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Segal Y, Mangioris G, Lennon V, Yang B, Dubey D, Flanagan EP, McKeon A, Mills JR, Toledano M, Vodopivec I, Pittock SJ, Zekeridou A. CSF cytokine, chemokine and injury biomarker profile of glial fibrillary acidic protein (GFAP) autoimmunity. Ann Clin Transl Neurol 2025; 12:855-860. [PMID: 39869499 PMCID: PMC12040519 DOI: 10.1002/acn3.52305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/10/2024] [Accepted: 12/26/2024] [Indexed: 01/29/2025] Open
Abstract
Defining the CSF cytokine/chemokine and injury biomarker signature of glial fibrillary acidic protein (GFAP) autoimmunity can inform immunopathogenesis. CSF GFAP-IgG-positive samples (N = 98) were tested for 17 cytokines/chemokines, neurofilament light chain (NfL), and GFAP (ELLA, Bio-Techne). Controls included non-inflammatory (N = 42), AQP4-IgG-positive (N = 83), CNS infections (N = 13), and neurosarcoidosis (N = 32). IL5, IL6, IL10, IL8/CXCL8, CXCL9, CXCL10, CXCL13, BAFF, GM-CSF, IFN-gamma, and TNF-alpha concentrations were higher compared to non-inflammatory controls (P < 0.01). GFAP concentrations were similar to those of AQP4-IgG-positive patients; NfL was higher (P < 0.001) and correlated with MRI changes and outcomes. CSF cytokine/chemokine findings in GFAP autoimmunity correlate with histopathology; GFAP and NfL hold promise as disease biomarkers.
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Affiliation(s)
- Yahel Segal
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
| | - Georgios Mangioris
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
| | - Vanda Lennon
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Binxia Yang
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
| | - Divyanshu Dubey
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Eoin P. Flanagan
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Andrew McKeon
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
| | - John R. Mills
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
| | - Michel Toledano
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Ivana Vodopivec
- Roche Product Development—NeuroscienceF. Hoffmann‐La Roche LtdBaselSwitzerland
| | - Sean J. Pittock
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
| | - Anastasia Zekeridou
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesotaUSA
- Department of NeurologyMayo ClinicRochesterMinnesotaUSA
- Center for MS and Autoimmune NeurologyMayo ClinicRochesterMinnesotaUSA
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Lee JE, Lim JY, Song SY, Park SH, Choi JH, Lim HK, Kim SW, Yang SH. Intranasal Administration of Human Neural Crest-Derived Nasal Turbinate Stem Cells Attenuates Microglia Activity in Mild Head Trauma Models. Tissue Eng Regen Med 2025; 22:327-337. [PMID: 40045144 PMCID: PMC11925815 DOI: 10.1007/s13770-025-00702-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/27/2024] [Accepted: 01/10/2025] [Indexed: 03/21/2025] Open
Abstract
BACKGROUND Mild head trauma often leads to long-term cognitive and neurological deficits. PLX3397, an inhibitor of colony-stimulating factor 1 receptor (CSF1R), offers promise as a therapeutic agent for traumatic brain injury (TBI) by targeting neuro-inflammation. Stem cell-based approaches are widely studied for neurological disorders. The objective of this study was to investigate therapeutic effect of intranasal administration of human neural crest-derived nasal turbinate stem cells (hNTSCs) on mild TBI in comparison with that of PLX3397. METHODS We developed a model of mice with repetitive and mild TBI following a weight-drop once a day for 5 days. PLX3397 (50 mg/kg, p. o.) was administered for 21 days. Intranasal administration of hNTSCs (1 × 106) was performed once. RESULTS Iba1 + and GFAP + cells were increased in the cortex and hippocampus of TBI models. Iba1 + cells and GFAP + cells were remarkably decreased in PLX3397 or hNTSC-treated TBI models. Administration of PLX3397 attenuated the decrease in neurobehavioral activity. Similar effects were observed in a TBI model with a single dose of hNTSC. CONCLUSION Intranasal administration of hNTSCs had a microglia-depleting effect. Administered hNTSCs were found around the cortex and hippocampus of TBI brains. This investigation may provide a promising path for therapeutic initiatives for repetitive and mild TBI.
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Affiliation(s)
- Jung Eun Lee
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbudaero, Paldal-Gu, Suwon, 16247, Republic of Korea
| | - Jung Yeon Lim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 065591, Republic of Korea
| | - Seung Yoon Song
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbudaero, Paldal-Gu, Suwon, 16247, Republic of Korea
| | - Sun Hwa Park
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 065591, Republic of Korea
| | - Jai Ho Choi
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Kook Lim
- Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Won Kim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 065591, Republic of Korea.
| | - Seung Ho Yang
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, 93 Jungbudaero, Paldal-Gu, Suwon, 16247, Republic of Korea.
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Xu Q, Gu L, Li Z, Gao L, Wei L, Shafiq Z, Chen S, Cai Q. Current Status of Research on Nanomaterials Combined with Mesenchymal Stem Cells for the Treatment of Ischemic Stroke. Neuromolecular Med 2024; 26:51. [PMID: 39644405 DOI: 10.1007/s12017-024-08819-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/13/2024] [Indexed: 12/09/2024]
Abstract
Ischemic stroke (IS) is a disease with high mortality and disability rates worldwide and is a serious threat to patient health. Owing to the narrow therapeutic window, effective treatments during the recovery period are limited. However, in recent years, mesenchymal stem cells (MSCs) have attracted attention and have shown therapeutic potential in IS treatment because of their abilities to home and secrete multiple bioactive substances and potential for differentiation and substitution. The therapeutic mechanisms of MSCs in IS include the regulatory effects of MSCs on microglia, the dual role of MSCs in astrocytes, how MSCs connect innate and adaptive immunity, the secretion of cytokines by MSCs to counteract apoptosis and MSC apoptosis, the promotion of angiogenesis by MSCs to favor the restoration of the blood‒brain barrier (BBB), and the potential function of local neural replacement by MSCs. However, the low graft survival rate, insufficient homing, poor targeting, and inability to achieve directional differentiation of MSCs limit their wide application. As an approach to compensate for the shortcomings of MSCs, scientists have used nanomaterials to assist MSCs in homing, survival and proliferation. In addition, the unique material of nanomaterials adds tracking, imaging and real-time monitoring to stroke treatment. The identification of effective treatments for stroke is urgently needed; thus, an understanding of how MSCs treat stroke and further improvements in the use of nanomaterials are necessary.
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Affiliation(s)
- Qingxue Xu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zhiyang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lun Gao
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lu Wei
- Department of Anesthesiology, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430200, China
| | - Zohaib Shafiq
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Shigui Chen
- The Institute for Advanced Studies, Wuhan University, 299 Bayi Road, Wuhan, 430072, Hubei, China.
| | - Qiang Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Samarakoon N, Chang T, Gunasekara V, Ratnayake P, Jayatillake R, Udagama P. Selected serum cytokines and vitamin D levels as potential prognostic markers of acute ischemic stroke. PLoS One 2024; 19:e0299631. [PMID: 38870172 PMCID: PMC11175438 DOI: 10.1371/journal.pone.0299631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/13/2024] [Indexed: 06/15/2024] Open
Abstract
Inflammation-derived oxidative stress is postulated to contribute to neuronal damage leading to poor clinical outcomes in Acute Ischemic Stroke (AIS). We aimed to investigate the association between serum levels of selected cytokines (IL-1β, IFN-γ, IL-4), and vitamin D in ischemic stroke progression, and their accuracy in predicting AIS prognosis, among Sri Lankans. We compared 60 AIS patients admitted in 4 phases post-stroke onset (<6 h; 6-24 h; 24-48 h; 48-96 h; n = 15/phase), with 15 age- and sex-matched controls. The 30-day functional outcome (FO) was assessed using the modified Rankin Scale (mRS). Serum cytokine and vitamin D levels were quantified using sandwich ELISAs, and competitive ELISA, respectively. The CombiROC web tool established optimal prognostic biomarker combinations. Serum IL-1β and IFN-γ were elevated in all four phases following stroke onset while IL-4 was elevated exclusively in the recovery phase (48-96 h) (p<0.05). Th1 bias polarization of the Th1:Th2 cytokine (IFN-γ:IL-4) ratio occurred with AIS progression while a Th2 bias occurred during AIS recovery (p<0.05). Lower serum IL-1β and higher IL-4 levels were associated with a good FO (p<0.05), while lower Vitamin D levels were related to a poor FO (p = 0.001). The triple-biomarker panel, IL-4- IFN-γ -Vit D, accurately predicted AIS prognosis (sensitivity = 100%, specificity = 91.9%, area under the curve = 0.98). Serum immunologic mediators IFN-γ, IL-4, and vitamin D may be useful biomarkers of AIS prognosis and may serve as therapeutic targets in improving stroke outcomes. Vitamin D supplementation may improve the prognosis of AIS patients. Furthermore, binary logistic model fitted for FO indicated Th1:Th2 cytokine ratio (IFN-γ:IL-4), vitamin D status, history of stroke, and ischemic heart disease as significant predictors of AIS prognosis.
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Affiliation(s)
- Nirmali Samarakoon
- Faculty of Science, Department of Zoology and Environment Sciences, University of Colombo, Colombo, Sri Lanka
| | - Thashi Chang
- Faculty of Medicine, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka
| | - Vimukthi Gunasekara
- Faculty of Science, Department of Zoology and Environment Sciences, University of Colombo, Colombo, Sri Lanka
| | - Praneeth Ratnayake
- Faculty of Science, Department of Zoology and Environment Sciences, University of Colombo, Colombo, Sri Lanka
| | - Rasika Jayatillake
- Faculty of Science, Department of Statistics, University of Colombo, Colombo, Sri Lanka
| | - Preethi Udagama
- Faculty of Science, Department of Zoology and Environment Sciences, University of Colombo, Colombo, Sri Lanka
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Moțățăianu A, Andone S, Stoian A, Bălașa R, Huțanu A, Sărmășan E. A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective. Int J Mol Sci 2024; 25:3782. [PMID: 38612591 PMCID: PMC11011909 DOI: 10.3390/ijms25073782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS.
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Affiliation(s)
- Anca Moțățăianu
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania; (A.M.); (S.A.); (A.S.); (R.B.); (E.S.)
- Department of Neurology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Sebastian Andone
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania; (A.M.); (S.A.); (A.S.); (R.B.); (E.S.)
- Department of Neurology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Adina Stoian
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania; (A.M.); (S.A.); (A.S.); (R.B.); (E.S.)
- Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Rodica Bălașa
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania; (A.M.); (S.A.); (A.S.); (R.B.); (E.S.)
- Department of Neurology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Adina Huțanu
- Department of Laboratory Medicine, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania
- Department of Laboratory Medicine, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Emanuela Sărmășan
- 1st Neurology Clinic, Mures County Clinical Emergency Hospital, 540136 Targu Mures, Romania; (A.M.); (S.A.); (A.S.); (R.B.); (E.S.)
