|
1
|
Umrath F, Wendt V, Gasparoni G, Narknava Y, Walter J, Lethaus B, Weber J, Carriel V, Avci-Adali M, Alexander D. Revitalizing the Epigenome of Adult Jaw Periosteal Cells: Enhancing Diversity in iPSC-Derived Mesenchymal Stem Cells (iMSCs). Cells 2025; 14:627. [PMID: 40358151 PMCID: PMC12071994 DOI: 10.3390/cells14090627] [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: 02/21/2025] [Revised: 04/11/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells (iMSCs). Using an optimized protocol, we generated iMSCs with a remarkable osteogenic potential while exhibiting lower expression levels of the senescence markers p16 and p21 compared to the original JPCs. This study aimed to explore the epigenetic landscape by comparing the DNA methylation and transcription profiles of iMSCs with their JPC precursors, seeking to uncover key differences. Additionally, this analysis provided an opportunity for us to investigate the potential rejuvenation effects associated with cellular reprogramming. To assess the safety of the generated cells, we evaluated their ability to form teratomas through subcutaneous injection into immunodeficient mice. Our findings revealed that, while the methylation profile of iMSCs closely mirrored that of JPCs, distinct iMSC-specific methylation patterns were evident. Strikingly, the application of DNA methylation (DNAm) clocks for biological age estimation showed a dramatic reduction in DNAm age to approximately zero in iPSCs-a rejuvenation effect that persisted in the derived iMSCs. This profound reset in biological age, together with our transcriptome data, indicate that iMSCs could possess an enhanced regenerative potential compared to adult MSCs. Future in vivo studies should validate this hypothesis.
Collapse
Affiliation(s)
- Felix Umrath
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (F.U.); (V.W.); (Y.N.); (B.L.)
- Department of Orthopaedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany
| | - Valerie Wendt
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (F.U.); (V.W.); (Y.N.); (B.L.)
| | - Gilles Gasparoni
- Department of Genetics and Epigenetics, Saarland University, 66123 Saarbrücken, Germany; (G.G.); (J.W.)
| | - Yasser Narknava
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (F.U.); (V.W.); (Y.N.); (B.L.)
| | - Jörn Walter
- Department of Genetics and Epigenetics, Saarland University, 66123 Saarbrücken, Germany; (G.G.); (J.W.)
| | - Bernd Lethaus
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (F.U.); (V.W.); (Y.N.); (B.L.)
| | - Josefin Weber
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (J.W.); (M.A.-A.)
| | - Victor Carriel
- Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, 18016 Granada, Spain;
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (J.W.); (M.A.-A.)
| | - Dorothea Alexander
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany; (F.U.); (V.W.); (Y.N.); (B.L.)
| |
Collapse
|
|
2
|
Hoseini SM, Montazeri F. The influence of cell source on the senescence of human mesenchymal stem/stromal cells. Hum Cell 2025; 38:87. [PMID: 40221541 DOI: 10.1007/s13577-025-01213-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.
Collapse
Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, No. 1. Safaeyeh. Bou-Al Ave., Yazd, 8916877391, Iran.
| |
Collapse
|
|
3
|
Ren H, Wang Y, Chen Y, Ma F, Shi Q, Wang Z, Gui Y, Liu J, Tang H. The therapeutic effects of induced pluripotent stem cell-derived mesenchymal stem cells on Parkinson's disease. IUBMB Life 2025; 77:e2936. [PMID: 39740935 DOI: 10.1002/iub.2936] [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: 08/13/2024] [Accepted: 10/12/2024] [Indexed: 01/02/2025]
Abstract
Parkinson's disease (PD), characterized by progressive degeneration of dopaminergic neurons in substantia nigra, has no disease-modifying therapy. Mesenchymal stem cell (MSC) therapy has shown great promise as a disease-modifying solution for PD. Induced pluripotent stem cell-derived MSC (iMSC) not only has stronger neural repair function, but also helps solve the problem of MSC heterogeneity. So we evaluated the therapeutic effects of iMSCs on PD. iMSCs were administered by tail vein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD models of C57BL/6 mice. The results showed iMSCs increased body weights, inhibited the prolongation of latencies to descend in pole tests, the decrease of grip strength in grip strength tests and increase of open arm entries in elevated plus maze test, and showed a trend to alleviate striatal dopamine loss. They indicate iMSCs might improve functions partially by preserving striatal dopamine in PD. We for the first time (1) found that iMSC has therapeutic effects on PD; (2) tested specifically muscle strength in cell therapy for PD and found it increases muscle strength; (3) found cell therapy alleviated the increase of entries into the open arms in PD. It suggests iMSC is a promising candidate for clinical investigations and drug development for PD.
