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Rust R, Nih LR, Liberale L, Yin H, El Amki M, Ong LK, Zlokovic BV. Brain repair mechanisms after cell therapy for stroke. Brain 2024; 147:3286-3305. [PMID: 38916992 PMCID: PMC11449145 DOI: 10.1093/brain/awae204] [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: 03/11/2024] [Revised: 06/04/2024] [Accepted: 06/08/2024] [Indexed: 06/27/2024] Open
Abstract
Cell-based therapies hold great promise for brain repair after stroke. While accumulating evidence confirms the preclinical and clinical benefits of cell therapies, the underlying mechanisms by which they promote brain repair remain unclear. Here, we briefly review endogenous mechanisms of brain repair after ischaemic stroke and then focus on how different stem and progenitor cell sources can promote brain repair. Specifically, we examine how transplanted cell grafts contribute to improved functional recovery either through direct cell replacement or by stimulating endogenous repair pathways. Additionally, we discuss recently implemented preclinical refinement methods, such as preconditioning, microcarriers, genetic safety switches and universal (immune evasive) cell transplants, as well as the therapeutic potential of these pharmacologic and genetic manipulations to further enhance the efficacy and safety of cell therapies. By gaining a deeper understanding of post-ischaemic repair mechanisms, prospective clinical trials may be further refined to advance post-stroke cell therapy to the clinic.
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Affiliation(s)
- Ruslan Rust
- Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Institute for Regenerative Medicine, University of Zurich, 8952 Schlieren, Switzerland
| | - Lina R Nih
- Department of Brain Health, University of Nevada, Las Vegas, NV 89154, USA
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Hao Yin
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Mohamad El Amki
- Department of Neurology, University Hospital and University of Zurich, 8091 Zurich, Switzerland
| | - Lin Kooi Ong
- School of Health and Medical Sciences & Centre for Health Research, University of Southern Queensland, Toowoomba, QLD 4350, Australia
| | - Berislav V Zlokovic
- Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Li X, Guan Y, Chen D, Li J, Yu W, Zou H, Liu B, Chen L, Chen Z. Immune Cells Promote BDNF Expression by Infiltrated Macrophages via Interleukin 4 in the Cerebral Ischemia of Male Rats. J Neurosci Res 2024; 102:e25379. [PMID: 39235282 DOI: 10.1002/jnr.25379] [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: 12/01/2023] [Revised: 07/30/2024] [Accepted: 08/10/2024] [Indexed: 09/06/2024]
Abstract
We reported that infiltrated Ly6C+ macrophages express brain-derived neurotrophic factor (BDNF) only at the cerebral cortex infarct in a rat dMCAO model. However, the changein neuron-expressed BDNF, the niche components that induce the Ly6C+ cells to express BDNF, and the cellular sources of these components, remain unclear. In this study, immunofluorescence double staining was performed to label BDNF and Ly6C on brain sections at 3, 24, and 48 h following distal middle cerebral artery occlusion (dMCAO) of male rats, and to stain BDNF with Ly6C, IL-4R, and IL-10R. A neutralizing anti-IL-4 antibody was injected into the infarct, and the IL-4 and BDNF concentrations in the subareas of the infarct were determined using enzyme-linked immunosorbent assay. To find out the cellular sources of IL-4, the markers for microglia, T cells, and neurons were co-stained with IL-4 separately. In certain infarct subareas, the main BDNF-expressing cells shifted quickly from NeuN+ neurons to Ly6C+ cells during 24-48 h post-stroke, and the Ly6C+/BDNF+ cells mostly expressed IL-4 receptor. Following IL-4 neutralizing antibody injection, the BDNF, IL-4 protein levels, and BDNF+/Ly6C+ cells decreased significantly. The main IL-4-expressing cell type in this infarct subarea is not neuron either, but immune cells, including microglia, monocyte, macrophages, and T cells. The neurons, maintained BDNF and IL-4 expression in the peri-infarct area. In conclusion, in a specific cerebral subarea of the rat dMCAO model, IL-4 secreted by immune cells is one of the main inducers for Ly6C+ cells to express BDNF.
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Affiliation(s)
- Xiaobo Li
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Yunqian Guan
- Cell Therapy Center, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Danni Chen
- Department of Clinical Medicine, Medical School of Yangzhou University, Yangzhou, China
| | - Jiyu Li
- Department of Orthopedic Oncology, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wenxiu Yu
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Haiqiang Zou
- Department of Neurology, The General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Bochao Liu
- Cell Therapy Center, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Ling Chen
- Department of Neurosurgery, PLA General Hospital, Beijing, China
| | - Zhiguo Chen
- Cell Therapy Center, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China
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Chen X, Qian W, Zhang Y, Zhao P, Lin X, Yang S, Zhuge Q, Ni H. Ginsenoside CK cooperates with bone mesenchymal stem cells to enhance angiogenesis post-stroke via GLUT1 and HIF-1α/VEGF pathway. Phytother Res 2024. [PMID: 38990183 DOI: 10.1002/ptr.8235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/08/2024] [Accepted: 04/23/2024] [Indexed: 07/12/2024]
Abstract
The transplantation of bone marrow mesenchymal stem cells (MSCs) in stroke is hindered by the restricted rates of survival and differentiation. Ginsenoside compound K (CK), is reported to have a neuroprotective effect and regulate energy metabolism. We applied CK to investigate if CK could promote the survival of MSCs and differentiation into brain microvascular endothelial-like cells (BMECs), thereby alleviating stroke symptoms. Therefore, transwell and middle cerebral artery occlusion (MCAO) models were used to mimic oxygen and glucose deprivation (OGD) in vitro and in vivo, respectively. Our results demonstrated that CK had a good affinity for GLUT1, which increased the expression of GLUT1 and the production of ATP, facilitated the proliferation and migration of MSCs, and activated the HIF-1α/VEGF signaling pathway to promote MSC differentiation. Moreover, CK cooperated with MSCs to protect BMECs, promote angiogenesis and vascular density, enhance neuronal and astrocytic proliferation, thereby reducing infarct volume and consequently improving neurobehavioral outcomes. These results suggest that the synergistic effects of CK and MSCs could potentially be a promising strategy for stroke.
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Affiliation(s)
- Xijun Chen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenqi Qian
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ying Zhang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Peiqi Zhao
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangxiang Lin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Su Yang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qichuan Zhuge
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haoqi Ni
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Labusca L, Zugun-Eloae F. Understanding host-graft crosstalk for predicting the outcome of stem cell transplantation. World J Stem Cells 2024; 16:232-236. [PMID: 38577233 PMCID: PMC10989282 DOI: 10.4252/wjsc.v16.i3.232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/14/2024] [Accepted: 02/18/2024] [Indexed: 03/25/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) hold great promise for tissue regeneration in debilitating disorders. Despite reported improvements, the short-term outcomes of MSC transplantation, which is possibly linked to poor cell survival, demand extensive investigation. Disease-associated stress microenvironments further complicate outcomes. This debate underscores the need for a deeper understanding of the phenotypes of transplanted MSCs and their environment-induced fluctuations. Additionally, questions arise about how to predict, track, and comprehend cell fate post-transplantation. In vivo cellular imaging has emerged as a critical requirement for both short- and long-term safety and efficacy studies. However, translating preclinical imaging methods to clinical settings remains challenging. The fate and function of transplanted cells within the host environment present intricate challenges, including MSC engraftment, variability, and inconsistencies between preclinical and clinical data. The study explored the impact of high glucose concentrations on MSC survival in diabetic environments, emphasizing mitochondrial factors. Preserving these factors may enhance MSC survival, suggesting potential strategies involving genetic modification, biomaterials, and nanoparticles. Understanding stressors in diabetic patients is crucial for predicting the effects of MSC-based therapies. These multifaceted challenges call for a holistic approach involving the incorporation of large-scale data, computational disease modeling, and possibly artificial intelligence to enable deterministic insights.