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Saleh RO, Majeed AA, Margiana R, Alkadir OKA, Almalki SG, Ghildiyal P, Samusenkov V, Jabber NK, Mustafa YF, Elawady A. Therapeutic gene delivery by mesenchymal stem cell for brain ischemia damage: Focus on molecular mechanisms in ischemic stroke. Cell Biochem Funct 2024; 42:e3957. [PMID: 38468129 DOI: 10.1002/cbf.3957] [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: 12/29/2023] [Revised: 02/02/2024] [Accepted: 02/12/2024] [Indexed: 03/13/2024]
Abstract
Cerebral ischemic damage is prevalent and the second highest cause of death globally across patient populations; it is as a substantial reason of morbidity and mortality. Mesenchymal stromal cells (MSCs) have garnered significant interest as a potential treatment for cerebral ischemic damage, as shown in ischemic stroke, because of their potent intrinsic features, which include self-regeneration, immunomodulation, and multi-potency. Additionally, MSCs are easily obtained, isolated, and cultured. Despite this, there are a number of obstacles that hinder the effectiveness of MSC-based treatment, such as adverse microenvironmental conditions both in vivo and in vitro. To overcome these obstacles, the naïve MSC has undergone a number of modification processes to enhance its innate therapeutic qualities. Genetic modification and preconditioning modification (with medications, growth factors, and other substances) are the two main categories into which these modification techniques can be separated. This field has advanced significantly and is still attracting attention and innovation. We examine these cutting-edge methods for preserving and even improving the natural biological functions and therapeutic potential of MSCs in relation to adhesion, migration, homing to the target site, survival, and delayed premature senescence. We address the use of genetically altered MSC in stroke-induced damage. Future strategies for improving the therapeutic result and addressing the difficulties associated with MSC modification are also discussed.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Ali A Majeed
- Department of Pathological Analyses, Faculty of Science, University of Kufa, Najaf, Iraq
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ola Kamal A Alkadir
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
| | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Pallavi Ghildiyal
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Vadim Samusenkov
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Ahmed Elawady
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
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7
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Mou Y, Sun C, Wei S, Song X, Wang H, Wang Y, Ren C, Song X. P2X7 receptor of olfactory bulb microglia plays a pathogenic role in stress-related depression in mice with allergic rhinitis. Neurobiol Dis 2024; 192:106432. [PMID: 38331352 DOI: 10.1016/j.nbd.2024.106432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024] Open
Abstract
The aim of this study was to explore the role and mechanism of the olfactory bulb (OB) microglial P2X7 receptor (P2X7R) in allergic rhinitis (AR)-related depression, with the objective of identifying a potential clinical target. An AR mouse model was induced using ovalbumin (OVA), while chronic stress was employed to induce depression. The study used P2X7R-specific antagonists and OB microglia-specific P2X7R knockdown mice as crucial tools. The results showed that mice in the OVA + stress group exhibited more pronounced depressive-like phenotypes. Furthermore, there was an observed increase in microglial activation in the OB, followed by a rise in the level of inflammation. The pharmacological inhibition of P2X7R significantly mitigated the depression-like phenotype and the OB inflammatory response in OVA + stress mice. Notably, the specific knockdown of microglial P2X7R in the OB resulted in a similar effect, possibly linked to the regulation of IL-1β via the "ATP-P2X7R-Caspase 1" axis. These findings collectively demonstrate that microglial P2X7R in the OB acts as a direct effector molecule in AR-related depression, and its inhibition may offer a novel strategy for clinical prevention and treatment.
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Affiliation(s)
- Yakui Mou
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Caiyu Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Postdoctoral Programme, Yantai Yuhuangding Hospital, Yantai, China
| | - Shizhuang Wei
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Xiaoyu Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Hanrui Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Yao Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Chao Ren
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Postdoctoral Programme, Yantai Yuhuangding Hospital, Yantai, China; Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China.
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China; Postdoctoral Programme, Yantai Yuhuangding Hospital, Yantai, China.
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8
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Sheikh AM, Yano S, Tabassum S, Nagai A. The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications. Int J Mol Sci 2024; 25:2169. [PMID: 38396849 PMCID: PMC10889477 DOI: 10.3390/ijms25042169] [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: 01/12/2024] [Revised: 02/03/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Degenerative diseases, encompassing a wide range of conditions affecting various organ systems, pose significant challenges to global healthcare systems. This comprehensive review explores the intricate interplay between the vascular system and degenerative diseases, shedding light on the underlying mechanisms and profound implications for disease progression and management. The pivotal role of the vascular system in maintaining tissue homeostasis is highlighted, as it serves as the conduit for oxygen, nutrients, and immune cells to vital organs and tissues. Due to the vital role of the vascular system in maintaining homeostasis, its dysfunction, characterized by impaired blood flow, endothelial dysfunction, and vascular inflammation, emerges as a common denominator of degenerative diseases across multiple systems. In the nervous system, we explored the influence of vascular factors on neurodegenerative diseases such as Alzheimer's and Parkinson's, emphasizing the critical role of cerebral blood flow regulation and the blood-brain barrier. Within the kidney system, the intricate relationship between vascular health and chronic kidney disease is scrutinized, unraveling the mechanisms by which hypertension and other vascular factors contribute to renal dysfunction. Throughout this review, we emphasize the clinical significance of understanding vascular involvement in degenerative diseases and potential therapeutic interventions targeting vascular health, highlighting emerging treatments and prevention strategies. In conclusion, a profound appreciation of the role of the vascular system in degenerative diseases is essential for advancing our understanding of degenerative disease pathogenesis and developing innovative approaches for prevention and treatment. This review provides a comprehensive foundation for researchers, clinicians, and policymakers seeking to address the intricate relationship between vascular health and degenerative diseases in pursuit of improved patient outcomes and enhanced public health.
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Affiliation(s)
- Abdullah Md. Sheikh
- Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan; (S.Y.); (S.T.); (A.N.)
| | - Shozo Yano
- Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan; (S.Y.); (S.T.); (A.N.)
| | - Shatera Tabassum
- Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan; (S.Y.); (S.T.); (A.N.)
| | - Atsushi Nagai
- Department of Laboratory Medicine, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan; (S.Y.); (S.T.); (A.N.)
- Department of Neurology, Faculty of Medicine, Shimane University, 89-1 Enya Cho, Izumo 693-8501, Japan
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Yan J, Liu T, Li Y, Zhang J, Shi B, Zhang F, Hou X, Zhang X, Cui W, Li J, Yao H, Li X, Gao Y, Jiang J. Effects of magnetically targeted iron oxide@polydopamine-labeled human umbilical cord mesenchymal stem cells in cerebral infarction in mice. Aging (Albany NY) 2023; 15:1130-1142. [PMID: 36812482 PMCID: PMC10008509 DOI: 10.18632/aging.204540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/08/2023] [Indexed: 02/24/2023]
Abstract
Mesenchymal stem cells are a potential therapeutic candidate for cerebral infarction due to their anti-inflammatory proprieties. However, ensuring the engraftment of sufficient cells into the affected brain area remains a challenge. Herein, magnetic targeting techniques were used for the transplantation of a large number of cells noninvasively. Mice subjected to pMCAO surgery were administered MSCs labeled or not with iron oxide@polydopamine nanoparticles by tail vein injection. Iron oxide@polydopamine particles were characterized by transmission electron microscopy, and labeled MSCs were characterized by flow cytometry and their differentiation potential was assessed in vitro. Following the systemic injection of iron oxide@polydopamine-labeled MSCs into pMCAO-induced mices, magnetic navigation increased the MSCs localization to the brain lesion site and reduced the lesion volume. Treatment with iron oxide@polydopamine-labeled MSCs also significantly inhibited M1 microglia polarization and increased M2 microglia cell infiltration. Furthermore, western blotting and immunohistochemical analysis demonstrated that microtubule-associated protein 2 and NeuN levels were upregulated the brain tissue of mice treated with iron oxide@polydopamine-labeled MSCs. Thus, iron oxide@polydopamine-labeled MSCs attenuated brain injury and protected neurons by preventing pro-inflammatory microglia activation. Overall, the proposed iron oxide@polydopamine-labeled MSCs approach may overcome the major drawback of the conventional MSCs therapy for the treatment of cerebral infarction.
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Affiliation(s)
- Jun Yan
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China.,Central Laboratory, Dalian Municipal Women and Children’s Medical Center (Group), Xigang District, Dalian 116012, China
| | - Te Liu
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Yang Li
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Jun Zhang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Bo Shi
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Fuqiang Zhang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Xuejia Hou
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Xiaowen Zhang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Wanxing Cui
- Georgetown University Hospital, Washington, DC 20007, USA
| | - Jing Li
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Hua Yao
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Xiuying Li
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
| | - Yufei Gao
- Department of Neurosurgery, China-Japan Union Hospital, Jilin University, Changchun 130031, Jilin, China
| | - Jinlan Jiang
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun 130000, Jilin, China
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10
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Hao L, Yang Y, Xu X, Guo X, Zhan Q. Modulatory effects of mesenchymal stem cells on microglia in ischemic stroke. Front Neurol 2023; 13:1073958. [PMID: 36742051 PMCID: PMC9889551 DOI: 10.3389/fneur.2022.1073958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
Ischemic stroke accounts for 70-80% of all stroke cases. Immunity plays an important role in the pathophysiology of ischemic stroke. Microglia are the first line of defense in the central nervous system. Microglial functions are largely dependent on their pro-inflammatory (M1-like) or anti-inflammatory (M2-like) phenotype. Modulating neuroinflammation via targeting microglia polarization toward anti-inflammatory phenotype might be a novel treatment for ischemic stroke. Mesenchymal stem cells (MSC) and MSC-derived extracellular vesicles (MSC-EVs) have been demonstrated to modulate microglia activation and phenotype polarization. In this review, we summarize the physiological characteristics and functions of microglia in the healthy brain, the activation and polarization of microglia in stroke brain, the effects of MSC/MSC-EVs on the activation of MSC in vitro and in vivo, and possible underlying mechanisms, providing evidence for a possible novel therapeutics for the treatment of ischemic stroke.
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Affiliation(s)
- Lei Hao
- Department of Neurology, The First Branch of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Yongtao Yang
- Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Xiaoli Xu
- Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Xiuming Guo
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China,*Correspondence: Xiuming Guo ✉
| | - Qunling Zhan
- Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing, China,Qunling Zhan ✉
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11
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Hay AJD, Murphy TJ, Popichak KA, Zabel MD, Moreno JA. Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro. Sci Rep 2022; 12:22567. [PMID: 36581683 PMCID: PMC9800558 DOI: 10.1038/s41598-022-26628-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/16/2022] [Indexed: 12/30/2022] Open
Abstract
Prion diseases are characterized by the cellular prion protein, PrPC, misfolding and aggregating into the infectious prion protein, PrPSc, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease. Mesenchymal stromal cells produce anti-inflammatory molecules when exposed to inflammatory signals and damaged tissue. Here, we show that adipose-derived mesenchymal stromal cells (AdMSCs) migrate toward prion-infected brain homogenate and produce the anti-inflammatory molecules transforming growth factor β (TGFβ) and tumor necrosis factor-stimulated gene 6 (TSG-6). In an in vitro model of prion exposure of both primary mixed glia and BV2 microglial cell line, co-culturing with AdMSCs led to a significant decrease in inflammatory cytokine mRNA and markers of reactive astrocytes and activated microglia. This protection against in vitro prion-associated inflammatory responses is independent of PrPSc replication. These data support a role for AdMSCs as a beneficial therapeutic for decreasing the early onset of glial inflammation and reprogramming glial cells to a protective phenotype.
