structure regeneration; however, the application in other than tooth structures has been attempted extensively. The availability from discarded or removed teeth can be an innate benefit as a source of autologous cells. Their origin from the neural crest results in exploitation of neurological and numerous other applications. This review briefly highlights current and future perspectives of the regenerative applications of tooth derived stem cells in areas beyond tooth regeneration.
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Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer's disease. Behav Brain Res 2015. [PMID: 26210934 DOI: 10.1016/j.bbr.2015.07.043] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by a decline in cognitive abilities and the appearance of β-amyloid plaques in the brain. Although the pathogenic mechanisms associated with AD are not fully understood, activated microglia releasing various neurotoxic factors, including pro-inflammatory cytokines and oxidative stress mediators, appear to play major roles. Here, we investigated the therapeutic benefits of a serum-free conditioned medium (CM) derived from the stem cells of human exfoliated deciduous teeth (SHEDs) in a mouse model of AD. The intranasal administration of SHEDs in these mice resulted in substantially improved cognitive function. SHED-CM contained factors involved in multiple neuroregenerative mechanisms, such as neuroprotection, axonal elongation, neurotransmission, the suppression of inflammation, and microglial regulation. Notably, SHED-CM attenuated the pro-inflammatory responses induced by β-amyloid plaques, and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like microglia. Our data suggest that SHED-CM may provide significant therapeutic benefits for AD.
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Naito E, Kudo D, Sekine SI, Watanabe K, Kobatake Y, Tamaoki N, Inden M, Iida K, Ito Y, Hozumi I, Shibata T, Maeda S, Kamishina H. Characterization of canine dental pulp cells and their neuroregenerative potential. In Vitro Cell Dev Biol Anim 2015; 51:1012-22. [PMID: 26170225 DOI: 10.1007/s11626-015-9935-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 06/18/2015] [Indexed: 12/13/2022]
Abstract
Dental pulp cells (DPCs) of various species have been studied for their potentials of differentiation into functional neurons and secretion of neurotrophic factors. In canine, DPCs have only been studied for cell surface markers and differentiation, but there is little direct evidence for therapeutic potentials for neurological disorders. The present study aimed to further characterize canine DPCs (cDPCs), particularly focusing on their neuroregenerative potentials. It was also reported that superparamagnetic iron oxide (SPIO) particles were useful for labeling of MSCs and tracking with magnetic resonance imaging (MRI). Our data suggested that cDPCs hold higher proliferation capacity than bone marrow stromal cells, the other type of mesenchymal stem cells which have been the target of intensive research. Canine DPCs constitutively expressed neural markers, suggesting a close relationship to the nervous system in their developmental origin. Canine DPCs promoted neuritogenesis of PC12 cells, most likely through secretion of neurotrophic factors. Furthermore, SPIO nanoparticles could be effectively transported to cDPCs without significant cytotoxicity and unfavorable effects on neuritogenesis. SPIO-labeled cDPCs embedded in agarose spinal cord phantoms were successfully visualized with a magnetic resonance imaging arousing a hope for noninvasive cell tracking in transplantation studies.
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Affiliation(s)
- Eiji Naito
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Daichi Kudo
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Shin-ichiro Sekine
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Kazuhiro Watanabe
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yui Kobatake
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Naritaka Tamaoki
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Masatoshi Inden
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Kazuki Iida
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yusuke Ito
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Isao Hozumi
- Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Toshiyuki Shibata
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Sadatoshi Maeda
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Hiroaki Kamishina
- Department of Veterinary Medicine, Faculty Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
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Chu W, Yuan J, Huang L, Xiang X, Zhu H, Chen F, Chen Y, Lin J, Feng H. Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats. Neurochem Res 2015; 40:1472-86. [PMID: 26023063 DOI: 10.1007/s11064-015-1618-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 04/02/2015] [Accepted: 05/18/2015] [Indexed: 11/29/2022]
Abstract
Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.