Collapse
Affiliation(s)
- Hao Ren
- College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Yuwei Wang
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Yingying Chen
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Feilong Ma
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Qing Shi
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Zichen Wang
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Yaoting Gui
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| | - Jianbo Liu
- College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Huiru Tang
- Cheerland Watson Precision Medicine Ltd, Shenzhen, China
| |
Collapse
|
|
4
|
Silva Couto P, Stibbs DJ, Rotondi MC, Khalife R, Wolf D, Takeuchi Y, Rafiq QA. Biological differences between adult and perinatal human mesenchymal stromal cells and their impact on the manufacturing processes. Cytotherapy 2024; 26:1429-1441. [PMID: 38970611 DOI: 10.1016/j.jcyt.2024.05.020] [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: 08/20/2023] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 07/08/2024]
Abstract
The biological properties of human mesenchymal stromal cells (hMSCs) have been explored in over a thousand clinical trials in the last decade. Although hMSCs can be isolated from multiple sources, the degree of biological similarity between cell populations from these sources remains to be determined. A comparative study was performed investigating the growth kinetics and functionality of hMSCs isolated from adipose tissue (AT), bone marrow (BM) and umbilical cord tissue (UCT) expanded in monolayer over five passages. Adult hMSCs (AT, BM) had a slower proliferation ability than the UCT-hMSCs, with no apparent differences in their glucose consumption profile. BM-hMSCs produced higher concentrations of endogenous vascular endothelial growth factor (VEGF) compared to AT- and UCT-hMSCs. This study also revealed that UCT-hMSCs were more efficiently transduced by a lentiviral vector carrying a VEGF gene than their adult counterparts. Following cellular immunophenotypic characterization, no differences across the sources were found in the expression levels of the typical markers used to identify hMSCs. This work established a systematic approach for cell source selection depending on the hMSC's intended clinical application.
Collapse
Affiliation(s)
- Pedro Silva Couto
- Department of Biochemical Engineering, University College London, London, UK
| | - Dale J Stibbs
- Department of Biochemical Engineering, University College London, London, UK
| | - Marco C Rotondi
- Department of Biochemical Engineering, University College London, London, UK
| | - Rana Khalife
- Department of Biochemical Engineering, University College London, London, UK
| | | | - Yasuhiro Takeuchi
- Division of Infection and Immunity, University College London, London, UK; Biotherapeutics and Advanced Therapies, Scientific Research and Innovation, Medicines and Healthcare products Regulatory Agency, Potters Bar, UK
| | - Qasim A Rafiq
- Department of Biochemical Engineering, University College London, London, UK.