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Affiliation(s)
- Arielle J. D. Hay
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA
| | - Tanner J. Murphy
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA
| | - Katriana A. Popichak
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
| | - Mark D. Zabel
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
| | - Julie A. Moreno
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
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12
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Exosomes in Cerebral Ischemia-Reperfusion Injury: Current Perspectives and Future Challenges. Brain Sci 2022; 12:brainsci12121657. [PMID: 36552117 PMCID: PMC9776031 DOI: 10.3390/brainsci12121657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/18/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Cerebral ischemia impedes the functional or metabolic demands of the central nervous system (CNS), which subsequently leads to irreversible brain damage. While recanalization of blocked vessels recovers cerebral blood flow, it can also aggravate brain injury, termed as ischemia/reperfusion (I/R) injury. Exosomes, nanometric membrane vesicles, attracted wide attention as carriers of biological macromolecules. In the brain, exosomes can be secreted by almost all types of cells, and their contents can be altered during the pathological and clinical processes of cerebral I/R injury. Herein, we will review the current literature on the possible role of cargos derived from exosomes and exosomes-mediated intercellular communication in cerebral I/R injury. The PubMed and Web of Science databases were searched through January 2015. The studies published in English were identified using search terms including "exosomes", "cerebral ischemia-reperfusion injury", "brain ischemia-reperfusion injury", and "stroke". We will also focus on the potential therapeutic effects of stem cell-derived exosomes and underlying mechanisms in cerebral I/R injury. Meanwhile, with the advantages of low immunogenicity and cytotoxicity, high bioavailability, and the capacity to pass through the blood-brain barrier, exosomes also attract more attention as therapeutic modalities for the treatment of cerebral I/R injury.
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13
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Tan N, Xin W, Huang M, Mao Y. Mesenchymal stem cell therapy for ischemic stroke: Novel insight into the crosstalk with immune cells. Front Neurol 2022; 13:1048113. [PMID: 36425795 PMCID: PMC9679024 DOI: 10.3389/fneur.2022.1048113] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/17/2022] [Indexed: 09/29/2023] Open
Abstract
Stroke, a cerebrovascular accident, is prevalent and the second highest cause of death globally across patient populations; it is as a significant cause of morbidity and mortality. Mesenchymal stem cell (MSC) transplantation is emerging as a promising treatment for alleviating neurological deficits, as indicated by a great number of animal and clinical studies. The potential of regulating the immune system is currently being explored as a therapeutic target after ischemic stroke. This study will discuss recent evidence that MSCs can harness the immune system by interacting with immune cells to boost neurologic recovery effectively. Moreover, a notion will be given to MSCs participating in multiple pathological processes, such as increasing cell survival angiogenesis and suppressing cell apoptosis and autophagy in several phases of ischemic stroke, consequently promoting neurological function recovery. We will conclude the review by highlighting the clinical opportunities for MSCs by reviewing the safety, feasibility, and efficacy of MSCs therapy.
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Affiliation(s)
- Nana Tan
- Department of Health Management, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenqiang Xin
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Min Huang
- Department of Health Management, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuling Mao
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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14
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Zhang Y, Song H, Wang J, Xi X, Cefalo P, Wood LJ, Luo X, Wang QM. Multiplex array analysis of serum cytokines offers minimal predictive value for cognitive function in the subacute phase after stroke. Front Neurol 2022; 13:886018. [PMID: 36330425 PMCID: PMC9622930 DOI: 10.3389/fneur.2022.886018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/29/2022] [Indexed: 10/28/2023] Open
Abstract
OBJECTIVE The effects of inflammation on post-stroke cognitive function are still unclear. This study investigated the correlation between the Th17-related cytokines in peripheral blood and post-stroke cognitive function after ischemic stroke in the subacute phase. DESIGN A retrospective cohort study. SETTING Academic acute inpatient rehabilitation facility. PARTICIPANTS One hundred and fourteen patients with first ischemic stroke were categorized as the poor cognitive recovery group (n = 58) or good cognitive recovery group (n = 56) based on their cognitive MRFS efficiency. INTERVENTIONS All subjects received routine physical, occupational, and speech-language pathology therapy. MAIN OUTCOME MEASURES Serum cytokines/chemokine (IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-17E, IL-17F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, GM-CSF, IFN-γ, MIP-3 α, TNF-α, and TNF-β) levels were measured in duplicate using Human Th17 magnetic bead panel and multiplex array analysis (Luminex-200 system). The primary functional outcome was a gain in functional independence measure (FIM) cognitive subscore at discharge. The secondary outcome measures were FIM total score at discharge, length of stay in the hospital, and discharge destination. Cognitive Montebello Rehabilitation Factor Score (MRFS) and cognitive MRFS efficiency were calculated. Demographic and clinical characteristics were obtained from the medical record. RESULTS The good cognitive recovery group had an interesting trend of higher IL-13 than the poor cognitive recovery group (good cognitive recovery group 257.82 ± 268.76 vs. poor cognitive recovery group 191.67 ± 201.82, p = 0.049, unit: pg/ml). However, Pearson's correlation analysis showed no significant correlation between cytokine levels and gain of cognition, cognitive MRFS, or cognitive MRFS efficiency. Receiver operating characteristic (ROC) analysis of cytokines also suggested a low accuracy of prediction as a predictor for post-stroke cognitive recovery improvement. CONCLUSION Our preliminary findings suggested that the level of serum cytokines had minimal predictive value for the recovery of cognitive function during the subacute inpatient rehabilitation after stroke.
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Affiliation(s)
- Yuling Zhang
- Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Haixin Song
- Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
- Rehabilitation Department, Sir Run Run Show Hospital, Hangzhou, China
| | - Jun Wang
- School of Medicine, Shenzhen University, Shenzhen, China
| | - Xiao Xi
- Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
- Department of Rehabilitation Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Philip Cefalo
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
| | - Lisa J. Wood
- William F. Connell School of Nursing at Boston College, Boston, MA, United States
| | - Xun Luo
- School of Medicine, Shenzhen University, Shenzhen, China
- Kerry Rehabilitation Medicine Research Institute, Shenzhen, China
| | - Qing Mei Wang
- Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
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15
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Sheikh AM, Yano S, Mitaki S, Tabassum S, Yamaguchi S, Nagai A. Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats. J Cent Nerv Syst Dis 2022; 14:11795735221123910. [PMID: 36106069 PMCID: PMC9465613 DOI: 10.1177/11795735221123910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 08/05/2022] [Indexed: 11/17/2022] Open
Abstract
Background Rho-kinase inhibition in a rat middle cerebral artery occlusion (MCAO) model
is reported to improve neurological functions and decrease infarction
size. Objective The objective of this study is to investigate the underlying mechanisms of
such improvement by evaluating the effects of Rho-kinase inhibition on
astrocytes and microglial accumulation and activation in this condition. Methods Adult male Sprague-Dawley (SD) rats were used to generate the MCAO model,
which received an I.P injection of a chemical Rho-kinase inhibitor (Fasudil-
5 mg/kg/day) or vehicle (PBS) for 2 and 4 days. Results Fasudil treatment significantly decreased the stroke volumes and water
content in the lesion areas, as revealed by MRI. Immunostaining and Western
blotting results demonstrated that Fasudil significantly decreased the
levels of Aquaporin-4, a water channel protein. The number of
GFAP+ astrocytes and Iba-1+ macrophage/microglia
was decreased in the lesion areas. Proinflammatory transcription factor
NF-κB protein levels were decreased in the Fasudil group 2 days after MCAO.
Also, proinflammatory mediators including TNF-α, IL-1β, and iNOS levels were
decreased. In vitro migration study using a human microglial cell line
(HMO6) confirmed the inhibitory effects of Fasudil on the process. Fasudil
also decreased combined IL-1β and IFNγ-induced NF-κB nuclear translocation
in HMO6. Moreover, Fasudil transiently decreased combined IL-1β and
IFNγ-induced iNOS, TNFα, and IL-1β mRNA levels in HMO6. Conclusion Our study demonstrates the inhibitory effects of Rho-kinase on NF-κB-mediated
glial activation and cerebral edema, which might be a promising therapeutic
target in acute cerebral ischemia conditions.
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Affiliation(s)
- Abdullah Md Sheikh
- Department of Laboratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan
| | - Shozo Yano
- Department of Laboratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan
| | - Shingo Mitaki
- Department of Neurology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Shatera Tabassum
- Department of Laboratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan
| | | | - Atsushi Nagai
- Department of Neurology, Shimane University Faculty of Medicine, Izumo, Japan
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16
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Luo C, Yao J, Bi H, Li Z, Li J, Xue G, Li K, Zhang S, Zan K, Meng W, Zhang Z, Chen H. Clinical Value of Inflammatory Cytokines in Patients with Aneurysmal Subarachnoid Hemorrhage. Clin Interv Aging 2022; 17:615-626. [PMID: 35502188 PMCID: PMC9056097 DOI: 10.2147/cia.s362854] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/20/2022] [Indexed: 12/16/2022] Open
Abstract
Background Inflammation is closely associated with prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH), which is orchestrated by inflammatory cytokines. Therefore, this study aimed to investigate the levels of inflammatory cytokines in the early stage of aSAH and their predictive value for prognosis. Methods In this retrospective study, 206 patients with aSAH were recruited and assigned to a severe group (WFNS grade ≥ 4) and a mild group (WFNS grade < 4) according to the severity of patients on admission. Flow cytometry was performed to detect the levels of 12 inflammatory cytokines in the serum of patients. Then, patients were grouped into a poor prognosis group (mRS score ≥ 4) and a good prognosis group (mRS score < 4) based on their prognosis after 3 months of discharge to compare the relationship between cytokines and prognosis. Propensity score matching (PSM) was utilized to control confounding factors. The correlation between inflammatory factors and prognosis was determined using Spearman correlation, and the predictive efficacy of inflammatory factors was tested by a receiver operating characteristic curve. Results Serum IL-1β, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α levels were significantly higher in the mild group than in the severe group and in the poor prognosis group than in the good prognosis group. After PSM, the differences in IL-1β, IL-5, IFN-α, and IFN-γ levels disappeared between the two groups, whereas IL-2, IL-6, IL-8, IL-10, and TNF-α levels remained higher in the poor prognosis group than in the good prognosis group. Additionally, IL-2, IL-6, IL-8, and IL-10 levels were positively correlated with mRS scores. Moreover, the predictive value was found to be the highest for IL-6 and the lowest for TNF-α. Conclusion Inflammation degree was related to the severity of aSAH. Inflammatory markers, including IL-6, IL-10, IL-8, IL-2, and TNF-α, might predict the poor prognosis of aSAH.