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Affiliation(s)
- Luminita Labusca
- Magnetic Materials and Sensors, National Institute of Research and Development for Technical Physics, Iasi 700050, Romania
- Orthopedics and Trauma, Emergency County Hospital Saint Spiridon, Iasi 700000, Romania.
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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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6
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Farzaneh M, Khoshnam SE. Functional Roles of Mesenchymal Stem Cell-derived Exosomes in Ischemic Stroke Treatment. Curr Stem Cell Res Ther 2024; 19:2-14. [PMID: 36567297 DOI: 10.2174/1574888x18666221222123818] [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: 04/24/2022] [Revised: 08/28/2022] [Accepted: 10/18/2022] [Indexed: 12/27/2022]
Abstract
Stroke is a life-threatening disease and one of the leading causes of death and physical disability worldwide. Currently, no drugs on the market promote neural recovery after stroke insult, and spontaneous remodeling processes are limited to induce recovery in the ischemic regions. Therefore, promoting a cell-based therapy has been needed to elevate the endogenous recovery process. Mesenchymal stem cells (MSCs) have been regarded as candidate cell sources for therapeutic purposes of ischemic stroke, and their therapeutic effects are mediated by exosomes. The microRNA cargo in these extracellular vesicles is mostly responsible for the positive effects. When it comes to the therapeutic viewpoint, MSCsderived exosomes could be a promising therapeutic strategy against ischemic stroke. The aim of this review is to discuss the current knowledge around the potential of MSCs-derived exosomes in the treatment of ischemic stroke.
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Affiliation(s)
- Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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7
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Asserson DB. Allogeneic Mesenchymal Stem Cells After In Vivo Transplantation: A Review. Cell Reprogram 2023; 25:264-276. [PMID: 37971885 DOI: 10.1089/cell.2023.0084] [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] [Indexed: 11/19/2023] Open
Abstract
Autologous mesenchymal stem cells (MSCs) are ideal for tissue regeneration because of their ability to circumvent host rejection, but their procurement and processing present logistical and time-sensitive challenges. Allogeneic MSCs provide an alternative cell-based therapy capable of positively affecting all human organ systems, and can be readily available. Extensive research has been conducted in the treatment of autoimmune, degenerative, and inflammatory diseases with such stem cells, and has demonstrated predominantly safe outcomes with minimal complications. Nevertheless, continued clinical trials are necessary to ascertain optimal harvest and transplant techniques.
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Affiliation(s)
- Derek B Asserson
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
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8
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Xu Z, Zhang G, Zhang X, Lei Y, Sun Y, He Y, Yang F, Nan W, Xing X, Li Y, Lin J. Menstrual blood-derived endometrial stem cells inhibit neuroinflammation by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 pathway. Int J Biochem Cell Biol 2023; 157:106386. [PMID: 36754162 DOI: 10.1016/j.biocel.2023.106386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/28/2022] [Accepted: 02/03/2023] [Indexed: 02/09/2023]
Abstract
Neuroinflammation is a common response in various neurological disorders. Mesenchymal stem cell-based treatment has become a promising therapy for neuroinflammation-associated diseases. However, the effects of mesenchymal stem cells are controversial, and the underlying mechanism is incompletely understood. In the present study, menstrual blood-derived endometrial stem cells were intravenously transplanted into a mouse model of neuroinflammation established by peripheral injection of lipopolysaccharide. Microglial cells challenged with lipopolysaccharide were cultured with conditioned medium from endometrial stem cells. The levels of cytokines were detected by enzyme-linked immunosorbent assay. Cell proliferation and death were detected by Cell Counting Kit 8 and flow cytometry, respectively. The expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (Casp1) were evaluated by western blotting. The results showed that intravenous transplantation of endometrial stem cells downregulated proinflammatory factors and upregulated anti-inflammatory factors in the brain of mice with neuroinflammation. Conditioned medium suppressed the inflammatory reaction and hyperactivation of microglial cells and protected microglial cells from cell death induced by lipopolysaccharide in vitro. The expression of TLR4, MyD88, NLRP3 and Casp1 in the brain of mice with neuroinflammation and in lipopolysaccharide-stimulated microglial cells was downregulated by endometrial stem cells and conditioned medium, respectively. These data suggested that menstrual blood-derived endometrial stem cells may suppress neuroinflammatory reactions partially by regulating microglia through the TLR4/MyD88/NLRP3/Casp1 signalling pathway. Our findings may be very useful for the development of an alternative stem cell-based therapy for neuroinflammation-associated disorders.
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Affiliation(s)
- Zhihao Xu
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China.
| | - Guoqing Zhang
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China
| | - Xiaoyue Zhang
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China
| | - Yu Lei
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China
| | - Yuliang Sun
- Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China; School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan, PR China
| | - Ya'nan He
- Zhongyuan Stem Cell Research Institute, Xinxiang 453003, Henan, PR China
| | - Fen Yang
- Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China; School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan, PR China
| | - Wenbin Nan
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China
| | - Xuekun Xing
- College of Public Health, Guilin Medical University, Guilin 541199, Guangxi, PR China
| | - Yonghai Li
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China
| | - Juntang Lin
- School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan, PR China; Stem Cells and Biotherapy Engineering and Technology Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, National Joint Engineering Laboratory of Stem Cells and Biotherapy, Xinxiang 453003, Henan, PR China; School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan, PR China.
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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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10
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Zhou L, Wang J, Huang J, Song X, Wu Y, Chen X, Tan Y, Yang Q. The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments. Front Neurol 2022; 13:1000777. [PMID: 36468067 PMCID: PMC9708730 DOI: 10.3389/fneur.2022.1000777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/03/2022] [Indexed: 09/08/2023] Open
Abstract
Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.
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Affiliation(s)
| | | | | | | | | | | | | | - Qin Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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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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12
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Wang Z, Wang X, Liao Y, Chen G, Xu K. Immune response treated with bone marrow mesenchymal stromal cells after stroke. Front Neurol 2022; 13:991379. [PMID: 36203971 PMCID: PMC9530191 DOI: 10.3389/fneur.2022.991379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Stroke is a leading cause of death and long-term disability worldwide. Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke. However, only a small part of patients could benefit from it. Therefore, finding a new treatment is necessary. Bone marrow mesenchymal stromal cells (BMSCs) provide a novel strategy for stroke patients. Now, many patients take stem cells to treat stroke. However, the researches of the precise inflammatory mechanism of cell replacement treatment are still rare. In this review, we summarize the immune response of BMSCs treated to stroke and may provide a new perspective for stem cell therapy.
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Affiliation(s)
- Zili Wang
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Xudong Wang
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Yidong Liao
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Guangtang Chen
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Kaya Xu
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Medicine, Guizhou Medical University, Guiyang, China
- *Correspondence: Kaya Xu
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13
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You C, Liu J, Qiu R, Xu L, Dai F, Ni Q, Qiu W. MiR-141 Modulates Bone Marrow Mesenchymal Stem Cells (BMSCs) Osteogenic/Adipogenic Differentiation Under Oxidative Stress. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BMSCs Osteogenic differentiation is beneficial to the construction of bone tissue engineering. Oxidative stress can affect BMSCs differentiation. MiR-141 regulates BMSCs proliferation. However, MiR-141’s role in BMSCs osteogenic/adipogenic differentiation under oxidative stress
is unclear. Mice BMSCs were assigned into control group; oxidative stress group; and si-MiR-141 group followed by detecting miR-141 level. After 14 days of osteogenesis or adipogenesis induction, RUNX2, OPN and FABP4 mRNA level was analyzed together with analysis of ROS and SOD content, ALP
activity and TGFβ/smad signaling protein level by Western blot. Under oxidative stress, MiR-141 was significantly upregulated and RUNX2 and OPN level was decreased, along with increased ROS content and FABP4 level, reduced SOD and ALP activity and expression of TGFβ1
and smad2 (P < 0.05). Transfection of MiR-141 siRNA into BMSCs under oxidative stress down-regulated MiR-141, significantly upregulated RUNX2 and OPN, reduced ROS, elevated SOD activity, downregulated FABP4, and increased ALP activity and TGFβ1 and smad2 expression (P
< 0.05). In conclusion, MiR-141 expression is increased in BMSCs under oxidative stress. Down-regulating MiR-141 improves the redox imbalance through TGFβ/smad signaling pathway, promotes osteogenic differentiation of BMSCs and inhibits differentiation to adipocytes.