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Affiliation(s)
- Weihua Chu
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 29, Gaotanyan Street, Shapingba District, Chongqing, 400038, China,
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Secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 promote recovery after rat spinal cord injury by altering macrophage polarity. J Neurosci 2015; 35:2452-64. [PMID: 25673840 DOI: 10.1523/jneurosci.4088-14.2015] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Engrafted mesenchymal stem cells from human deciduous dental pulp (SHEDs) support recovery from neural insults via paracrine mechanisms that are poorly understood. Here we show that the conditioned serum-free medium (CM) from SHEDs, administered intrathecally into rat injured spinal cord during the acute postinjury period, caused remarkable functional recovery. The ability of SHED-CM to induce recovery was associated with an immunoregulatory activity that induced anti-inflammatory M2-like macrophages. Secretome analysis of the SHED-CM revealed a previously unrecognized set of inducers for anti-inflammatory M2-like macrophages: monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9). Depleting MCP-1 and ED-Siglec-9 from the SHED-CM prominently reduced its ability to induce M2-like macrophages and to promote functional recovery after spinal cord injury (SCI). The combination of MCP-1 and ED-Siglec-9 synergistically promoted the M2-like differentiation of bone marrow-derived macrophages in vitro, and this effect was abolished by a selective antagonist for CC chemokine receptor 2 (CCR2) or by the genetic knock-out of CCR2. Furthermore, MCP-1 and ED-Siglec-9 administration into the injured spinal cord induced M2-like macrophages and led to a marked recovery of hindlimb locomotor function after SCI. The inhibition of this M2 induction through the inactivation of CCR2 function abolished the therapeutic effects of both SHED-CM and MCP-1/ED-Siglec-9. Macrophages activated by MCP-1 and ED-Siglec-9 extended neurite and suppressed apoptosis of primary cerebellar granule neurons against the neurotoxic effects of chondroitin sulfate proteoglycans. Our data suggest that the unique combination of MCP-1 and ED-Siglec-9 repairs the SCI through anti-inflammatory M2-like macrophage induction.
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Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J, Xu GT, Liang A, Liu S. Concise Reviews: Characteristics and Potential Applications of Human Dental Tissue-Derived Mesenchymal Stem Cells. Stem Cells 2015; 33:627-38. [PMID: 25447379 DOI: 10.1002/stem.1909] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 10/21/2014] [Accepted: 11/07/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Junjun Liu
- Department of Ophthalmology; Shanghai Tenth People's Hospital
| | - Fang Yu
- Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology; Tongji University; Shanghai People's Republic of China
| | - Yao Sun
- Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology; Tongji University; Shanghai People's Republic of China
| | - Beizhan Jiang
- Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology; Tongji University; Shanghai People's Republic of China
| | - Wenjun Zhang
- Translational Center for Stem Cell Research, Tongji Hospital; Tongji University School of Medicine; Shanghai People's Republic of China
| | - Jianhua Yang
- Department of Ophthalmology; Shanghai Tenth People's Hospital
| | - Guo-Tong Xu
- Department of Ophthalmology; Shanghai Tenth People's Hospital
| | - Aibin Liang
- Translational Center for Stem Cell Research, Tongji Hospital; Tongji University School of Medicine; Shanghai People's Republic of China
| | - Shangfeng Liu
- Department of Ophthalmology; Shanghai Tenth People's Hospital
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Kerkis I, Kerkis A, Lizier NF, Wenceslau CV. Dental Stem Cells: Risk and Responsibilities. Regen Med 2015. [DOI: 10.1007/978-1-4471-6542-2_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Lee JH, Um S, Song IS, Kim HY, Seo BM. Neurogenic differentiation of human dental stem cells in vitro. J Korean Assoc Oral Maxillofac Surg 2014; 40:173-80. [PMID: 25247147 PMCID: PMC4170666 DOI: 10.5125/jkaoms.2014.40.4.173] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 06/27/2014] [Accepted: 07/01/2014] [Indexed: 12/13/2022] Open
Abstract
Objectives The purpose of this study was to investigate the neurogenic differentiation of human dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), and stem cells from apical papilla (SCAP). Materials and Methods After induction of neurogenic differentiation using commercial differentiation medium, expression levels of neural markers, microtubule-associated protein 2 (MAP2), class III β-tubulin, and glial fibrillary acidic protein (GFAP) were identified using reverse transcriptase polymerase chain reaction (PCR), real-time PCR, and immunocytochemistry. Results The induced cells showed neuron-like morphologies, similar to axons, dendrites, and perikaryons, which are composed of neurons in DPSCs, PDLSCs, and SCAP. The mRNA levels of neuronal markers tended to increase in differentiated cells. The expression of MAP2 and β-tubulin III also increased at the protein level in differentiation groups, even though GFAP was not detected via immunocytochemistry. Conclusion Human dental stem cells including DPSCs, PDLSCs, and SCAP may have neurogenic differentiation capability in vitro. The presented data support the use of human dental stem cells as a possible alternative source of stem cells for therapeutic utility in the treatment of neurological diseases.