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Shen Z, Tang X, Zhang Y, Jia Y, Guo X, Guo X, Bao J, Xie X, Xing Y, Xing J, Tian S. Efficacy and safety of mesenchymal stem cell therapies for ischemic stroke: a systematic review and meta-analysis. Stem Cells Transl Med 2024; 13:886-897. [PMID: 39159204 PMCID: PMC11386217 DOI: 10.1093/stcltm/szae040] [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: 10/26/2023] [Accepted: 05/05/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND The efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of ischemic stroke (IS) remains controversial. Therefore, this study aimed to evaluate the efficacy and safety of MSCs for IS. METHODS A literature search until May 23, 2023, was conducted using PubMed, EMBASE, the Cochrane Library, and the Web of Science to identify studies on stem cell therapy for IS. Interventional and observational clinical studies of MSCs in patients with IS were included, and the safety and efficacy were assessed. Two reviewers extracted data and assessed the quality independently. The meta-analysis was performed using RevMan5.4. RESULTS Fifteen randomized controlled trials (RCTs) and 15 non-randomized trials, including 1217 patients (624 and 593 in the intervention and control arms, respectively), were analyzed. MSCs significantly improved patients' activities of daily living according to the modified Rankin scale (mean difference [MD]: -0.26; 95% confidence interval [CI]: -0.50 to -0.01; P = .04) and National Institutes of Health Stroke Scale score (MD: -1.69; 95% CI: -2.66 to -0.73; P < .001) in RCTs. MSC treatment was associated with lower mortality rates in RCTs (risk ratio: 0.44; 95% CI: 0.28-0.69; P < .001). Fever and headache were among the most reported adverse effects. CONCLUSIONS Based on our review, MSC transplantation improves neurological deficits and daily activities in patients with IS. In the future, prospective studies with large sample sizes are needed for stem cell studies in ischemic stroke. This meta-analysis has been registered at PROSPERO with CRD42022347156.
Collapse
Affiliation(s)
- Zhiyuan Shen
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Xian Tang
- Department of Rehabilitation Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Yaxin Zhang
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Yicun Jia
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Xin Guo
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Xiaosu Guo
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Junqiang Bao
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Xiongwei Xie
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Yuan Xing
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Jun Xing
- Department of Rehabilitation Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
| | - Shujuan Tian
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei 050030, People’s Republic of China
- Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei 050030, People’s Republic of China
| |
Collapse
|
|
7
|
Maged G, Abdelsamed MA, Wang H, Lotfy A. The potency of mesenchymal stem/stromal cells: does donor sex matter? Stem Cell Res Ther 2024; 15:112. [PMID: 38644508 PMCID: PMC11034072 DOI: 10.1186/s13287-024-03722-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/05/2024] [Indexed: 04/23/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising therapeutic tool in cell therapy and tissue engineering because of their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential. To achieve optimal results as a therapeutic tool, factors affecting MSC potency, including but not limited to cell source, donor age, and cell batch, have been investigated. Although the sex of the donor has been attributed as a potential factor that can influence MSC potency and efficacy, the impact of donor sex on MSC characteristics has not been carefully investigated. In this review, we summarize published studies demonstrating donor-sex-related MSC heterogeneity and emphasize the importance of disclosing donor sex as a key factor affecting MSC potency in cell therapy.
Collapse
Affiliation(s)
- Ghada Maged
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Menna A Abdelsamed
- Biotechnology and Life Sciences Department, Faculty of Postgraduate studies for Advanced Sciences, Beni-Suef University, Beni Suef, Egypt
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, 29425, Charleston, SC, USA.
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
| | - Ahmed Lotfy
- Department of Surgery, Medical University of South Carolina, 29425, Charleston, SC, USA.
| |
Collapse
|
|
8
|
Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Collapse
Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
Namestnikova DD, Kovalenko DB, Pokusaeva IA, Chudakova DA, Gubskiy IL, Yarygin KN, Baklaushev VP. Mesenchymal stem cells in the treatment of ischemic stroke. КЛИНИЧЕСКАЯ ПРАКТИКА 2024; 14:49-64. [DOI: 10.17816/clinpract624157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
Over the past two decades, multiple preclinical studies have shown that transplantation of mesenchymal stem cells leads to a pronounced positive effect in animals with experimental stroke. Based on the promising results of preclinical studies, several clinical trials on the transplantation of mesenchymal stem cells to stroke patients have also been conducted. In this review, we present and analyze the results of completed clinical trials dedicated to the mesenchymal stem cells transplantation in patients with ischemic stroke. According to the obtained results, it can be concluded that transplantation of mesenchymal stem cells is safe and feasible from the economic and biomedical point of view. For the further implementa-tion of this promising approach into the clinical practice, randomized, placebo-controlled, multicenter clinical trials are needed with a large sample of patients and optimized cell transplantation protocols and patient inclusion criteria. In this review we also discuss possi-ble strategies to enhance the effectiveness of cell therapy with the use of mesenchymal stem cells.