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Affiliation(s)
- Cong Luo
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Jiaxin Yao
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Haoran Bi
- Department of Biostatistics, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Zhen Li
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Ju Li
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Guosong Xue
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Ke Li
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Shenyang Zhang
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Kun Zan
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Wenqing Meng
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
| | - Zunsheng Zhang
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
- Correspondence: Zunsheng Zhang; Hao Chen, Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai West Road, Quanshan District, Xuzhou, Jiangsu, People’s Republic of China, Tel +86-13913473179; +86-15252006510, Email ;
| | - Hao Chen
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China
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17
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Xin WQ, Wei W, Pan YL, Cui BL, Yang XY, Bähr M, Doeppner TR. Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia. World J Stem Cells 2021; 13:1030-1048. [PMID: 34567423 PMCID: PMC8422926 DOI: 10.4252/wjsc.v13.i8.1030] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation plays an important role in the pathological process of ischemic stroke, and systemic inflammation affects patient prognosis. As resident immune cells in the brain, microglia are significantly involved in immune defense and tissue repair under various pathological conditions, including cerebral ischemia. Although the differentiation of M1 and M2 microglia is certainly oversimplified, changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia. Recent evidence indicates that both mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) regulate inflammation and modify tissue repair under preclinical stroke conditions. However, the precise mechanisms of these signaling pathways, especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia, have not been sufficiently unveiled. Hence, this review summarizes the state-of-the-art knowledge on MSC- and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways, including cytokines, neurotrophic factors, transcription factors, and microRNAs.
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Affiliation(s)
- Wen-Qiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Yong-Li Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Bao-Long Cui
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Xin-Yu Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mathias Bähr
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
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18
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Moon S, Chang MS, Koh SH, Choi YK. Repair Mechanisms of the Neurovascular Unit after Ischemic Stroke with a Focus on VEGF. Int J Mol Sci 2021; 22:ijms22168543. [PMID: 34445248 PMCID: PMC8395233 DOI: 10.3390/ijms22168543] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/22/2021] [Accepted: 08/02/2021] [Indexed: 12/23/2022] Open
Abstract
The functional neural circuits are partially repaired after an ischemic stroke in the central nervous system (CNS). In the CNS, neurovascular units, including neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes maintain homeostasis; however, these cellular networks are damaged after an ischemic stroke. The present review discusses the repair potential of stem cells (i.e., mesenchymal stem cells, endothelial precursor cells, and neural stem cells) and gaseous molecules (i.e., nitric oxide and carbon monoxide) with respect to neuroprotection in the acute phase and regeneration in the late phase after an ischemic stroke. Commonly shared molecular mechanisms in the neurovascular unit are associated with the vascular endothelial growth factor (VEGF) and its related factors. Stem cells and gaseous molecules may exert therapeutic effects by diminishing VEGF-mediated vascular leakage and facilitating VEGF-mediated regenerative capacity. This review presents an in-depth discussion of the regeneration ability by which endogenous neural stem cells and endothelial cells produce neurons and vessels capable of replacing injured neurons and vessels in the CNS.
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Affiliation(s)
- Sunhong Moon
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Korea;
| | - Mi-Sook Chang
- Department of Oral Anatomy, Seoul National University School of Dentistry, Seoul 03080, Korea;
| | - Seong-Ho Koh
- Department of Neurology, Hanyang University Guri Hospital, Guri 11923, Korea;
| | - Yoon Kyung Choi
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Korea;
- Correspondence: ; Tel.: +82-2-450-0558; Fax: +82-2-444-3490
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Asgharzade S, Talaei A, Farkhondeh T, Forouzanfar F. Combining Growth Factor and Stem Cell Therapy for Stroke Rehabilitation, A Review. Curr Drug Targets 2021; 21:781-791. [PMID: 31914912 DOI: 10.2174/1389450121666200107100747] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/28/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022]
Abstract
Stroke is a serious, life-threatening condition demanding vigorous search for new therapies. Recent research has focused on stem cell-based therapies as a viable choice following ischemic stroke, based on studies displaying that stem cells transplanted to the brain not only survive but also cause functional recovery. Growth factors defined as polypeptides that regulate the growth and differentiation of many cell types. Many studies have demonstrated that combined use of growth factors may increase results by the stimulation of endogenous neurogenesis, anti-inflammatory, neuroprotection properties, and enhancement of stem cell survival rates and so may be more effective than a single stem cell therapy. This paper reviews and discusses the most promising new stroke recovery research, including combination treatment.
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Affiliation(s)
- Samira Asgharzade
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Andisheh Talaei
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Forouzanfar
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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20
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Tapia-Bustos A, Lespay-Rebolledo C, Vío V, Pérez-Lobos R, Casanova-Ortiz E, Ezquer F, Herrera-Marschitz M, Morales P. Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats. Int J Mol Sci 2021; 22:ijms22063275. [PMID: 33806988 PMCID: PMC8004671 DOI: 10.3390/ijms22063275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/07/2021] [Accepted: 03/15/2021] [Indexed: 01/09/2023] Open
Abstract
The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.
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Affiliation(s)
- Andrea Tapia-Bustos
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
- Faculty of Medicine, School of Pharmacy, Universidad Andres Bello, Santiago 8370149, Chile
| | - Carolyne Lespay-Rebolledo
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
| | - Valentina Vío
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
| | - Ronald Pérez-Lobos
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
| | - Emmanuel Casanova-Ortiz
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
| | - Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago 7710162, Chile;
| | - Mario Herrera-Marschitz
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
- Correspondence: (M.H.-M.); (P.M.); Tel.: +56-229786788 (M.H.-M. & P.M.)
| | - Paola Morales
- Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (A.T.-B.); (C.L.-R.); (V.V.); (R.P.-L.); (E.C.-O.)
- Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
- Correspondence: (M.H.-M.); (P.M.); Tel.: +56-229786788 (M.H.-M. & P.M.)
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21
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Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell. J Mol Med (Berl) 2021; 99:637-650. [PMID: 33641066 DOI: 10.1007/s00109-021-02055-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 01/29/2021] [Accepted: 02/21/2021] [Indexed: 12/14/2022]
Abstract
Primary ovarian insufficiency (POI) is defined as a reduction in ovarian function before the expected age of menopause. POI is known to increase the risk of cardiovascular disorders, osteoporosis, cognitive decline, and mood disorders, resulting in a reduced quality of life. Appropriate hormone replacement for premenopausal women decreases these adverse health risks and improves quality of life for women with POI, but does not prolong life expectancy. The potential etiologies of POI include chromosomal abnormalities and genetic mutations, autoimmune factors, and iatrogenic causes, including surgery, chemotherapy, and radiation therapy. A major association is suggested to exist between reproductive longevity and the DNA damage pathway response genes. DNA damage and repair in ovarian granulosa cells is strongly associated with POI. Depletion of oocytes with damaged DNA occurs through different cell death mechanisms, such as apoptosis, autophagy, and necroptosis, mediated by the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/forkhead transcription factors 3 (FOXO3) pathway. Mesenchymal stem cells (MSCs) are characterized by the ability of self-renewal and differentiation and play an important role in the regeneration of injured tissues. Transplantation of MSCs has been shown to functionally restore ovarian reserve in a POI mouse model. Recent advances in stem cell therapy are likely to be translated to new therapeutic options bringing new hope to patients with POI. The aim of this review is to summarize the pathogenic mechanisms that involve cell death and DNA damage and repair pathways and to discuss the stem cell-based therapies as potential therapeutic options for this gynecologic pathology.
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22
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Alteration of Neural Stem Cell Functions in Ataxia and Male Sterility Mice: A Possible Role of β-Tubulin Glutamylation in Neurodegeneration. Cells 2021; 10:cells10010155. [PMID: 33466875 PMCID: PMC7830091 DOI: 10.3390/cells10010155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 12/20/2022] Open
Abstract
Ataxia and Male Sterility (AMS) is a mutant mouse strain that contains a missense mutation in the coding region of Nna1, a gene that encodes a deglutamylase. AMS mice exhibit early cerebellar Purkinje cell degeneration and an ataxic phenotype in an autosomal recessive manner. To understand the underlying mechanism, we generated neuronal stem cell (NSC) lines from wild-type (NMW7), Nna1 mutation heterozygous (NME), and Nna1 mutation homozygous (NMO1) mouse brains. The NNA1 levels were decreased, and the glutamylated tubulin levels were increased in NMO1 cultures as well as in the cerebellum of AMS mice at both 15 and 30 days of age. However, total β-tubulin protein levels were not altered in the AMS cerebellum. In NMO1 neurosphere cultures, β-tubulin protein levels were increased without changes at the transcriptional level. NMO1 grew faster than other NSC lines, and some of the neurospheres were attached to the plate after 3 days. Immunostaining revealed that SOX2 and nestin levels were decreased in NMO1 neurospheres and that the neuronal differentiation potentials were reduced in NMO1 cells compared to NME or NMW7 cells. These results demonstrate that the AMS mutation decreased the NNA1 levels and increased glutamylation in the cerebellum of AMS mice. The observed changes in glutamylation might alter NSC properties and the neuron maturation process, leading to Purkinje cell death in AMS mice.
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23
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Kim E, Cho S. CNS and peripheral immunity in cerebral ischemia: partition and interaction. Exp Neurol 2021; 335:113508. [PMID: 33065078 PMCID: PMC7750306 DOI: 10.1016/j.expneurol.2020.113508] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/28/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
Abstract
Stroke elicits excessive immune activation in the injured brain tissue. This well-recognized neural inflammation in the brain is not just an intrinsic organ response but also a result of additional intricate interactions between infiltrating peripheral immune cells and the resident immune cells in the affected areas. Given that there is a finite number of immune cells in the organism at the time of stroke, the partitioned immune systems of the central nervous system (CNS) and periphery must appropriately distribute the limited pool of immune cells between the two domains, mounting a necessary post-stroke inflammatory response by supplying a sufficient number of immune cells into the brain while maintaining peripheral immunity. Stroke pathophysiology has mainly been neurocentric in focus, but understanding the distinct roles of the CNS and peripheral immunity in their concerted action against ischemic insults is crucial. This review will discuss stroke-induced influences of the peripheral immune system on CNS injury/repair and of neural inflammation on peripheral immunity, and how comorbidity influences each.
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Affiliation(s)
- Eunhee Kim
- Vivian L. Smith Department of Neurosurgery at University of Texas Health Science Center at Houston, Houston, TX, United States of America
| | - Sunghee Cho
- Burke Neurological Institute, White Plains, NY, United States of America; Feil Brain Mind Research Institute, Weill Cornell Medicine, New York, NY, United States of America.
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24
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Nishida F, Zappa Villar MF, Zanuzzi CN, Sisti MS, Camiña AE, Reggiani PC, Portiansky EL. Intracerebroventricular Delivery of Human Umbilical Cord Mesenchymal Stem Cells as a Promising Therapy for Repairing the Spinal Cord Injury Induced by Kainic Acid. Stem Cell Rev Rep 2020; 16:167-180. [PMID: 31760626 DOI: 10.1007/s12015-019-09934-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Spinal cord injury (SCI) is a common pathological condition that leads to permanent or temporal loss of motor and autonomic functions. Kainic acid (KA), an agonist of kainate receptors, a type of ionotropic glutamate receptor, is widely used to induce experimental neurodegeneration models of CNS. Mesenchymal Stem Cells (MSC) therapy applied at the injured nervous tissue have emerged as a promising therapeutic treatment. Here we used a validated SCI experimental model in which an intraparenchymal injection of KA into the C5 segment of rat spinal cord induced an excitotoxic lesion. Three days later, experimental animals were treated with an intracerebroventricular injection of human umbilical cord (hUC) MSC whereas control group only received saline solution. Sensory and motor skills as well as neuronal and glial reaction of both groups were recorded. Differences in motor behavior, neuronal counting and glial responses were observed between hUC-MSC-treated and untreated rats. According to the obtained results, we suggest that hUC-MSC therapy delivered into the fourth ventricle using the intracerebroventricular via can exert a neuroprotective or neurorestorative effect on KA-injected animals.