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Affiliation(s)
- Joo-Hee Lee
- Biotooth Engineering Lab, Department of Oral and Maxillofacial Surgery and Craniomaxillofacial Life Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Soyoun Um
- Biotooth Engineering Lab, Department of Oral and Maxillofacial Surgery and Craniomaxillofacial Life Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea. ; Dental Regenerative Biotechnology, Department of Dental Science, School of Dentistry, Seoul National University, Seoul, Korea
| | - In-Seok Song
- Biotooth Engineering Lab, Department of Oral and Maxillofacial Surgery and Craniomaxillofacial Life Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea. ; Division of Oral and Maxillofacial Surgery, Department of Dentistry, Korea University Anam Hospital, Seoul, Korea
| | - Hui Young Kim
- Biotooth Engineering Lab, Department of Oral and Maxillofacial Surgery and Craniomaxillofacial Life Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Byoung Moo Seo
- Biotooth Engineering Lab, Department of Oral and Maxillofacial Surgery and Craniomaxillofacial Life Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
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Kabir R, Gupta M, Aggarwal A, Sharma D, Sarin A, Kola MZ. Imperative role of dental pulp stem cells in regenerative therapies: a systematic review. Niger J Surg 2014; 20:1-8. [PMID: 24665194 PMCID: PMC3953626 DOI: 10.4103/1117-6806.127092] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Stem cells are primitive cells that can differentiate and regenerate organs in different parts of the body such as heart, bones, muscles and nervous system. This has been a field of great clinical interest with immense possibilities of using the stem cells in regeneration of human organ those are damaged due to disease, developmental defects and accident. The knowledge of stem cell technology is increasing quickly in all medical specialties and in dental field too. Stem cells of dental origin appears to hold the key to various cell-based therapies in regenerative medicine, but most avenues are in experimental stages and many procedures are undergoing standardization and validation. Long-term preservation of SHED cells or DPSC is becoming a popular consideration, similar to the banking of umbilical cord blood. Dental pulp stem cells (DPSCs) are the adult multipotent cells that reside in the cell rich zone of the dental pulp. The multipotent nature of these DPSCs may be utilized in both dental and medical applications. A systematic review of the literature was performed using various internet based search engines (PubMed, Medline Plus, Cochrane, Medknow, Ebsco, Science Direct, Hinari, WebMD, IndMed, Embase) using keywords like “dental pulp stem cells”, “regeneration”, “medical applications”, “tissue engineering”. DPSCs appears to be a promising innovation for the re-growth of tissues however, long term clinical studies need to be carried out that could establish some authentic guidelines in this perspective.
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Affiliation(s)
- Ramchandra Kabir
- Department of Conservative Dentistry and Endodontics, Seema Dental College and Hospital, Rishikesh, India
| | - Manish Gupta
- Department of Oral Medicine and Radiology, Shree Bankey Bihari Dental College and Research Centre, Ghaziabad, Uttar Pradesh, India
| | - Avanti Aggarwal
- Department of Oral Medicine and Radiology, Rajasthan Dental College, Jaipur, Rajasthan, India
| | - Deepak Sharma
- Department of Conservative Dentistry and Endodontics, College of Dental Science and Hospital, Rau, Indore, Madhya Pradesh, India
| | - Anurag Sarin
- Department of Conservative Dentistry, Shree Bankey Bihari Dental College and Research Centre, Ghaziabad, Uttar Pradesh, India
| | - Mohammed Zaheer Kola
- Department of Prosthodontics, College of Dentistry, Salman bin Abdulaziz University, Alkharj (KSA)
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