Collapse
Affiliation(s)
- Daria D. Namestnikova
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
| | | | | | | | - Ilya L. Gubskiy
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
| | | | - Vladimir P. Baklaushev
- Federal Center of Brain Research and Neurotechnologies
- Pirogov Russian National Research Medical University
- Federal Scientific and Clinical Center for Specialized Medical Assistance and Medical Technologies of the Federal Medical Biological Agency
| |
Collapse
|
|
11
|
Sun W, Lv J, Guo S, Lv M. Cellular microenvironment: a key for tuning mesenchymal stem cell senescence. Front Cell Dev Biol 2023; 11:1323678. [PMID: 38111850 PMCID: PMC10725964 DOI: 10.3389/fcell.2023.1323678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/17/2023] [Indexed: 12/20/2023] Open
Abstract
Mesenchymal stem cells (MSCs) possess the ability to self-renew and differentiate into multiple cell types, making them highly suitable for use as seed cells in tissue engineering. These can be derived from various sources and have been found to play crucial roles in several physiological processes, such as tissue repair, immune regulation, and intercellular communication. However, the limited capacity for cell proliferation and the secretion of senescence-associated secreted phenotypes (SASPs) pose challenges for the clinical application of MSCs. In this review, we provide a comprehensive summary of the senescence characteristics of MSCs and examine the different features of cellular microenvironments studied thus far. Additionally, we discuss the mechanisms by which cellular microenvironments regulate the senescence process of MSCs, offering insights into preserving their functionality and enhancing their effectiveness.
Collapse
Affiliation(s)
| | | | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Mengzhu Lv
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
12
|
Mohammadi TC, Jazi K, Bolouriyan A, Soleymanitabar A. Stem cells in treatment of crohn's disease: Recent advances and future directions. Transpl Immunol 2023; 80:101903. [PMID: 37541629 DOI: 10.1016/j.trim.2023.101903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy. METHODS Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section. RESULTS AND CONCLUSION Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.
Collapse
Affiliation(s)
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Alireza Bolouriyan
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
13
|
Prakash N, Kim J, Jeon J, Kim S, Arai Y, Bello AB, Park H, Lee SH. Progress and emerging techniques for biomaterial-based derivation of mesenchymal stem cells (MSCs) from pluripotent stem cells (PSCs). Biomater Res 2023; 27:31. [PMID: 37072836 PMCID: PMC10114339 DOI: 10.1186/s40824-023-00371-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/26/2023] [Indexed: 04/20/2023] Open
Abstract
The use of mesenchymal stem cells (MSCs) for clinical purposes has skyrocketed in the past decade. Their multilineage differentiation potentials and immunomodulatory properties have facilitated the discovery of therapies for various illnesses. MSCs can be isolated from infant and adult tissue sources, which means they are easily available. However, this raises concerns because of the heterogeneity among the various MSC sources, which limits their effective use. Variabilities arise from donor- and tissue-specific differences, such as age, sex, and tissue source. Moreover, adult-sourced MSCs have limited proliferation potentials, which hinders their long-term therapeutic efficacy. These limitations of adult MSCs have prompted researchers to develop a new method for generating MSCs. Pluripotent stem cells (PSCs), such as embryonic stem cells and induced PSCs (iPSCs), can differentiate into various types of cells. Herein, a thorough review of the characteristics, functions, and clinical importance of MSCs is presented. The existing sources of MSCs, including adult- and infant-based sources, are compared. The most recent techniques for deriving MSCs from iPSCs, with a focus on biomaterial-assisted methods in both two- and three-dimensional culture systems, are listed and elaborated. Finally, several opportunities to develop improved methods for efficiently producing MSCs with the aim of advancing their various clinical applications are described.