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Affiliation(s)
- Chuanfei You
- Department of Orthopedics, Peoples Hospital of Siyang County, Suqian, Jiangsu, 223700, China
| | - Jun Liu
- Department of Orthopaedics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210009, China
| | - Ruoyu Qiu
- Department of Rheumatoid Immunity, Nanjing Gulou Hospital Group Suqian People’s Hospital, Suqian, Jiangsu, 223800, China
| | - Leijun Xu
- Department of Orthopedics, Peoples Hospital of Siyang County, Suqian, Jiangsu, 223700, China
| | - Furen Dai
- Department of Orthopedics, Peoples Hospital of Siyang County, Suqian, Jiangsu, 223700, China
| | - Qianzhao Ni
- Department of Orthopedics, Peoples Hospital of Siyang County, Suqian, Jiangsu, 223700, China
| | - Weisheng Qiu
- Department of Orthopedics, Peoples Hospital of Siyang County, Suqian, Jiangsu, 223700, China
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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15
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Zheng J, Mao X, Wang D, Xia S. Preconditioned MSCs Alleviate Cerebral Ischemia-Reperfusion Injury in Rats by Improving the Neurological Function and the Inhibition of Apoptosis. Brain Sci 2022; 12:631. [PMID: 35625017 PMCID: PMC9140028 DOI: 10.3390/brainsci12050631] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have great application prospects in the treatment of ischemic injury. However, their long-time cultivation before transplantation and poor survival after transplantation greatly limit the therapeutic effect and applications. This study aimed to investigate whether MSCs under the ischemic microenvironment could improve their survival and better alleviate cerebral ischemic injury. Firstly, we used ischemic brain tissue to culture MSCs and evaluated the functional changes of MSCs. Then a middle cerebral artery occlusion (MCAO) model was induced in rats, and the pretreated MSCs were injected via the tail vein. The adhesive removal test, rotarod test, modified neurological severity score, and pathological analyses were applied to assess the rats' neurological function. Then the expression of neuron and apoptosis related markers was detected. The results indicated that ischemic brain tissue pretreated MSCs promoted the proliferation and the release of the growth factors of MSCs. Meanwhile, in MCAO model rats, transplantation of pretreated MSCs enhanced the neurogenesis, attenuated behavioral changes, reduced infarct size, and inhibited apoptosis. The expression of B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), NF-L, and NeuN were increased, while BCL2-Associated X (Bax) and Caspase-3 decreased. Our results suggest that MSCs pretreatment with stroke brain tissue could be an effective strategy in treating cerebral ischemic injury.
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Affiliation(s)
- Jin Zheng
- Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China
| | - Xueyu Mao
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
| | - Delong Wang
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
| | - Shiliang Xia
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai 201199, China; (X.M.); (D.W.); (S.X.)
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16
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Yang L, Qian J, Yang B, He Q, Wang J, Weng Q. Challenges and Improvements of Novel Therapies for Ischemic Stroke. Front Pharmacol 2021; 12:721156. [PMID: 34658860 PMCID: PMC8514732 DOI: 10.3389/fphar.2021.721156] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/10/2021] [Indexed: 01/01/2023] Open
Abstract
Stroke is the third most common disease all over the world, which is regarded as a hotspot in medical research because of its high mortality and morbidity. Stroke, especially ischemic stroke, causes severe neural cell death, and no effective therapy is currently available for neuroregeneration after stroke. Although many therapies have been shown to be effective in preclinical studies of ischemic stroke, almost none of them passed clinical trials, and the reasons for most failures have not been well identified. In this review, we focus on several novel methods, such as traditional Chinese medicine, stem cell therapy, and exosomes that have not been used for ischemic stroke till recent decades. We summarize the proposed basic mechanisms underlying these therapies and related clinical results, discussing advantages and current limitations for each therapy emphatically. Based on the limitations such as side effects, narrow therapeutic window, and less accumulation at the injury region, structure transformation and drug combination are subsequently applied, providing a deep understanding to develop effective treatment strategies for ischemic stroke in the near future.
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Affiliation(s)
- Lijun Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jing Qian
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Zhejiang Center for Drug and Cosmetic Evaluation, Hangzhou, China
| | - Bo Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiajia Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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17
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De Paz D, Aviña AE, Cardona E, Lee CM, Lin CH, Lin CH, Wei FC, Wang AYL. The Mandible Ameliorates Facial Allograft Rejection and Is Associated with the Development of Regulatory T Cells and Mixed Chimerism. Int J Mol Sci 2021; 22:11104. [PMID: 34681764 PMCID: PMC8537927 DOI: 10.3390/ijms222011104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/07/2021] [Accepted: 10/11/2021] [Indexed: 11/16/2022] Open
Abstract
Vascularized composite allografts contain various tissue components and possess relative antigenicity, eliciting different degrees of alloimmune responses. To investigate the strategies for achieving facial allograft tolerance, we established a mouse hemiface transplant model, including the skin, muscle, mandible, mucosa, and vessels. However, the immunomodulatory effects of the mandible on facial allografts remain unclear. To understand the effects of the mandible on facial allograft survival, we compared the diversities of different facial allograft-elicited alloimmunity between a facial osteomyocutaneous allograft (OMC), including skin, muscle, oral mucosa, and vessels, and especially the mandible, and a myocutaneous allograft (MC) including the skin, muscle, oral mucosa, and vessels, but not the mandible. The different facial allografts of a BALB/c donor were transplanted into a heterotopic neck defect on fully major histocompatibility complex-mismatched C57BL/6 mice. The allogeneic OMC (Allo-OMC) group exhibited significant prolongation of facial allograft survival compared to the allogeneic MC group, both in the presence and absence of FK506 immunosuppressive drugs. With the use of FK506 monotherapy (2 mg/kg) for 21 days, the allo-OMC group, including the mandible, showed prolongation of facial allograft survival of up to 65 days, whereas the myocutaneous allograft, without the mandible, only survived for 34 days. The Allo-OMC group also displayed decreased lymphocyte infiltration into the facial allograft. Both groups showed similar percentages of B cells, T cells, natural killer cells, macrophages, and dendritic cells in the blood, spleen, and lymph nodes. However, a decrease in pro-inflammatory T helper 1 cells and an increase in anti-inflammatory regulatory T cells were observed in the blood and lymph nodes of the Allo-OMC group. Significantly increased percentages of donor immune cells were also observed in three lymphoid organs of the Allo-OMC group, suggesting mixed chimerism induction. These results indicated that the mandible has the potential to induce anti-inflammatory effects and mixed chimerism for prolonging facial allograft survival. The immunomodulatory understanding of the mandible could contribute to reducing the use of immunosuppressive regimens in clinical face allotransplantation including the mandible.
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Affiliation(s)
- Dante De Paz
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
- Department of Head and Neck Surgery, National Police Hospital, Lima 15072, Peru
| | - Ana Elena Aviña
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Esteban Cardona
- Department of Plastic Surgery, Clínica IPS Universitaria León XIII, University of Antioquia, Medellín 050010, Colombia;
| | - Chin-Ming Lee
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Chia-Hsien Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Cheng-Hung Lin
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
| | - Fu-Chan Wei
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (D.D.P.); (A.E.A.); (C.-H.L.); (F.-C.W.)
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Aline Yen Ling Wang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (C.-M.L.); (C.-H.L.)