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Affiliation(s)
- Fabián Nishida
- Image Analysis Laboratory, School of Veterinary Sciences, National University of La Plata (UNLP), Calles 60 y 118, 1900, La Plata, Buenos Aires, Argentina.,National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina
| | - María F Zappa Villar
- National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina.,INIBIOLP, School of Medical Sciences, UNLP, La Plata, Buenos Aires, Argentina.,Department of Histology and of Embryology B, School of Medical Sciences, UNLP, La Plata, Buenos Aires, Argentina
| | - Carolina N Zanuzzi
- Image Analysis Laboratory, School of Veterinary Sciences, National University of La Plata (UNLP), Calles 60 y 118, 1900, La Plata, Buenos Aires, Argentina. .,National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina. .,Department of Histology and Embryology, School of Veterinary Sciences, UNLP, La Plata, Buenos Aires, Argentina.
| | - María S Sisti
- Image Analysis Laboratory, School of Veterinary Sciences, National University of La Plata (UNLP), Calles 60 y 118, 1900, La Plata, Buenos Aires, Argentina.,National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina
| | - Agustina E Camiña
- Image Analysis Laboratory, School of Veterinary Sciences, National University of La Plata (UNLP), Calles 60 y 118, 1900, La Plata, Buenos Aires, Argentina
| | - Paula C Reggiani
- National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina.,INIBIOLP, School of Medical Sciences, UNLP, La Plata, Buenos Aires, Argentina.,Department of Histology and of Embryology B, School of Medical Sciences, UNLP, La Plata, Buenos Aires, Argentina
| | - Enrique L Portiansky
- Image Analysis Laboratory, School of Veterinary Sciences, National University of La Plata (UNLP), Calles 60 y 118, 1900, La Plata, Buenos Aires, Argentina.,National Research Council of Science and Technology (CONICET), Buenos Aires, Argentina
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25
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Ng NN, Thakor AS. Locoregional delivery of stem cell-based therapies. Sci Transl Med 2020; 12:eaba4564. [PMID: 32522806 DOI: 10.1126/scitranslmed.aba4564] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/24/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022]
Abstract
Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.
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Affiliation(s)
- Nathan Norton Ng
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Avnesh Sinh Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
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26
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Das M, Mayilsamy K, Mohapatra SS, Mohapatra S. Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects. Rev Neurosci 2020; 30:839-855. [PMID: 31203262 DOI: 10.1515/revneuro-2019-0002] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
Traumatic brain injury (TBI) is a major cause of injury-related mortality and morbidity in the USA and around the world. The survivors may suffer from cognitive and memory deficits, vision and hearing loss, movement disorders, and different psychological problems. The primary insult causes neuronal damage and activates astrocytes and microglia which evokes immune responses causing further damage to the brain. Clinical trials of drugs to recover the neuronal loss are not very successful. Regenerative approaches for TBI using mesenchymal stem cells (MSCs) seem promising. Results of preclinical research have shown that transplantation of MSCs reduced secondary neurodegeneration and neuroinflammation, promoted neurogenesis and angiogenesis, and improved functional outcome in the experimental animals. The functional improvement is not necessarily related to cell engraftment; rather, immunomodulation by molecular factors secreted by MSCs is responsible for the beneficial effects of this therapy. However, MSC therapy has a few drawbacks including tumor formation, which can be avoided by the use of MSC-derived exosomes. This review has focused on the research works published in the field of regenerative therapy using MSCs after TBI and its future direction.
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Affiliation(s)
- Mahasweta Das
- James A. Haley Veterans Hospital, Tampa, FL 33612, USA.,Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA
| | - Karthick Mayilsamy
- James A. Haley Veterans Hospital, Tampa, FL 33612, USA.,Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA
| | - Shyam S Mohapatra
- James A. Haley Veterans Hospital, Tampa, FL 33612, USA.,Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA
| | - Subhra Mohapatra
- James A. Haley Veterans Hospital, Tampa, FL 33612, USA.,Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA
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iTRAQ-based proteomic analysis after mesenchymal stem cell line transplantation for ischemic stroke. Brain Res 2020; 1742:146900. [PMID: 32445714 DOI: 10.1016/j.brainres.2020.146900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 05/01/2020] [Accepted: 05/18/2020] [Indexed: 02/01/2023]
Abstract
Transplantation with mesenchymal stem cells (MSCs) has been reported to promote functional recovery in animal models of ischemic stroke. However, the molecular mechanisms underlying the therapeutic effects of MSC transplantation have been only partially elucidated. The purpose of this study was to comprehensively identify changes in brain proteins in rats treated with MSCs for ischemic stroke, and to explore the multi-target mechanisms of MSCs using a proteomics-based strategy. Twenty-eight proteins were found to be differentially expressed following B10 MSC transplantation in adult male Wistar rats, as assessed using isobaric tagging for relative and absolute protein quantification (iTRAQ). Subsequent bioinformatic analysis revealed that these proteins were mainly associated with energy metabolism, glutamate excitotoxicity, oxidative stress, and brain structural and functional plasticity. Immunohistochemical staining revealed decreased expression of EAAT1 in the phosphate-buffered saline group as opposed to normal levels in the B10 transplantation group. Furthermore, ATP levels were also significantly higher in the B10 transplantation group, thus supporting the iTRAQ results. Our results suggest that the therapeutic effects of B10 transplantation might arise from the modulation of the acute ischemic cascade via multiple molecular pathways. Thus, our findings provide valuable clues to elucidate the mechanisms underlying the therapeutic effects of MSC transplantation in ischemic stroke.
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28
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TNF-α Pretreatment Improves the Survival and Function of Transplanted Human Neural Progenitor Cells Following Hypoxic-Ischemic Brain Injury. Cells 2020; 9:cells9051195. [PMID: 32403417 PMCID: PMC7291333 DOI: 10.3390/cells9051195] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/28/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Neural progenitor cells (NPCs) therapy offers great promise in hypoxic-ischemic (HI) brain injury. However, the poor survival of implanted NPCs in the HI host environment limits their therapeutic effects. Tumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that is induced in response to a variety of pathological processes including inflammation and immunity. On the other hand, TNF-α has protective effects on cell apoptosis and death and affects the differentiation, proliferation, and survival of neural stem/progenitor cells in the brain. The present study investigated whether TNF-α pretreatment on human NPCs (hNPCs) enhances the effectiveness of cell transplantation therapy under ischemic brain. Fetal brain tissue-derived hNPCs were pretreated with TNF-α before being used in vitro experiments or transplantation. TNF-α significantly increased expression of cIAP2, and the use of short hairpin RNA-mediated knockdown of cIAP2 demonstrated that cIAP2 protected hNPCs against HI-induced cytotoxicity. In addition, pretreatment of hNPCs with TNF-α mediated neuroprotection by altering microglia polarization via increased expression of CX3CL1 and by enhancing expression of neurotrophic factors. Furthermore, transplantation of TNF-α-treated hNPCs reduced infarct volume and improved neurological functions in comparison with non-pretreated hNPCs or vehicle. These findings show that TNF-α pretreatment, which protects hNPCs from HI-injured brain-induced apoptosis and increases neuroprotection, is a simple and safe approach to improve the survival of transplanted hNPCs and the therapeutic efficacy of hNPCs in HI brain injury.
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Wu Y, Yang LW, Zhai XY, Liu JC. A Comparison of Intracerebral Transplantation of RMNE6 Cells and MSCs on Ischemic Stroke Models. Neurol India 2019; 67:1482-1490. [PMID: 31857541 DOI: 10.4103/0028-3886.273641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Cell therapy using stem cells is promising for stroke patients; however, stem cell therapy faces many problems. RMNE6 cells, a new stem cell line, are superior to other stem cell lines. Mesenchymal stem cells (MSCs) appear to be a promising candidate for stroke patients. In the current study, we determined the therapeutic effects of RMNE6 cells on a middle cerebral artery occlusion (MCAO) model of rats and identified the differences between RMNE6 cells and MSCs with respect to therapeutic effects. Material and Methods RMNE6 and Enhanced green fluorescent protein (EGFP)-labeled MSCs were transplanted into the ischemic brains of MCAO rats. The behavior of rats was examined using the rotarod test with neuroradiologic assessment using magnetic resonance imaging (MRI). Four weeks after cell transplantation, the rats were investigated by immunofluorescence staining to explore the fates of the graft cells. Result After transplantation, RMNE6 cells and MSCs survived and migrated toward the injured area without differentiation. There was tumorigenesis in the brains transplanted with RMNE6 cells. Cell transplantation had no effects on the size of the ischemic volume. The behavior of the model animals showed no significant improvement. Conclusion MSCs are still the preferred cells for cell replacement in stroke therapy, while RMNE6 cells need to be modified.
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Affiliation(s)
- Yun Wu
- Department of Basic Medicine, Shanxi University of Chinese Medicine, Shanxi, Jinzhong, China
| | - Li-Wang Yang
- Department of Basic Medicine, Shanxi University of Chinese Medicine, Shanxi, Jinzhong, China
| | - Xiao-Yan Zhai
- Department of Basic Medicine, Shanxi University of Chinese Medicine, Shanxi, Jinzhong, China
| | - Jian-Chun Liu
- Department of Basic Medicine, Shanxi University of Chinese Medicine, Shanxi, Jinzhong, China
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Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats. Mol Neurobiol 2019; 57:600-615. [DOI: 10.1007/s12035-019-01729-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022]
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31
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Perego C, Fumagalli S, Miteva K, Kallikourdis M, De Simoni MG. Combined Genetic Deletion of IL (Interleukin)-4, IL-5, IL-9, and IL-13 Does Not Affect Ischemic Brain Injury in Mice. Stroke 2019; 50:2207-2215. [DOI: 10.1161/strokeaha.119.025196] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background and Purpose—
After ischemic injury, microglia and infiltrated macrophages may acquire different polarization phenotypes promoting inflammation and injury (M1) or repair and protection (M2). There is evidence that immunomodulation, via type 2 helper T-cells (Th2) cytokines, exerts neuroprotection after ischemia. We investigated the consequences of simultaneous genetic deletion of Th2 cytokines (IL [interleukin]-4, IL-5, IL-9, IL-13) on the histopathologic outcome, microglia and infiltrated macrophages markers, and ischemic microenvironment at different time points after ischemic injury in mice subjected to permanent occlusion of the middle cerebral artery.
Methods—
Wild-type and Th2 cytokine-deficient mice (4KO) were subjected to permanent occlusion of the middle cerebral artery by electrocoagulation and followed up to 5 weeks after permanent occlusion of the middle cerebral artery. Neuropathologic outcome was assessed at 24 hours (n=6), 7 days (n=6), and 5 weeks (n=6–7) by examination of the ischemic lesion, neuronal count, microglia and infiltrated macrophages markers, brain atrophy, collagen deposition, and GFAP (glial fibrillary acidic protein) immunohistochemistry. Selected gene expression was investigated at 7 days (n=6).