Collapse
Affiliation(s)
- Nityanand Prakash
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jiseong Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jieun Jeon
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Siyeon Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Yoshie Arai
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Alvin Bacero Bello
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, 06911, Korea.
| | - Soo-Hong Lee
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
| |
Collapse
|
|
14
|
Behzadifard M, Aboutaleb N, Dolatshahi M, Khorramizadeh M, Mirshekari Jahangiri H, Kord Z, Nazarinia D. Neuroprotective Effects of Conditioned Medium of Mesenchymal Stem Cells (MSC-CM) as a Therapy for Ischemic Stroke Recovery: A Systematic Review. Neurochem Res 2022; 48:1280-1292. [PMID: 36581731 DOI: 10.1007/s11064-022-03848-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/12/2022] [Accepted: 12/17/2022] [Indexed: 12/31/2022]
Abstract
It has been reported that the therapeutic potential of stem cells is mainly mediated by their paracrine factors. In order to identify the effects of conditioned medium of mesenchymal stem cells (MSC-CM) against stroke, a systematic review was conducted. We searched PubMed, Scopus, and ISI Web of Science databases for all available articles relevant to the effects of MSC-CM against the middle cerebral artery occlusion (MCAO) model of ischemic stroke until August 2022. The quality of the included studies was evaluated using The STAIR scale. During the systematic search, a total of 356 published articles were found. A total of 15 datasets were included following screening for eligibility. The type of cerebral ischemia was the MCAO model and CM was obtained from MSCs. The results showed that the therapeutic time window can be considered a crucial factor when researchers use MSC-CM for stroke therapy. In addition, MSC-CM therapy contributes to functional recovery and reduces infarct volume after stroke by targeting different cellular signaling pathways. Our findings showed that MSC-CM therapy has the ability to improve functional recovery and attenuate brain infarct volume after ischemic stroke in preclinical studies. We hope our study accelerates needed progress towards clinical trials.
Collapse
Affiliation(s)
- Mahin Behzadifard
- Department of Laboratory Sciences, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Dolatshahi
- Department of Physiology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Maryam Khorramizadeh
- Department of Medical Physics, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | | | - Zeynab Kord
- Department of Anaesthesiology, School of Allied Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Donya Nazarinia
- Department of Laboratory Sciences, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran. .,Department of Physiology, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
| |
Collapse
|
|
15
|
Yamaguchi S, Yoshida M, Horie N, Satoh K, Fukuda Y, Ishizaka S, Ogawa K, Morofuji Y, Hiu T, Izumo T, Kawakami S, Nishida N, Matsuo T. Stem Cell Therapy for Acute/Subacute Ischemic Stroke with a Focus on Intraarterial Stem Cell Transplantation: From Basic Research to Clinical Trials. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 10:bioengineering10010033. [PMID: 36671605 PMCID: PMC9854681 DOI: 10.3390/bioengineering10010033] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022]
Abstract
Stem cell therapy for ischemic stroke holds great promise for the treatment of neurological impairment and has moved from the laboratory into early clinical trials. The mechanism of action of stem cell therapy includes the bystander effect and cell replacement. The bystander effect plays an important role in the acute to subacute phase, and cell replacement plays an important role in the subacute to chronic phase. Intraarterial (IA) transplantation is less invasive than intraparenchymal transplantation and can provide more cells in the affected brain region than intravenous transplantation. However, transplanted cell migration was reported to be insufficient, and few transplanted cells were retained in the brain for an extended period. Therefore, the bystander effect was considered the main mechanism of action of IA stem cell transplantation. In most clinical trials, IA transplantation was performed during the acute and subacute phases. Although clinical trials of IA transplantation demonstrated safety, they did not demonstrate satisfactory efficacy in improving patient outcomes. To increase efficacy, increased migration of transplanted cells and production of long surviving and effective stem cells would be crucial. Given the lack of knowledge on this subject, we review and summarize the mechanisms of action of transplanted stem cells and recent advancements in preclinical and clinical studies to provide information and guidance for further advancement of acute/subacute phase IA stem cell transplantation therapy for ischemic stroke.