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18
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Shi W, Zhao M, Shi G. Effect of Sirtuin1 (Sirt1) on Bone Marrow Mesenchymal Stem Cells (BMSCs) Osteogenesis/Adipogenesis via β-Catenin/The Transcription Factor T Cell Factor 1 (TCF1)/Runt-Related Transcription Factor 2 (RUNX2). J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have self-renewal potential. Sirt1 regulates cell differentiation and apoptosis. However, Sirt1’s effect on BMSCs osteogenic/adipogenic differentiation has not been fully elucidated. SD rats were randomly divided into Osteoporosis (OP)
group and sham operation group. OP rat BMSCs were isolated and assigned into control group, NC group and Sirt1 siRNA group followed by analysis of Sirt1 level by Real-time PCR, cell proliferation by MTT assay, expression of OC, OPN and FABP4 level by real time PCR, and β-Catenin/TCF1/Runx2
protein expression by Western blot. In OP group, Sirt1 expression was significantly increased and BMSCs proliferation was decreased along with reduced OC and OPN mRNA expression, increased FABP4 expression and reduced β-Catenin/TCF1/Runx2 expression compared with sham operation
group (P < 0.05). In Sirt1 siRNA group, Sirt1 expression was significantly reduced, BMSCs proliferation was increased, OC and OPN mRNA expression was increased, FABP4 expression was decreased, and β-Catenin/TCF1/Runx2 expression was increased compared to OP group (P
< 0.05). Sirt1 is increased in osteoporosis. Down-regulating Sirt1 in osteoporotic BMSCs can regulate β-Catenin/TCF1/Runx2 signaling and promote BMSCs osteogenic differentiation and inhibit adipogenic differentiation.
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Affiliation(s)
- Wenji Shi
- Department of Orthopedics, Ningbo First Hospital, Ningbo, Zhejiang, 315010, China
| | - Mingxing Zhao
- Department of Orthopedics, Liangzhu Hospital, Yuhang District, Hangzhou, Zhejiang, 311113, China
| | - Guangxia Shi
- Department of Internal Medicine, Ningbo First Hospital, Ningbo, Zhejiang, 315010, China
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19
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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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20
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Guan Y, Wang R, Li X, Zou H, Yu W, Liang Z, Li L, Chen L, Zhou L, Chen Z. Astrocytes constitute the major TNF-α-producing cell population in the infarct cortex in dMCAO rats receiving intravenous MSC infusion. Biomed Pharmacother 2021; 142:111971. [PMID: 34343893 DOI: 10.1016/j.biopha.2021.111971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/16/2022] Open
Abstract
Recent studies report that inhibiting TNF-α might be a novel therapeutic strategy for managing brain ischemia. Our previous study reported that mesenchymal stem cell (MSC) transplantation could suppress TNF-α level in both serum and brain. However, the cell type(s) that contribute to the production of TNF-α during ischemia following MSC transplantation has not been well studied. In the present study, we found by fluorescent immunohistochemistry, that 7.95 ± 6.17% of TNF-α+ cells co-expressed Iba-1 in the infarct area of dMCAO rats, a majority of which were found to be CD68+ (activated microglia), suggesting that resident microglial population were not the major source of TNF-α expression. 68.49 ± 5.12% of the TNF-α+ cells in the infarct area could be labeled by GFAP, a specific marker for astrocytes, indicating that resident GFAP+ astrocytes might be the major source of TNF-α expression in the infarct area. In addition to the infarct area, the GFAP+/TNF-α+ double-positive astrocytes accounted for 73.68 ± 7.48% of the TNF-α+ cells in striatum and corpus callosum. The infiltrating cells, including monocytes and lymphocytes, were not the main source of TNF-α either. In response to MSC transplantation, the total TNF-α+ cells as well as the percentage of TNF-α-expressing astrocytes were significantly reduced in the infarct area, suggesting that MSC transplantation could suppress the expression of TNF-α by astrocytes. Taken together, the results demonstrated that resident astrocytes, but not microglia, were the major source of TNF-α expression and could be suppressed by MSC infusion.
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Affiliation(s)
- Yunqian Guan
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
| | - Ren Wang
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Xiaobo Li
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Haiqiang Zou
- Department of Neurology, the General Hospital of Guangzhou Military Command, Guangzhou, China
| | - Wenxiu Yu
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Zhaohui Liang
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Lei Li
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, China
| | - Ling Chen
- Department of neurosurgery, PLA General Hospital, Beijing, China
| | - Liping Zhou
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China.
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China.
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21
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Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke. Stem Cells Int 2021; 2021:9923566. [PMID: 34221026 PMCID: PMC8219421 DOI: 10.1155/2021/9923566] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/27/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke (IS) is a serious cerebrovascular disease with high morbidity and disability worldwide. Despite the great efforts that have been made, the prognosis of patients with IS remains unsatisfactory. Notably, recent studies indicated that mesenchymal stem cell (MSCs) therapy is becoming a novel research hotspot with large potential in treating multiple human diseases including IS. The current article is aimed at reviewing the progress of MSC treatment on IS. The mechanism of MSCs in the treatment of IS involved with immune regulation, neuroprotection, angiogenesis, and neural circuit reconstruction. In addition, nutritional cytokines, mitochondria, and extracellular vesicles (EVs) may be the main mediators of the therapeutic effect of MSCs. Transplantation of MSCs-derived EVs (MSCs-EVs) affords a better neuroprotective against IS when compared with transplantation of MSCs alone. MSC therapy can prolong the treatment time window of ischemic stroke, and early administration within 7 days after stroke may be the best treatment opportunity. The deliver routine consists of intraventricular, intravascular, intranasal, and intraperitoneal. Furthermore, several methods such as hypoxic preconditioning and gene technology could increase the homing and survival ability of MSCs after transplantation. In addition, MSCs combined with some drugs or physical therapy measures also show better neurological improvement. These data supported the notion that MSC therapy might be a promising therapeutic strategy for IS. And the application of new technology will promote MSC therapy of IS.
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von Linstow CU, Hindkjær SM, Nielsen PV, Degn M, Lambertsen KL, Finsen B, Clausen BH. Bone Marrow-Derived IL-1Ra Increases TNF Levels Poststroke. Cells 2021; 10:956. [PMID: 33924148 PMCID: PMC8074385 DOI: 10.3390/cells10040956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/09/2021] [Accepted: 04/15/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist (IL-1Ra) are key players in stroke, a disease in which cell-based therapies have shown great potential. Having shown an infarct-reducing effect of bone marrow (BM) cells, especially cells with high IL-1Ra expression, we here investigated the effect of BM cells on TNF and other stroke-related mediators in mice after transient middle cerebral artery occlusion (tMCAo) and in vitro using adult microglial cultures. We analyzed stroke-related genes and inflammatory mediators using qPCR stroke Tier panels, electrochemiluminescence, or enzyme-linked immunosorbent assays. We found a significant correlation and cellular colocalization between microglial-derived TNF and IL-1Ra, though IL-1Ra production was TNF independent. BM treatment significantly increased TNF, interleukin (IL)-10, and IL-4 levels, while C-X-C motif ligand 1 (CXCL1), IL-12p70, and Toll-like receptor 2 (TLR2) decreased, suggesting that BM treatment favors an anti-inflammatory environment. Hierarchical clustering identified Tnf and IL-1rn within the same gene cluster, and subsequent STRING analysis identified TLR2 as a shared receptor. Although IL-1Ra producing BM cells specifically modulated TNF levels, this was TLR2 independent. These results demonstrate BM cells as modulators of poststroke inflammation with beneficial effects on poststroke outcomes and place TNF and IL-1Ra as key players of the defense response after tMCAo.