Results—
4KO mice showed no difference in lesion and neuronal count 7 days and up to 5 weeks after permanent occlusion of the middle cerebral artery compared with wild type. Ischemic 4KO mice had lower CD16/32 expression at 24 hours, lower CD11b and CD16/32 expression at 7 days than wild type. They had higher CD206 expression at 24 hours, higher CD206 and arginase1 at 7 days, and increased mRNA for CXCL9 (chemokine [C-X-C motif] ligand 9) compared with wild type. Additional histopathologic analysis, including brain atrophy, gliotic scar, and collagenous scar confirmed no difference between genotypes at 5 weeks.
Conclusions—
This study casts light on the proposed neuroprotective function of Th2 cytokines, showing that combined IL-4, IL-5, IL-9, IL-13 deletion does not affect the neuropathologic response to ischemic stroke in the subacute and chronic phases. Our findings indicate that Th2 cytokines are not an essential neuroimmunological cue able to drive the brain’s ischemic outcome.
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Affiliation(s)
- Carlo Perego
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS (C.P., S.F., M.-G.D.S.)
- Milan, Italy (C.P., S.F., M.-G.D.S.)
| | - Stefano Fumagalli
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS (C.P., S.F., M.-G.D.S.)
- Milan, Italy (C.P., S.F., M.-G.D.S.)
| | - Kapka Miteva
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS (C.P., S.F., M.-G.D.S.)
- Direzione Scientifica, Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano, Milano, Italy (K.M., M.K.)
| | - Marinos Kallikourdis
- Direzione Scientifica, Adaptive Immunity Laboratory, Humanitas Clinical and Research Center, Rozzano, Milano, Italy (K.M., M.K.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy (M.K.)
| | - Maria-Grazia De Simoni
- From the Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS (C.P., S.F., M.-G.D.S.)
- Milan, Italy (C.P., S.F., M.-G.D.S.)
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Li X, Lin S, Chen X, Huang W, Li Q, Zhang H, Chen X, Yang S, Jin K, Shao B. The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke. Aging Dis 2019; 10:544-556. [PMID: 31164999 PMCID: PMC6538221 DOI: 10.14336/ad.2018.0820] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 08/20/2018] [Indexed: 12/12/2022] Open
Abstract
The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.
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Affiliation(s)
- Xianmei Li
- 1Department of Rehabilitation, Wenzhou People's Hospital, Wenzhou, China
| | - Siyang Lin
- 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoli Chen
- 1Department of Rehabilitation, Wenzhou People's Hospital, Wenzhou, China
| | - Wensi Huang
- 3Department of Neurology, The People's Hospital of Pingyang, Wenzhou, China
| | - Qian Li
- 4Department of Neurology, Jinhua Municipal Central Hospital, Wenzhou, China
| | - Hongxia Zhang
- 5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
| | - Xudong Chen
- 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shaohua Yang
- 5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
| | - Kunlin Jin
- 5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
| | - Bei Shao
- 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Gao X, Wu D, Dou L, Zhang H, Huang L, Zeng J, Zhang Y, Yang C, Li H, Liu L, Ma B, Yuan Q. Protective effects of mesenchymal stem cells overexpressing extracellular regulating kinase 1/2 against stroke in rats. Brain Res Bull 2019; 149:42-52. [PMID: 31002912 DOI: 10.1016/j.brainresbull.2019.04.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 02/28/2019] [Accepted: 04/09/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Although transplantation of bone marrow-derived mesenchymal stem cells (MSCs) has shown beneficial effects on stroke, lower survival of MSCs limits effects. Extracellular regulating kinase 1/2 signaling (ERK1/2) is crucial for cell survival, differentiation, and proliferation. This study was designed to explore whether MSCs modified by over-expressing ERK1/2 may reinforce beneficial effects on stroke in rats. METHODS rat MSCs transfected with ERK1/2 and empty lentivirus to generate MSCs overexpressing ERK1/2 (ERK/MSCs) and MSCs (as a control), respectively. In vitro, ERK/MSCs were plated and exposed to glutamate-induced condition, and viability of ERK/MSCs was measured. Furthermore, neural induction of ERK/MSCs was investigated in vitro. Cerebral ischemic rats were induced by occluding middle cerebral artery, and then were stereotaxically injected into ipsilateral right lateral ventricle with ERK/MSCs or MSCs 3 days after stroke and survived for 7 or 14 days after injection. RESULTS ERK/MSCs showed better viability in physiological and glutamate-induced neurotoxic conditions compared to MSCs. After neural induction, more neurons were be differentiated from ERK/MSCs than from MSCs. After transplantation, more numbers of grafted cells and improved functional recovery were observed in ERK/MSCs-treated rats compared with MSCs-treated rats. Compared with MSCs treatment, ERK/MSCs treatment significantly increased proliferation of neural stem cells in the subventricle zone (SVZ) and the MAP2/nestin double-labeled cells adjacent to the SVZ, enhanced the numbers of reactive astrocytes while suppressed microglial activation. Besides, TNF-α level was elevated in ERK/MSCs-treated rats. CONCLUSION ERK/MSCs transplantation showed better functional recovery after stroke in rats, likely in part through enhancing survival of MSCs and possibly by modulating the proliferation, neuronal de-differentiation and neuroinflammation.
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Affiliation(s)
- Xiaoqing Gao
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China; Department of Anatomy and Neurobiology, Southwest Medical University, Luzhou, 646000, China
| | - Dandan Wu
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Ling Dou
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Haibo Zhang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Liang Huang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Jiaqi Zeng
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Yiiie Zhang
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Chaoxian Yang
- Department of Anatomy and Neurobiology, Southwest Medical University, Luzhou, 646000, China
| | - Huanhuan Li
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Lifen Liu
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Bin Ma
- Department of Molecular and Biomedical Sciences, School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
| | - Qionglan Yuan
- Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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Liu W, Li R, Yin J, Guo S, Chen Y, Fan H, Li G, Li Z, Li X, Zhang X, He X, Duan C. Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch. J Neuroinflammation 2019; 16:8. [PMID: 30646897 PMCID: PMC6334441 DOI: 10.1186/s12974-019-1396-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition. METHODS The Sprague-Dawley rats SAH model was induced by endovascular perforation method. BMSCs (3 × 106 cells) were transplanted intravenously into rats, and N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a Notch1 activation inhibitor, and Notch1 small interfering RNA (siRNA) were injected intracerebroventricularly. The effects of BMSCs on EBI were assayed by neurological score, brain water content (BWC), blood-brain barrier (BBB) permeability, magnetic resonance imaging, hematoxylin and eosin staining, and Fluoro-Jade C staining. Immunofluorescence and immunohistochemistry staining, Western blotting, and quantitative real-time polymerase chain reaction were used to analyze various proteins and transcript levels. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay. RESULTS BMSCs treatment mitigated the neurobehavioral dysfunction, BWC and BBB disruption associated with EBI after SAH, reduced ionized calcium binding adapter molecule 1 and cluster of differentiation 68 staining and interleukin (IL)-1 beta, IL-6 and tumor necrosis factor alpha expression in the left hemisphere but concurrently increased IL-10 expression. DAPT or Notch1 siRNA administration reduced Notch1 signaling pathway activation following SAH, ameliorated neurobehavioral impairments, and BBB disruption; increased BWC and neuronal degeneration; and inhibited activation of microglia and production of pro-inflammatory factors. The augmentation of Notch1 signal pathway agents and phosphorylation of nuclear factor-κB after SAH were suppressed by BMSCs but the levels of Botch were upregulated in the ipsilateral hemisphere. Botch knockdown in BMSCs abrogated the protective effects of BMSCs treatment on EBI and the suppressive effects of BMSCs on Notch1 expression. CONCLUSIONS BMSCs treatment alleviated neurobehavioral impairments and the inflammatory response in EBI after SAH; these effects may be attributed to Botch upregulation in brain tissue, which subsequently inhibited the Notch1 signaling pathway.
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Affiliation(s)
- Wenchao Liu
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Ran Li
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Jian Yin
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Shenquan Guo
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Yunchang Chen
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Haiyan Fan
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Gancheng Li
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Zhenjun Li
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Xifeng Li
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Xin Zhang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Xuying He
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
| | - Chuanzhi Duan
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510282 China
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Chen T, Wu Y, Gu W, Xu Q. Response of vascular mesenchymal stem/progenitor cells to hyperlipidemia. Cell Mol Life Sci 2018; 75:4079-4091. [PMID: 29946805 PMCID: PMC11105685 DOI: 10.1007/s00018-018-2859-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 06/14/2018] [Accepted: 06/20/2018] [Indexed: 12/29/2022]
Abstract
Hyperlipidemia is a risk factor for atherosclerosis that is characterized by lipid accumulation, inflammatory cell infiltration, and smooth muscle cell proliferation. It is well known that hyperlipidemia is a stimulator for endothelial dysfunction and smooth muscle cell migration during vascular disease development. Recently, it was found that vessel wall contains a variable number of mesenchymal stem cells (MSCs) that are quiescent in physiological conditions, but can be activated by a variety of stimuli, e.g., increased lipid level or hyperlipidemia. Vascular MSCs displayed characteristics of stem cells which can differentiate into several types of cells, e.g., smooth muscle cells, adipocytic, chondrocytic, and osteocytic lineages. In vitro, lipid loading can induce MSC migration and chemokines secretion. After MSC migration into the intima, they play an essential role in inflammatory response and cell accumulation during the initiation and progression of atherosclerosis. In addition, MSC transplantation has been explored as a therapeutic approach to treat atherosclerosis in animal models. In this review, we aim to summarize current progress in characterizing the identity of vascular MSCs and to discuss the mechanisms involved in the response of vascular stem/progenitor cells to lipid loading, as well as to explore therapeutic strategies for vascular diseases and shed new light on regenerative medicine.
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Affiliation(s)
- Ting Chen
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Yutao Wu
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Wenduo Gu
- School of Cardiovascular Medicine and Sciences, King's BHF Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
- School of Cardiovascular Medicine and Sciences, King's BHF Centre, 125 Coldharbour Lane, London, SE5 9NU, UK.
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Shiota Y, Nagai A, Sheikh AM, Mitaki S, Mishima S, Yano S, Haque MA, Kobayashi S, Yamaguchi S. Transplantation of a bone marrow mesenchymal stem cell line increases neuronal progenitor cell migration in a cerebral ischemia animal model. Sci Rep 2018; 8:14951. [PMID: 30297706 PMCID: PMC6175868 DOI: 10.1038/s41598-018-33030-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 09/18/2018] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is demonstrated to improve functional and pathological recovery in cerebral ischemia. To understand the underlying mechanism, we transplanted a MSC line (B10) in a rat middle cerebral artery occlusion (MCAO) model and checked the proliferation and migration of neuronal progenitor cells (NPCs). B10 transplantation increased NPCs in the subventricular zone and their migration towards the lesion area at an earlier time. Fourteen days after MCAO, some NPCs were differentiated to neurons and astrocytes. Although B10 transplantation increased total number of both astrocytes and neurons, it only increased the differentiation of NPC to astrocyte. The mRNA of polysialylation enzyme ST8SiaIV and a chemokine SDF-1 were persistently increased in B10-transplanted groups. SDF-1-positive cell number was increased in the core and penumbra area, which was expressed in macrophage/microglia and transplanted B10 cells at 3 days after MCAO. Furthermore, SDF-1 mRNA expression in cell culture was high in B10 compared to a microglia (HMO) or a neuronal (A1) cell line. B10 culture supernatant increased in vitro A1 cell migration, which was significantly inhibited by siRNA-mediated SDF-1 silencing in B10. Thus, our results suggested that MSC transplantation increased endogenous NPC migration in cerebral ischemic condition by increasing chemokine and polysialylation enzyme expression, which could be helpful for the restorative management of cerebral ischemia.