Collapse
Affiliation(s)
- Susumu Yamaguchi
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
- Department of Neurosurgery, Sasebo General Hospital, Nagasaki 857-8511, Japan
- Correspondence: ; Tel.: +81-095-819-7375
| | - Michiharu Yoshida
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
- Department of Neurosurgery, Sasebo General Hospital, Nagasaki 857-8511, Japan
| | - Nobutaka Horie
- Department of Neurosurgery, Hiroshima University, Hiroshima 734-8551, Japan
| | - Katsuya Satoh
- Department of Occupational Therapy Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Yuutaka Fukuda
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Shunsuke Ishizaka
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Koki Ogawa
- Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan
| | - Yoichi Morofuji
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Takeshi Hiu
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Tsuyoshi Izumo
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Shigeru Kawakami
- Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan
| | - Noriyuki Nishida
- Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
| | - Takayuki Matsuo
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| |
Collapse
|
|
16
|
Karamali F, Behtaj S, Babaei-Abraki S, Hadady H, Atefi A, Savoj S, Soroushzadeh S, Najafian S, Nasr Esfahani MH, Klassen H. Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision. J Transl Med 2022; 20:572. [PMID: 36476500 PMCID: PMC9727916 DOI: 10.1186/s12967-022-03738-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/29/2022] [Indexed: 12/12/2022] Open
Abstract
Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina's ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.
Collapse
Affiliation(s)
- Fereshteh Karamali
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sanaz Behtaj
- grid.1022.10000 0004 0437 5432Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Queensland, Australia ,grid.1022.10000 0004 0437 5432Menzies Health Institute Queensland, Griffith University, Southport, QLD 4222 Australia
| | - Shahnaz Babaei-Abraki
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hanieh Hadady
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Atefeh Atefi
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Soraya Savoj
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sareh Soroushzadeh
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Samaneh Najafian
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr Esfahani
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Henry Klassen
- grid.266093.80000 0001 0668 7243Gavin Herbert Eye Institute, Irvine, CA USA
| |
Collapse
|
|
17
|
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.
Collapse
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
| |
Collapse
|
|
18
|
Soares MBP, Gonçalves RGJ, Vasques JF, da Silva-Junior AJ, Gubert F, Santos GC, de Santana TA, Almeida Sampaio GL, Silva DN, Dominici M, Mendez-Otero R. Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases. Front Mol Neurosci 2022; 15:883378. [PMID: 35782379 PMCID: PMC9244712 DOI: 10.3389/fnmol.2022.883378] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022] Open
Abstract
Neurological disorders include a wide spectrum of clinical conditions affecting the central and peripheral nervous systems. For these conditions, which affect hundreds of millions of people worldwide, generally limited or no treatments are available, and cell-based therapies have been intensively investigated in preclinical and clinical studies. Among the available cell types, mesenchymal stem/stromal cells (MSCs) have been widely studied but as yet no cell-based treatment exists for neurological disease. We review current knowledge of the therapeutic potential of MSC-based therapies for neurological diseases, as well as possible mechanisms of action that may be explored to hasten the development of new and effective treatments. We also discuss the challenges for culture conditions, quality control, and the development of potency tests, aiming to generate more efficient cell therapy products for neurological disorders.