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Affiliation(s)
- Christian Ulrich von Linstow
- Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA;
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
| | - Sofie Mozart Hindkjær
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
| | - Pernille Vinther Nielsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
| | - Matilda Degn
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, 2100 Copenhagen, Denmark;
| | - Kate Lykke Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
- Department of Neurology, Odense University Hospital, 5000 Odense, Denmark
- BRIDGE—Brain Research—Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Bente Finsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
- BRIDGE—Brain Research—Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Bettina Hjelm Clausen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.M.H.); (P.V.N.); (K.L.L.); (B.F.)
- BRIDGE—Brain Research—Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
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Zhang XL, Zhang XG, Huang YR, Zheng YY, Ying PJ, Zhang XJ, Lu X, Wang YJ, Zheng GQ. Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review. Front Cell Neurosci 2021; 15:628908. [PMID: 33935650 PMCID: PMC8079818 DOI: 10.3389/fncel.2021.628908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/24/2021] [Indexed: 12/21/2022] Open
Abstract
Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, −3.37; 95% confidence interval, −3.83 to −2.90) and infarct volume (effect size, −11.37; 95% confidence interval, −12.89 to −9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.
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Affiliation(s)
- Xi-Le Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Guang Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan-Ran Huang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan-Yan Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peng-Jie Ying
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Jie Zhang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao Lu
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi-Jing Wang
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guo-Qing Zheng
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Zhang H, Tian Y, Shi X, Yuan W, Liu L, Yang Y. Effect of Liver Kinase B1 on Osteogenic/Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in High Glucose Environment. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) present reduced proliferation under high glucose condition. Liver kinase B1 (LKB1) can maintain the homeostasis of hematopoietic stem cells. However, whether LKB1 regulates BMSCs osteogenic/adipogenic differentiation under high glucose is unclear.
Rat BMSCs were isolated and separated into control group, high glucose group, and LKB1 group (BMSCs were transfected with pc-DNA 3.1-LKB1 plasmid under high glucose condition) followed by analysis of LKB1 expression by Real time PCR and Western blot, osteocalcin, type I collagen, RUNX2 and
OPN mRNA level by real-time PCR, FABP4 and PPARγ2 level by western blot. In high glucose group, LKB1 expression was significantly decreased, with reduced expression of osteocalcin, type I collagen, RUNX2 and OPN mRNA and elevated FABP4 and PPARγ2 level compared to control group
(P < 0.05). Transfection of LKB1 plasmid reduced LKB1 expression, upregulated osteocalcin, type I collagen, RUNX2 and OPN mRNA and downregulated FABP4 and PPARγ2. Compared with the high glucose group, there was a statistical difference (P <0.05). High glucose can
inhibit LKB1 expression and BMSCs osteogenic differentiation, and promote adipogenic differentiation. Upregulating LKB1 expression can promote BMSCs osteogenic differentiation.
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Affiliation(s)
- Hao Zhang
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
| | - Yuan Tian
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
| | - Xiaolin Shi
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
| | - Weidong Yuan
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
| | - Lei Liu
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
| | - Yongming Yang
- Department of Orthopedics Department One, The No. 2 Hospital of Baoding, Baoding City, Hebei Province, 071051, China
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Song W, Wang J, Zhang Y, Ma T, Wang K. Effect of Substance P on Differentiation of Bone Marrow Stromal Stem Cells Under Oxidative Stress. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone marrow stromal stem cells (BMSCs) can be used to treat bone defects but BMSCs are damaged under oxidative stress. The neuropeptide substance P (SP) involves various cellular activities. However, SP’s role in BMSCs differentiation under oxidative stress is unknown. Rat BMSCs
were isolated and assigned into control group; oxidative stress group treated with 200 μM H2O2; and SP group, in which 10 mM SP was added under oxidative stress followed by analysis of SP secretion by ELISA, cell proliferation by MTT method, Caspase3 activity, Bax
and Bcl-2 level by Real time PCR, ALP activity ROS and SOD content as well as NF-κB level by Western blot. Under oxidative stress, SP secretion was significantly decreased, BMSCs proliferation was inhibited, Caspase3 activity and Bax expression increased, Bcl-2 and ALP activity was decreased
along with increased ROS activity and NF-κB level and reduced SOD activity (P <0.05), adding SP to BMSCs under oxidative stress can significantly promote SP secretion and cell proliferation, reduce Caspase3 activity and Bax expression, increase Bcl-2 expression and ALP activity,
decreased ROS activity and NF-κB level, and elevated SOD activity (P <0.05). SP secretion from BMSCs cells was reduced under oxidative stress. Up-regulation of SP in BMSCs cells under oxidative stress can inhibit BMSCs apoptosis and promote cell proliferation and osteogenesis
by regulating NF-κB.
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Affiliation(s)
- Wei Song
- First Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, 710004, China
| | - Jun Wang
- Department of Joint Surgery, Hong-Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, Shanxi, 710054, China
| | - Yumin Zhang
- Department of Joint Surgery, Hong-Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, Shanxi, 710054, China
| | - Tao Ma
- Department of Joint Surgery, Hong-Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, Shanxi, 710054, China
| | - Kunzheng Wang
- First Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, 710004, China
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26
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Zhang C, Wang Y, Sun K, Yu D, Tian S. Effects of Melatonin on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Inflammatory Environment by Regulating Mammalian Target of Rapamycin/Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Human bone marrow mesenchymal stem cells (BMSCs) differentiation into special cell types is affected by inflammation. Melatonin has various effects such as anti-oxidation and immune regulation. However, melatonin’s effect on BMSCs osteogenic differentiation during inflammation
has not been elucidated. Rat BMSCs were isolated and assigned into control group, inflammation group (1 μg/ml lipopolysaccharide, LPS) and melatonin group (100 μM melatonin was added to LPSstimulated BMSCs cells) followed by analysis of BMSCs proliferation by MTT assay, Caspase 3 and
ALP activity, expression of Runx2 and OP by Real time PCR, ROS content and SOD activity, TNF-α and IL-1β secretion by ELISA and mTOR/PI3K/AKT signaling protein level by Western blot. LPS action on BMSCs significantly inhibits BMSCs proliferation, promotes Caspase 3 activity, inhibits
ALP activity, decreases Runx2 and OP expression and SOD activity, increases ROS content and TNF-α and IL-1β secretion as well as reduced mTOR and p-PI3K level (P <0.05). Melatonin addition significantly reversed the above changes (P <0.05). Melatonin can regulate oxidative
stress, inhibit inflammation, and promote BMSCs proliferation and osteogenic differentiation in inflammatory environment by activating mTOR/PI3K/AKT signaling pathway.
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Affiliation(s)
- Chi Zhang
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266555, China
| | - Yuanhe Wang
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266555, China
| | - Kang Sun
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266555, China
| | - Dingzhu Yu
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266555, China
| | - Shaoqi Tian
- Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266555, China
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Spellicy SE, Hess DC. The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment. Front Cell Dev Biol 2021; 9:647415. [PMID: 33796535 PMCID: PMC8007866 DOI: 10.3389/fcell.2021.647415] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/25/2021] [Indexed: 11/13/2022] Open
Abstract
Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.
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Affiliation(s)
- Samantha E Spellicy
- MD-Ph.D. Program, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David C Hess
- Dean's Office, Medical College of Georgia at Augusta University, Augusta, GA, United States
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28
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Additive Behavioral Improvement after Combined Cell Therapy and Rehabilitation Despite Long-Term Microglia Presence in Stroke Rats. Int J Mol Sci 2021; 22:ijms22041512. [PMID: 33546370 PMCID: PMC7913568 DOI: 10.3390/ijms22041512] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 12/17/2022] Open
Abstract
Microglia are involved in the post-stroke immunomodulation of brain plasticity, repair, and reorganization. Here, we evaluated whether adipose-tissue-derived mesenchymal stem cells (ADMSCs) and/or rehabilitation improve behavioral recovery by modulating long-term perilesional inflammation and creating a recovery-permissive environment in a rat model of ischemic stroke. Methods: A two-way mixed lymphocyte reaction was used to assess the immunomodulatory capacity of ADMSCs in vitro. Two or 7 days after permanent middle cerebral artery occlusion (pMCAO), rats were intravenously administered ADMSCs or vehicle and housed in a standard or enriched environment (EE). Behavioral performance was assessed with a cylinder test, then we performed stereological and ImageJ/Fiji quantifications of ionized calcium-binding adaptor molecule 1 (Iba1) cells and blood–brain barrier (BBB) leakage. Results: Human ADMSCs were immunosuppressive in vitro. The cylinder test showed partial spontaneous behavioral recovery of pMCAO rats, which was further improved by combined ADMSCs and housing in EE on days 21 and 42 (p < 0.05). We detected an ischemia-induced increase in numbers, staining intensity, and branch length of Iba1+ microglia/macrophages as well as BBB leakage in the perilesional cortex. However, these were not different among pMCAO groups. Conclusion: Combined cell therapy and rehabilitation additively improved behavioral outcome despite long-term perilesional microglia presence in stroke rats.