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Affiliation(s)
- Yuri Shiota
- Clinical Laboratory Division, Shimane University Hospital, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | - Atsushi Nagai
- Clinical Laboratory Division, Shimane University Hospital, 89-1 Enya Cho, Izumo, 693-8501, Japan. .,Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan.
| | - Abdullah Md Sheikh
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | - Shingo Mitaki
- Department of Internal Medicine III, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | - Seiji Mishima
- Clinical Laboratory Division, Shimane University Hospital, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | - Shozo Yano
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | - Md Ahsanul Haque
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan
| | | | - Shuhei Yamaguchi
- Department of Internal Medicine III, Shimane University School of Medicine, 89-1 Enya Cho, Izumo, 693-8501, Japan
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Sheikh AM, Yano S, Mitaki S, Haque MA, Yamaguchi S, Nagai A. A Mesenchymal stem cell line (B10) increases angiogenesis in a rat MCAO model. Exp Neurol 2018; 311:182-193. [PMID: 30291853 DOI: 10.1016/j.expneurol.2018.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 08/29/2018] [Accepted: 10/01/2018] [Indexed: 12/13/2022]
Abstract
A human mesenchymal stem cell line (B10) transplantation has been shown to improve ischemia-induced neurological deficits in animal stroke models. To understand the underlying mechanism, we have investigated the effects of B10 transplantation on cerebral angiogenesis in a rat middle cerebral artery occlusion (MCAO) model. B10 cells were transplanted intravenously 24 h after MCAO. Immunofluorescence staining results showed that compared to PBS-groups, vWF positive vessel and endoglin positive new vessels were increased in B10-transplanted MCAO groups in the lesion areas. The mRNA of angiogenesis factors including placental growth factor and hypoxia inducible factor (HIF)-1α were increased 3 days after MCAO in the core and IBZ areas of B10-transplanted group. Angiopoetin1 mRNA was increased only in the IBZ. Western blotting results showed that HIF-1α and vascular endothelial growth factor (VEGF) proteins were increased in B10-transplanted group. Both HIF-1α and VEGF were expressed in macrophage/microglia in the core area. In the IBZ, however, HIF-1α was expressed both in astrocytes and macrophage/microglia, while VEGF was expressed only in macrophage/microglia. Moreover, TGFβ protein levels were found to be increased in B10-transplanted group in the core and IBZ regions. Cell culture experiments using a human microglia cell line (HMO6) and B10 showed that IL-1β induced VEGF mRNA expression in both cell types. IL-1β was found to be highly expressed in B10 cells, and its co-culture with HMO6 further increased that in B10. Co-culture increased VEGF mRNA in both B10 and HMO6. In the rat brains, IL-1β was expressed in macrophage/microglia and transplanted-B10 cells in the core. IL-1β positive cell number was increased slightly, but significantly in B10-transplanted rats. To explore further, IL-1β expression was silenced in B10 cells by transfecting mRNA specific siRNA, and then transplanted in MCAO rats. Immunostaining result showed that endoglin positive area was decreased in IL-1β-silenced B10 transplanted groups compared to nonsilenced-B10 transplanted groups. Interestingly, vessel-like structure appeared as early as 3 days after MCAO in IL-1β-silenced B10-transplanted group. Thus our results demonstrated that B10 cells increased angiogenesis in MCAO rat model, through the regulation of HIF-1α and VEGF expression, where IL-1β might play a role.
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Affiliation(s)
- Abdullah Md Sheikh
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Shozo Yano
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Shingo Mitaki
- Department of Neurology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Md Ahsanul Haque
- Department of Neurology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Shuhei Yamaguchi
- Department of Neurology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Atsushi Nagai
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan.
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Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab 2018; 38:1276-1292. [PMID: 29768965 PMCID: PMC6077926 DOI: 10.1177/0271678x18776802] [Citation(s) in RCA: 176] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) hold great potential as a regenerative therapy for stroke, leading to increased repair and functional recovery in animal models of cerebral ischaemia. While it was initially hypothesised that cell replacement was an important mechanism of action of MSCs, focus has shifted to their paracrine actions or the so called "bystander" effect. MSCs secrete a wide array of growth factors, chemokines, cytokines and extracellular vesicles, commonly referred to as the MSC secretome. There is evidence suggesting the MSC secretome can promote repair through a number of mechanisms including preventing cell apoptosis, modulating the inflammatory response and promoting endogenous repair mechanisms such as angiogenesis and neurogenesis. In this review, we will discuss the in vitro approaches currently being employed to drive the MSC secretome towards a more anti-inflammatory and regenerative phenotype. We will then examine the role of the secretome in promoting repair and improving recovery in preclinical models of cerebral ischaemia.
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Affiliation(s)
- Catriona J Cunningham
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Elena Redondo-Castro
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Wang S, Hu S, Wang J, Liu Y, Zhao R, Tong M, Cui H, Wu N, Chen X. Conditioned medium from bone marrow-derived mesenchymal stem cells inhibits vascular calcification through blockade of the BMP2-Smad1/5/8 signaling pathway. Stem Cell Res Ther 2018; 9:160. [PMID: 29895327 PMCID: PMC5998505 DOI: 10.1186/s13287-018-0894-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 04/17/2018] [Accepted: 05/02/2018] [Indexed: 12/13/2022] Open
Abstract
Background Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis and is a significant contributor to cardiovascular morbidity and mortality. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important role in arterial calcification and is characterized by cellular necrosis, inflammation, and lipoprotein and phospholipid complexes, especially in atherosclerotic calcification. The conditioned medium from bone marrow-derived mesenchymal stem cells (MSC-CM) is well known as a rich source of autologous cytokines and is universally used for tissue regeneration in current clinical medicine. Here, we demonstrate that MSC-CM inhibits beta-glycerophosphate (β-GP)-induced vascular calcification through blockade of the bone morphogenetic protein-2 (BMP2)–Smad1/5/8 signaling pathway. Methods VSMC calcification was induced by β-GP followed by treatment with MSC-CM. Mineral deposition was assessed by Alizarin Red S staining. Intracellular calcium content was determined colorimetrically by the o-cresolphthalein complexone method and alkaline phosphatase (ALP) activity was measured by the para-nitrophenyl phosphate method. Expression of BMP2, BMPR1A, BMPR1B, BMPR2, msh homeobox 2 (Msx2), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC), representative osteoblastic markers, was assessed using real-time polymerase chain reaction analysis while the protein expression of BMP2, Runx2, and phosphorylated Smad1/5/8 was detected by western blot analysis. Results Our data demonstrated that MSC-CM inhibits osteoblastic differentiation and mineralization of VSMCs as evidenced by decreased calcium content, ALP activity, and decreased expression of BMP-2, Runx2, Msx2, and OC. MSC-CM suppressed the expression of phosphorylated Smad1/5/8 and the β-GP-induced translocation from the cytoplasm to the nucleus. Further study demonstrated that human recombinant BMP-2 overcame the suppression of VSMC calcification by MSC-CM. Conclusion MSC-CM may act as a novel therapy for VSMC calcification by mediating the BMP2–Smad1/5/8 signaling pathway
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Affiliation(s)
- Shuangshuang Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Siwang Hu
- Spine Tumor Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Jian Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Yahui Liu
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Ruochi Zhao
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Maoqing Tong
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Hanbin Cui
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Nan Wu
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
| | - Xiaomin Chen
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China.
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Boshuizen MCS, Steinberg GK. Stem Cell-Based Immunomodulation After Stroke: Effects on Brain Repair Processes. Stroke 2018; 49:1563-1570. [PMID: 29724892 DOI: 10.1161/strokeaha.117.020465] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/05/2018] [Accepted: 03/20/2018] [Indexed: 01/01/2023]
Affiliation(s)
- Marieke C S Boshuizen
- From the Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, CA
| | - Gary K Steinberg
- From the Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, CA.
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41
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Ko DY, Patel M, Lee HJ, Jeong B. Coordinating Thermogel for Stem Cell Spheroids and Their Cyto-Effectiveness. ADVANCED FUNCTIONAL MATERIALS 2018; 28:1706286. [DOI: 10.1002/adfm.201706286] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Du Young Ko
- Department of Chemistry and Nanoscience; Ewha Womans University; 52 Ewhayeodae-gil Seodaemun-gu Seoul 03760 Korea
| | - Madhumita Patel
- Department of Chemistry and Nanoscience; Ewha Womans University; 52 Ewhayeodae-gil Seodaemun-gu Seoul 03760 Korea
| | - Hyun Jung Lee
- Department of Chemistry and Nanoscience; Ewha Womans University; 52 Ewhayeodae-gil Seodaemun-gu Seoul 03760 Korea
| | - Byeongmoon Jeong
- Department of Chemistry and Nanoscience; Ewha Womans University; 52 Ewhayeodae-gil Seodaemun-gu Seoul 03760 Korea
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Chen C, Chu SF, Liu DD, Zhang Z, Kong LL, Zhou X, Chen NH. Chemokines play complex roles in cerebral ischemia. Neurochem Int 2018. [DOI: 10.1016/j.neuint.2017.06.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Sarmah D, Kaur H, Saraf J, Pravalika K, Goswami A, Kalia K, Borah A, Wang X, Dave KR, Yavagal DR, Bhattacharya P. Getting Closer to an Effective Intervention of Ischemic Stroke: The Big Promise of Stem Cell. Transl Stroke Res 2017; 9:356-374. [PMID: 29075984 DOI: 10.1007/s12975-017-0580-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/12/2017] [Accepted: 10/17/2017] [Indexed: 12/13/2022]
Abstract
Stem cell therapy for ischemic stroke has widely been explored. Results from both preclinical and clinical studies have immensely supported the judicious use of stem cells as therapy. These provide an attractive means for preserving and replacing the damaged brain tissues following an ischemic attack. Since the past few years, researchers have used various types of stem cells to replenish insulted neuronal and glial cells in neurological disorders. In the present review, we discuss different types of stem cells employed for the treatment of ischemic stroke and mechanisms and challenges these cells face once introduced into the living system. Further, we also present different ways to maneuver and overcome challenges to translate the advances made at the preclinical level to clinics.
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Affiliation(s)
- Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Jackson Saraf
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Kanta Pravalika
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Avirag Goswami
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kiran Kalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Dileep R Yavagal
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, 382355, India.
- Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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How to use stem cells for repair in stroke patients. Rev Neurol (Paris) 2017; 173:572-576. [PMID: 29033030 DOI: 10.1016/j.neurol.2017.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 08/25/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022]
Abstract
Regenerative cell therapy is a promising therapeutic strategy in neurology, most notably to improve stroke recovery. Although tolerability and feasibility have apparently been validated, many questions remain as to what is the best type of cells to use, the best route and the post-stroke delay for administration. Two main strategies have currently emerged: intravenous injection of mesenchymal stem cells with systemic trophic support; and intracerebral grafting of neural stem cells with brain repair effects at the lesion site. Multicenter clinical trials have just begun and are starting to assess the efficacy of these treatments on functional recovery. However, experimental studies also need to be conducted in parallel to precisely identify the mechanisms of action regarding the pathophysiology of brain plasticity, notably when stroke occurs with comorbidities. Such studies should also evaluate the potential of cell grafting combined with injectable biomaterials.
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Li F, Guo X, Chen SY. Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. Front Cardiovasc Med 2017; 4:32. [PMID: 28589127 PMCID: PMC5438961 DOI: 10.3389/fcvm.2017.00032] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/01/2017] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.
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Affiliation(s)
- Feifei Li
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA.,The Department of Cardiovascular Surgery, Union Hospital, Wuhan, China
| | - Xia Guo
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
| | - Shi-You Chen
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
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Inoue M, Yamada J, Aomatsu-Kikuchi E, Satoh K, Kondo H, Ishisaki A, Chosa N. SCRG1 suppresses LPS-induced CCL22 production through ERK1/2 activation in mouse macrophage Raw264.7 cells. Mol Med Rep 2017; 15:4069-4076. [PMID: 28440453 PMCID: PMC5436279 DOI: 10.3892/mmr.2017.6492] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 04/06/2017] [Indexed: 12/11/2022] Open
Abstract
Recently, we identified the scrapie responsive gene 1 (SCRG1) secreted from mesenchymal stem cells (MSCs) and its receptor bone marrow stromal cell antigen 1 (BST1) as positive regulators of stem cell qualities such as self-renewal, migration abilities, and osteogenic differentiation potential. Here, we examined the effect of the paracrine activity of SCRG1 in macrophages. The mouse macrophage-like cell line Raw264.7 expressed BST1/β1 or BST1/β2 integrin as possible SCRG1 receptors. Unexpectedly, recombinant SCRG1 did not enhance cell proliferation, migration, or adhesion in these macrophages. However, further examination of the effect of SCRG1 in Raw264.7 cells did reveal a potent anti-inflammatory effect whereby SCRG1 suppressed LPS-induced CCL22 production. SCRG1 also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in these cells and, moreover, a mitogen-activated protein kinase (MAPK)/ERK kinase inhibitor U0126 significantly suppressed the effect of SCRG1 on LPS-induced chemokine CCL22 production. Taken together, these data indicate that SCRG1 signals through the MAPK pathway and suppresses the LPS signaling pathway. CCL22 is generally known to be chemotactic for monocytes, dendritic cells, natural killer cells and chronically activated T lymphocytes, suggesting that MSC-derived SCRG1 may block infiltration of these cells. A mechanism is proposed by which MSCs play their immunosuppressive role through suppressing chemokine expression in monocyte/macrophage lineage cells.
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Affiliation(s)
- Manabu Inoue
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan
| | - Junko Yamada
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan
| | - Emiko Aomatsu-Kikuchi
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan
| | - Kazuro Satoh
- Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University School of Dentistry, Morioka, Iwate 020‑8505, Japan
| | - Hisatomo Kondo
- Department of Prosthodontics and Oral Implantology, Iwate Medical University School of Dentistry, Morioka, Iwate 020‑8505, Japan
| | - Akira Ishisaki
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan
| | - Naoyuki Chosa
- Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan
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IL-5 blocks apoptosis and tau hyperphosphorylation induced by Aβ 25-35 peptide in PC12 cells. J Physiol Biochem 2017; 73:259-266. [PMID: 28132394 DOI: 10.1007/s13105-017-0550-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 01/18/2017] [Indexed: 12/22/2022]
Abstract
The primary features of Alzheimer's disease (AD) are extracellular amyloid plaques consisting mainly of deposits of amyloid β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs). Sets of evidence suggest that interleukin-5 (IL-5) is involved in the pathogenesis of AD. Herein, we investigated the protective role of IL-5 in PC12 cells, to provide new insights into understanding this disease. Western blot was employed to assess the protein levels of Bax and phospho-tau as well as phospho-JAK2; MTT assay was performed to decipher cell viability. Treatment of IL-5 decreased Aβ25-35-induced tau phosphorylation and apoptosis, effects blunted by JAK2 inhibition. IL-5 prevents Aβ25-35-evoked tau protein hyperphosphorylation and apoptosis through JAK2 signaling.
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Enhancement of Anti-Inflammatory and Osteogenic Abilities of Mesenchymal Stem Cells via Cell-to-Cell Adhesion to Periodontal Ligament-Derived Fibroblasts. Stem Cells Int 2017; 2017:3296498. [PMID: 28167967 PMCID: PMC5266859 DOI: 10.1155/2017/3296498] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 12/14/2016] [Accepted: 12/22/2016] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are involved in anti-inflammatory events and tissue repair; these functions are activated by their migration or homing to inflammatory tissues in response to various chemokines. However, the mechanism by which MSCs interact with other cell types in inflammatory tissue remains unclear. We investigated the role of periodontal ligament fibroblasts (PDL-Fs) in regulating the anti-inflammatory and osteogenic abilities of bone marrow-derived- (BM-) MSCs. The expression of monocyte chemotactic protein- (MCP-)1 was significantly enhanced by stimulation of PDL-Fs with inflammatory cytokines. MCP-1 induced the migratory ability of BM-MSCs but not PDL-Fs. Expression levels of anti-inflammatory and inflammatory cytokines were increased and decreased, respectively, by direct-contact coculture between MSCs and PDL-Fs. In addition, the direct-contact coculture enhanced the expression of MSC markers that play important roles in the self-renewal and maintenance of multipotency of MSCs, which in turn induced the osteogenic ability of the cells. These results suggest that MCP-1 induces the migration and homing of BM-MSCs into the PDL inflammatory tissue. The subsequent adherence of MSCs to PDL-Fs plays an immunomodulatory role to terminate inflammation during wound healing and upregulates the expression stem cell markers to enhance the stemness of MSCs, thereby facilitating bone formation in damaged PDL tissue.
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Pena-Philippides JC, Caballero-Garrido E, Lordkipanidze T, Roitbak T. In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response. J Neuroinflammation 2016; 13:287. [PMID: 27829437 PMCID: PMC5103429 DOI: 10.1186/s12974-016-0753-x] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/27/2016] [Indexed: 12/12/2022] Open
Abstract
Background MicroRNA miR-155 is implicated in modulation of the inflammatory processes in various pathological conditions. In our previous studies, we demonstrated that in vivo inhibition of miR-155 promotes functional recovery after mouse experimental stroke. In the present study, we explored if this beneficial effect is associated with miR-155 inhibition-induced alterations in post-stroke inflammatory response. Methods Intravenous injections of a specific miR-155 inhibitor were initiated at 48 h after mouse distal middle cerebral artery occlusion (dMCAO). Temporal changes in the expression of cytokines and key molecules associated with cytokine signaling were assessed at 7, 14, and 21 days after dMCAO, using mouse cytokine gene and protein arrays and Western blot analyses. Electron and immunofluorescence confocal microscopy techniques were used to evaluate the ultrastructural changes, as well as altered expression of specific phenotypic markers, at different time points after dMCAO. Results In the inhibitor-injected mice (inhibitor group), there was a significant decrease in CCL12 and CXCL3 cytokine expression at 7 days and significantly increased levels of major cytokines IL-10, IL-4, IL-6, MIP-1α, IL-5, and IL-17 at 14 days after dMCAO. These temporal changes correlated with altered expression of miR-155 target proteins SOCS-1, SHIP-1, and C/EBP-β and phosphorylation levels of cytokine signaling regulator STAT-3. Electron microscopy showed decreased number of phagocytically active peri-vascular microglia/macrophages in the inhibitor samples. Immunofluorescence and Western blot of these samples demonstrated that expression of leukocyte/ macrophage marker CD45 and phagocytosis marker CD68 was reduced at 7 days, and in contrast, significantly increased at 14 days after dMCAO, as compared to controls. Conclusions Based on our findings, we propose that in vivo miR-155 inhibition following mouse stroke significantly alters the time course of the expression of major cytokines and inflammation-associated molecules, which could influence inflammation process and tissue repair after experimental cerebral ischemia. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0753-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Juan Carlos Pena-Philippides
- Department of Neurosurgery, University of New Mexico Health Sciences Center, 1101 Yale Blvd, Albuquerque, NM, 87106-3834, USA
| | - Ernesto Caballero-Garrido
- Department of Neurosurgery, University of New Mexico Health Sciences Center, 1101 Yale Blvd, Albuquerque, NM, 87106-3834, USA
| | | | - Tamara Roitbak
- Department of Neurosurgery, University of New Mexico Health Sciences Center, 1101 Yale Blvd, Albuquerque, NM, 87106-3834, USA.
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Liu L, Song H, Duan H, Chai J, Yang J, Li X, Yu Y, Zhang X, Hu X, Xiao M, Feng R, Yin H, Hu Q, Yang L, Du J, Li T. TSG-6 secreted by human umbilical cord-MSCs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and JNK signaling. Sci Rep 2016; 6:30121. [PMID: 27444207 PMCID: PMC4957124 DOI: 10.1038/srep30121] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
The hMSCs have become a promising approach for inflammation treatment in acute phase. Our previous study has demonstrated that human umbilical cord-MSCs could alleviate the inflammatory reaction of severely burned wound. In this study, we further investigated the potential role and mechanism of the MSCs on severe burn-induced excessive inflammation. Wistar rats were randomly divided into following groups: Sham, Burn, Burn+MSCs, Burn+MAPKs inhibitors, and Burn, Burn+MSCs, Burn+Vehicle, Burn+siTSG-6, Burn+rhTSG-6 in the both experiments. It was found that MSCs could only down-regulate P38 and JNK signaling, but had no effect on ERK in peritoneal macrophages of severe burn rats. Furthermore, suppression of P38 and JNK activations significantly reduced the excessive inflammation induced by severe burn. TSG-6 was secreted by MSCs using different inflammatory mediators. TSG-6 from MSCs and recombinant human (rh)TSG-6 all significantly reduced activations of P38 and JNK signaling induced by severe burn and then attenuated excessive inflammations. On the contrary, knockdown TSG-6 in the cells significantly increased phosphorylation of P38 and JNK signaling and reduced therapeutic effect of the MSCs on excessive inflammation. Taken together, this study suggested TSG-6 from MSCs attenuated severe burn-induced excessive inflammation via inhibiting activation of P38 and JNK signaling.
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Affiliation(s)
- Lingying Liu
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Huifeng Song
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Hongjie Duan
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Jiake Chai
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Jing Yang
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Xiao Li
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Yonghui Yu
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Xulong Zhang
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Xiaohong Hu
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Mengjing Xiao
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Rui Feng
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Huinan Yin
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Quan Hu
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Longlong Yang
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Jundong Du
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
| | - Tianran Li
- Department of Burn & Plastic Surgery, the First Affiliated Hospital to PLA General Hospital
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