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Chen L, Hu J, Zhou B, Li Y, Wei K, Wang J, Lv H, Zeng F. Effect of Integrin-Linked Kinase on Osteogenesis of Bone Marrow Mesenchymal Stem Cells in Inflammatory Environment via Regulating Mitogen Activated Protein Kinase/Protein Kinase B Signaling Pathway. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Osteoarthritis (OA) pathogenesis involves inflammation, age, weight and other factors. Integrin-linked kinase (ILK) regulates cell apoptosis, metastasis, and growth. However, whether ILK affects bone formation of bone marrow mesenchymal stem cells in an inflammatory environment has
not been elucidated. Rat BMSCs were isolated and assigned into control group, inflammation group (lipopolysaccharide was added to cells); and si-ILK group (ILK siRNA was transfected into the inflammation group BMSCs) followed by analysis of cell proliferation by MTT assay, expression of ILK,
Runx2 and OP by real time PCR, ALp activity, TNF-α and IL-6 secretion by ELISA and MAPK/AKT signaling protein expression by western blot. Compared to control, ILK in BMSCs cells in inflammatory environment was significantly upregulated, resulting in inhibition of cell proliferation,
decreased ALP activity, reduced expression of osteogenic genes Runx2 and OP, increased secretion of TNF-α and IL-6, and downregulated p-AKT (P < 0.05); transfection of ILK siRNA down-regulated ILK in inflammatory environment BMSCs, which significantly increased BMSCs
cell proliferation, increased ALP activity and expression of Runx2 and OP, decreased TNF-α and IL-6 secretion and increased p-AKT expression (P < 0.05). ILK expression is increased in BMSCs in an inflammatory environment. Down-regulation of ILK in BMSCs cells in an inflammatory
environment can regulate MAPK/AKT signaling, inhibit inflammatory factors secretion, thereby promoting BMSCs proliferation and osteogenesis differentiation.
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Affiliation(s)
- Liyuan Chen
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Jieliang Hu
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Baojun Zhou
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Yan Li
- Department of Electrophysiology, People’s Hospital of Xingguo County, Ganzhou, Jiangxi, 342400, China
| | - Kongxing Wei
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Jinglei Wang
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Hongyan Lv
- Second Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine (First People’s Hospital of Baiyin City), Baiyin, Gansu, 730900, China
| | - Fanyun Zeng
- Emergency Traumatic Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou People’s Hospital), Ganzhou, Jiangxi, 341000, China
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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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Liang ZH, Gu JJ, Yu WX, Guan YQ, Khater M, Li XB. Bone marrow mesenchymal stem cell transplantation downregulates plasma level and the microglia expression of transforming growth factor β1 in the acute phase of cerebral cortex ischemia. Chronic Dis Transl Med 2020; 6:270-280. [PMID: 33336172 PMCID: PMC7729118 DOI: 10.1016/j.cdtm.2020.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Indexed: 11/30/2022] Open
Abstract
Background Both bone marrow mesenchymal stem cell (BM-MSC) and transforming growth factor-β1 (TGF-β1) have a strong anti-inflammatory capacity in stroke. But their relationship has not been well addressed. In this study, we investigated how intravenous BM-MSC transplantation in rats effected the expression of TGF-β1 48 h post cerebral ischemia, and we analyzed the main cells that produce TGF-β1. Methods We used a distal middle cerebral artery occlusion (dMCAO) model in twenty Sprague–Dawley (SD) rats. The rats were randomly divided into two groups: the ischemic control group and the postischemic BM-MSC transplantation group. One hour after the dMCAO model was established, the rats were injected in the tail vein with either 1 ml saline or 1 × 106 BM-MSCs suspended in 1 ml saline. ELISAs were used to detect TGF-β1 content in the brain infarct core area, striatum and the plasma at 48 h after cerebral infarction. Immunofluorescent staining of brain tissue sections for TGF-β1, Iba-1, CD68 and NeuN was performed to determine the number and the proportion of double stained cells and to detect possible TGF-β1 producing cells in the brain tissue. Results Forty-eight hours after ischemia, the TGF-β1 content in the infarcted area of the BM-MSC transplantation group (23.94 ± 4.48 pg/ml) was significantly lower than it was in the ischemic control group (34.18 ± 4.32 pg/ml) (F = 13.534, P = 0.006). The TGF-β1 content in the rat plasma in the BM-MSC transplantation group (75.91 ± 12.53 pg/ml) was significantly lower than it was in the ischemic control group (131.18 ± 16.07 pg/ml) (F = 36.779, P = 0.0002), suggesting that after transplantation of BM-MSCs, TGF-β1 levels in the plasma decreased, but there was no significant change in the striatum area. Immunofluorescence staining showed that the total number of nucleated cells (1037.67 ± 222.16 cells/mm2) in the infarcted area after transplantation was significantly higher than that in the ischemic control group (391.67 ± 69.50 cells/mm2) (F = 92.421, P < 0.01); the number of TGF-β1+ cells after transplantation (35.00 ± 13.66 cells/mm2) was significantly reduced in comparison to that in the ischemic control group (72.33 ± 32.08 cells/mm2) (F = 37.680, P < 0.01). The number of TGF-β1+/Iba-1+ microglia cells in the transplantation group (3.67 ± 3.17 cells/mm2) was significantly reduced in comparison to that of the ischemic control group (13.67 ± 5.52 cells/mm2) (F = 29.641, P < 0.01). The proportion of TGF-β1+/Iba-1+ microglia cells out of all Iba-1+ microglia cells after transplantation (4.38 ± 3.18%) was significantly decreased compared with that in the ischemic control group (12.81 ± 4.86%) (F = 28.125, P < 0.01). Conclusions Iba-1+ microglia is one of the main cell types that express TGF-β1. Intravenous transplantation of BM-MSCs does not cooperate with TGF-β1+ cells in immune-regulation, but reduces the TGF-β1 content in the infarcted area and in the plasma at 48 h after cerebral infarction.
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Affiliation(s)
- Zhao-Hui Liang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.,Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Jian-Juan Gu
- Department of Obstetrics and Gynecology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Wen-Xiu Yu
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Yun-Qian Guan
- Department of Cell Biology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Mostafa Khater
- Pharmacology and Toxicology Department, Augusta University, Georgia 30912, USA
| | - Xiao-Bo Li
- Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, Jiangsu 225001, China
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Ramdan M, Bigdeli MR, Khaksar S, Aliaghaei A. Evaluating the effect of transplanting umbilical cord matrix stem cells on ischemic tolerance in an animal model of stroke. Neurol Res 2020; 43:225-238. [PMID: 33167823 DOI: 10.1080/01616412.2020.1839698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Stroke, a cerebrovascular disease, has been introduced as the second cause of death and physical disability in the world. Recently, cell-based therapy has been considered by the scientific community as a promising strategy for reducing ischemic damages. The stem cells of the umbilical cord release growth and neurotrophic factors. The remarkable properties of these cells are the reason why they were selected as a potential candidate in the present research. METHODS In this study, the impact of transplanting umbilical cord stem cells on injuries resulting from ischemia was investigated. The male rats were categorized into three major. Using stereotaxic surgery, stem cells were injected to the right striatum of the brain. One week after transplantation, cerebral ischemic induction surgery was performed. The rats in the transplantation + ischemia group were separately divided into distinct sub-groups to explore the score of the neurological deficits, infarction volume, integrity of the blood-brain barrier, and brain edema. RESULTS In this study, a significant decrease was observed in the neurological deficits of the transplantation + ischemia group compared with those of the control group. Similarly, the volume of infarction, the permeability of the blood-brain barrier, and edema were significantly reduced in the transplantation + ischemia group in comparison with those of the control group. CONCLUSION The pretreatment of the transplanted umbilical cord stem cells in the striatum of ischemic rats possibly leads to restorative events, exerting a decreasing effect on cell death. Subsequently, these events may improve the motor ability and reduce ischemic injuries.
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Affiliation(s)
- Mahmoud Ramdan
- Department of Animal Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University , Tehran, Iran
| | - Mohammad Reza Bigdeli
- Department of Animal Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University , Tehran, Iran.,Inistitute for Cognitive and Brain Science, Shahid Beheshti University , Tehran, Iran
| | - Sepideh Khaksar
- Department of Plant Sciences, Biological Sciences, Alzahra University , Tehran, Iran
| | - Abbas Aliaghaei
- Anatomy Department, Shahid Beheshti University of Medical Sciences , Tehran, Iran
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Lu M, Guo J, Wu B, Zhou Y, Wu M, Farzaneh M, Khoshnam SE. Mesenchymal Stem Cell-Mediated Mitochondrial Transfer: a Therapeutic Approach for Ischemic Stroke. Transl Stroke Res 2020; 12:212-229. [PMID: 32975692 DOI: 10.1007/s12975-020-00853-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 12/17/2022]
Abstract
Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction is one of the hallmarks of stroke-induced neuronal death, and maintaining mitochondrial function is essential in cell survival and neurological progress following ischemic stroke. Stem cell-mediated mitochondrial transfer represents an emerging therapeutic approach for ischemic stroke. Accumulating evidence suggests that mesenchymal stem cells (MSCs) can directly transfer healthy mitochondria to damaged cells, and rescue mitochondrial damage-provoked tissue degeneration. This review summarizes the research on MSCs-mediated mitochondrial transfer as a therapeutic strategy against ischemic stroke.
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Affiliation(s)
- Meng Lu
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.,Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Jindong Guo
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Bowen Wu
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Biochemistry, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Yuhui Zhou
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, China.,Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China.,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China
| | - Mishan Wu
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang, 050091, China. .,Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
| | - Maryam Farzaneh
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Peripheral Circulation and Astrocytes Contribute to the MSC-Mediated Increase in IGF-1 Levels in the Infarct Cortex in a dMCAO Rat Model. Stem Cells Int 2020; 2020:8853444. [PMID: 32952570 PMCID: PMC7481998 DOI: 10.1155/2020/8853444] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/31/2020] [Accepted: 08/10/2020] [Indexed: 02/01/2023] Open
Abstract
Materials and Methods Ischemic brain injury was induced by dMCAO in Sprague-Dawley rats. The transplantation group received MSC infusion 1 h after dMCAO. Expression of IGF-1 in GFAP+ astrocytes, Iba-1+ microglia/macrophages, CD3+ lymphocytes, Ly6C+ monocytes/macrophages, and neutrophil elastase (NE)+ neutrophils was examined to determine the contribution of these cells to the increase of IGF-1. ELISA was performed to examine IGF-1 levels in blood plasma at days 2, 4, and 7 after ischemia onset. Results In total, only 5-6% of Iba-1+ microglia were colabeled with IGF-1 in the infarct cortex, corpus callosum, and striatum at day 2 post-dMCAO. MSC transplantation did not lead to a higher proportion of Iba-1+ cells that coexpressed IGF-1. In the infarct cortex, all Iba-1+/IGF-1+ double-positive cells were also positive for CD68. In the infarct, corpus callosum, and striatum, the majority (50-80%) of GFAP+ cells were colabeled with ramified IGF-1 signals. The number of GFAP+/IGF-1+ cells was further increased following MSC treatment. In the infarct cortex, approximately 15% of IGF-1+ cells were double-positive for CD3. MSC treatment reduced the number of infiltrated CD3+/IGF-1+ cells by 70%. In the infarct, few Ly6C+ monocytes/macrophages or NE+ neutrophils expressed IGF-1, and MSC treatment did not induce a higher percentage of these cells that coexpressed IGF-1. The IGF-1 level in peripheral blood plasma was significantly higher in the MSC group than in the ischemia control group. Conclusion The MSC-mediated increase in IGF-1 levels in the infarct cortex mainly derives from two sources, astrocytes in brain and blood plasma in periphery. Manipulating the IGF-1 level in the peripheral circulation may lead to a higher level of IGF-1 in brain, which could be conducive to recovery at the early stage of dMCAO.
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Mesenchymal stem cell therapy for ischemic stroke: A look into treatment mechanism and therapeutic potential. J Neurol 2020; 268:4095-4107. [DOI: 10.1007/s00415-020-10138-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022]
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Wen RX, Shen H, Huang SX, Wang LP, Li ZW, Peng P, Mamtilahun M, Tang YH, Shen FX, Tian HL, Yang GY, Zhang ZJ. P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis. CNS Neurosci Ther 2020; 26:416-429. [PMID: 32154670 PMCID: PMC7080436 DOI: 10.1111/cns.13296] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/01/2020] [Accepted: 02/01/2020] [Indexed: 02/06/2023] Open
Abstract
Introduction Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. Aim To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. Results The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis. Conclusion Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.
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Affiliation(s)
- Ruo-Xue Wen
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Shen
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Shu-Xian Huang
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Li-Ping Wang
- Department of Neurology, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zong-Wei Li
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Peng Peng
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Muyassar Mamtilahun
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yao-Hui Tang
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Fan-Xia Shen
- Department of Neurology, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Heng-Li Tian
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Yuan Yang
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Department of Neurology, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Jun Zhang
- Shanghai JiaoTong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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Lin QM, Tang XH, Lin SR, Chen BD, Chen F. Bone marrow-derived mesenchymal stem cell transplantation attenuates overexpression of inflammatory mediators in rat brain after cardiopulmonary resuscitation. Neural Regen Res 2020; 15:324-331. [PMID: 31552906 PMCID: PMC6905325 DOI: 10.4103/1673-5374.265563] [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] [Indexed: 12/30/2022] Open
Abstract
Emerging evidence suggests that bone marrow-derived mesenchymal stem cell transplantation improves neurological function after cardiac arrest and cardiopulmonary resuscitation; however, the precise mechanisms remain unclear. This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cell treatment on expression profiles of multiple cytokines in the brain after cardiac arrest and cardiopulmonary resuscitation. Cardiac arrest was induced in rats by asphyxia and cardiopulmonary resuscitation was initiated 6 minutes after cardiac arrest. One hour after successful cardiopulmonary resuscitation, rats were injected with either phosphate-buffered saline (control) or 1 × 106 bone marrow-derived mesenchymal stem cells via the tail vein. Serum S100B levels were measured by enzyme-linked immunosorbent assay and neurological deficit scores were evaluated to assess brain damage at 3 days after cardiopulmonary resuscitation. Serum S100B levels were remarkably decreased and neurological deficit scores were obviously improved in the mesenchymal stem cell group compared with the phosphate-buffered saline group. Brains were isolated from the rats and expression levels of 90 proteins were determined using a RayBio Rat Antibody Array, to investigate the cytokine profiles. Brain levels of the inflammatory mediators tumor necrosis factor-α, interferon-γ, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, macrophage inflammatory protein-3α, macrophage-derived chemokine, and matrix metalloproteinase-2 were decreased ≥ 1.5-fold, while levels of the anti-inflammatory factor interleukin-10 were increased ≥ 1.5-fold in the mesenchymal stem cell group compared with the control group. Donor mesenchymal stem cells were detected by immunofluorescence to determine their distribution in the damaged brain, and were primarily observed in the cerebral cortex. These results indicate that bone marrow-derived mesenchymal stem cell transplantation attenuates brain damage induced by cardiac arrest and cardiopulmonary resuscitation, possibly via regulation of inflammatory mediators. This experimental protocol was approved by the Institutional Animal Care and Use Committee of Fujian Medical University, China in January 2016 (approval No. 2016079).
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Affiliation(s)
- Qing-Ming Lin
- Institute of Fujian Emergency Medicine, Clinical College of Fujian Medical University; Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Emergency Center, Fuzhou, Fujian Province, China
| | - Xia-Hong Tang
- Institute of Fujian Emergency Medicine, Clinical College of Fujian Medical University; Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Emergency Center, Fuzhou, Fujian Province, China
| | - Shi-Rong Lin
- Institute of Fujian Emergency Medicine, Clinical College of Fujian Medical University; Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Emergency Center, Fuzhou, Fujian Province, China
| | - Ben-Dun Chen
- Institute of Fujian Emergency Medicine, Clinical College of Fujian Medical University; Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Emergency Center, Fuzhou, Fujian Province, China
| | - Feng Chen
- Institute of Fujian Emergency Medicine, Clinical College of Fujian Medical University; Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Emergency Center, Fuzhou, Fujian Province, China
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Corey S, Abraham DI, Kaneko Y, Lee JY, Borlongan CV. Selective endovascular cooling for stroke entails brain-derived neurotrophic factor and splenic IL-10 modulation. Brain Res 2019; 1722:146380. [PMID: 31415765 DOI: 10.1016/j.brainres.2019.146380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/08/2019] [Accepted: 08/12/2019] [Indexed: 12/27/2022]
Abstract
Stroke poses a serious health and economic burden, and the lack of treatment options necessitates a viable therapy. Hypothermia represents a promising stroke therapy, yet side effects of full-body cooling, such as pneumonia, limit its clinical application. Selective endovascular cooling (SEC), via infusion of cold saline through the intraarterial artery, represents an attractive alternative by locally cooling the brain while preserving body temperature. However, the mechanisms underlying SEC are poorly understood. Brain-derived neurotrophic factor (BDNF) is a widely recognized promotor of neuroplasticity and biomarker of stroke outcomes, as well as its association with inflammation, such as IL-10. Stroke-induced neuroinflammation exacerbates damage and stems from peripheral organs, namely the spleen. The spleen has emerged as a therapeutic target for stroke, yet the effect of SEC on the splenic inflammatory response is unknown. Here, we aimed to elucidate the local and peripheral mechanisms driving SEC as a neuroprotective stroke therapy by examining brain BDNF and splenic IL-10 expression. Animals that received SEC prior to stroke displayed elevated brain BDNF expression ipsilaterally and contralaterally across the cortex, striatum, and hippocampus. SEC also upregulated splenic IL-10, suggesting alteration of the peripheral inflammatory response. The oxygen-glucose deprivation in vitro model of stroke further demonstrated that "cold" rat splenocytes protected rat primary neurons by upregulating BDNF and IL-10. Altogether these data support BDNF- and IL-10-based mechanisms underlying the neuroprotective potential of SEC therapy for stroke, and further advance the concept of exploiting the pathological link between brain and spleen as therapeutic targets.
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Affiliation(s)
- Sydney Corey
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA
| | - Diego Incontri Abraham
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA
| | - Yuji Kaneko
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA
| | - Jea-Young Lee
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA
| | - Cesar V Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.
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Yang X, Zhang S, Huang D, Wang Z, Chen X, Luo X, Lei M, Yu F, Chen X, Huang P. Treatment of refractory secondary hemophagocytic lymphohistiocytosis with umbilical cord mesenchymal stem cells. J Int Med Res 2019; 47:2135-2144. [PMID: 30961409 PMCID: PMC6567783 DOI: 10.1177/0300060519836533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. Mesenchymal stem cells (MSCs) generate an immunosuppressive microenvironment by secreting cytokines and have been used to treat autoimmune diseases. We report the first case of refractory secondary HLH treated with umbilical cord MSCs. A 52-year-old Chinese female patient with a history of type 2 diabetes was diagnosed with refractory secondary HLH based upon the HLH-2004 protocol and was treated by infusion of third-party umbilical cord MSCs (1.4 × 106 cells/kg of body weight, 70 × 106 cells in total) from the stem cell bank of Hainan Province. Body temperature recovered to normal on the sixth day after infusion with umbilical cord MSCs, and the levels of inflammatory factors macrophage inflammatory protein (MIP)-1α, interleukin (IL)-12p70, stromal cell-derived factor (SDF)-1α, and IL-7 decreased significantly. Blood glucose levels were significantly lower than before treatment, and the amount of insulin needed was significantly reduced. Umbilical cord MSCs can relieve the symptoms of refractory secondary HLH and have a therapeutic effect on insulin resistance in type 2 diabetes mellitus.
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Affiliation(s)
- Xiaoyang Yang
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Shufang Zhang
- 2 Central Laboratory, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Denggao Huang
- 2 Central Laboratory, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Zhiming Wang
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Xiaoxia Chen
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Xiansheng Luo
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Meiqing Lei
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Feng Yu
- 1 Department of Hematology, Affiliated Haikou Hospital Xiangya School Central South University & Haikou Municipal People's Hospital, Haikou, PR China
| | - Xiaobo Chen
- 3 Stem cell bank of Hainan Province & Hainan Heze Biotechnology Co., Ltd., Haikou, PR China
| | - Peilong Huang
- 3 Stem cell bank of Hainan Province & Hainan Heze Biotechnology Co., Ltd., Haikou, PR China
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Tatebayashi K, Takagi T, Fujita M, Doe N, Nakagomi T, Matsuyama T, Yoshimura S. Adipose-derived stem cell therapy inhibits the deterioration of cerebral infarction by altering macrophage kinetics. Brain Res 2019; 1712:139-150. [PMID: 30721668 DOI: 10.1016/j.brainres.2019.01.037] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/27/2019] [Accepted: 01/29/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION We previously established a method to isolate and culture human adipose-derived stem cells (hADSCs) using fetal bovine serum and showed the therapeutic impact on cerebral infarction. Recently, we modified the culture method with the use of serum-free media for future clinical applications. This study aims to evaluate whether intravenous administration of hADSCs induced by the serum-free culture method would improve neurobehavioral deficits in mice with cerebral infarction. RESULTS Induced hADSCs possessed the characteristics of mesenchymal stem cells and withstood a freeze-thaw process. hADSC administration improved neurobehavioral deficits in MCAO-treated mice and suppressed brain atrophy at the chronic phase. Although hADSC administration did not affect serum cytokine profiles, it decreased the number of CD11b+ monocytes in the spleen. Concomitantly, hADSC administration increased the local accumulation of CD11b+CD163+ M2 macrophages into the border zone of the cerebral infarction at 4 days post-MCAO (the acute phase). DISCUSSION Our data indicate that the systemic administration of hADSCs can improve the neurobehavioral deficits that occur after cerebral infarction by modulating the acute immune response mediated by CD11b+CD163+ M2 macrophages in infarcted lesions.
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Affiliation(s)
- Kotaro Tatebayashi
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Toshinori Takagi
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Mitsugu Fujita
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Department of Microbiology, Kindai University, Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
| | - Nobutaka Doe
- Laboratory of Neurogenesis and CNS Repair, Hyōgo College of Medicine, Nishinomiya, Hyogo, Japan; General Education Center, Hyogo University of Health Sciences, Kobe, Hyogo, Japan
| | - Takayuki Nakagomi
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tomohiro Matsuyama
- Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Shinichi Yoshimura
- Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
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