Collapse
Affiliation(s)
- Milena B. P. Soares
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Renata G. J. Gonçalves
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana F. Vasques
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Almir J. da Silva-Junior
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Gubert
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Girlaine Café Santos
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Thaís Alves de Santana
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | - Gabriela Louise Almeida Sampaio
- Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (IGM-FIOCRUZ/BA), Salvador, Brazil
- Instituto SENAI de Sistemas Avançados de Saúde (CIMATEC ISI-SAS), Centro Universitário SENAI/CIMATEC, Salvador, Brazil
| | | | - Massimo Dominici
- Laboratory of Cellular Therapy, Division of Oncology, University of Modena and Reggio Emilia (UNIMORE), Modena, Italy
| | - Rosalia Mendez-Otero
- Laboratório de Neurobiologia Celular e Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
19
|
Zoehler B, Fracaro L, Boldrini-Leite LM, da Silva JS, Travers PJ, Brofman PRS, Bicalho MDG, Senegaglia AC. HLA-G and CD152 Expression Levels Encourage the Use of Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells as an Alternative for Immunosuppressive Therapy. Cells 2022; 11:cells11081339. [PMID: 35456019 PMCID: PMC9032010 DOI: 10.3390/cells11081339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 12/04/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been used in immunosuppressive therapy due to their therapeutic effects, with the HLA-G molecule seeming to play a fundamental role. This work evaluated alternative MSC sources to bone marrow (BM), namely, umbilical cord tissue (UC), adipose tissue (AD) and dental pulp tissue (DP), and the influence of interferon-γ (IFN-γ) and hypoxia on the cultivation of these cells for use in immunosuppression therapies. Expression of costimulatory markers CD40, CD80 and CD86 and immunosuppressive molecules CD152 and HLA-G was analyzed. Lymphocyte inhibition assays were also performed. Sequencing of the HLA-G gene from exons 1 to 5 was performed using next-generation sequencing to determine the presence of alleles. UC-derived MSCs (UCMSCs) expressed higher CD152 and HLA-G1 under standard cultivation. UCMSCs and DP-derived MSCs (DPSCs) secreted similar levels of HLA-G5. All MSC sources inhibited the proliferation of peripheral blood mononuclear cells (PBMCs); growth under regular versus hypoxic conditions resulted in similar levels of inhibition. When IFN-γ was added, PBMC growth was inhibited to a lesser extent by UCMSCs. The HLA-G*01:04:01:01 allele appears to generate a more efficient MSC response in inhibiting lymphocyte proliferation. However, the strength of this conclusion was limited by the small sample size. UCMSCs are an excellent alternative to BM in immunosuppressive therapy: they express high concentrations of inhibitory molecules and can be cultivated without stimuli, which minimizes cost.
Collapse
Affiliation(s)
- Bernardo Zoehler
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
- Correspondence: (B.Z.); (A.C.S.)
| | - Letícia Fracaro
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - Lidiane Maria Boldrini-Leite
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - José Samuel da Silva
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
| | - Paul J. Travers
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK;
| | - Paulo Roberto Slud Brofman
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - Maria da Graça Bicalho
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
| | - Alexandra Cristina Senegaglia
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
- Correspondence: (B.Z.); (A.C.S.)
| |
Collapse
|
|
20
|
Mesenchymal Stem Cells in the Treatment of Human Spinal Cord Injury: The Effect on Individual Values of pNF-H, GFAP, S100 Proteins and Selected Growth Factors, Cytokines and Chemokines. Curr Issues Mol Biol 2022; 44:578-596. [PMID: 35723326 PMCID: PMC8929137 DOI: 10.3390/cimb44020040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 11/21/2022] Open
Abstract
At present, there is no effective way to treat the consequences of spinal cord injury (SCI). SCI leads to the death of neural and glial cells and widespread neuroinflammation with persisting for several weeks after the injury. Mesenchymal stem cells (MSCs) therapy is one of the most promising approaches in the treatment of this injury. The aim of this study was to characterize the expression profile of multiple cytokines, chemokines, growth factors, and so-called neuromarkers in the serum of an SCI patient treated with autologous bone marrow-derived MSCs (BM-MSCs). SCI resulted in a significant increase in the levels of neuromarkers and proteins involved in the inflammatory process. BM-MSCs administration resulted in significant changes in the levels of neuromarkers (S100, GFAP, and pNF-H) as well as changes in the expression of proteins and growth factors involved in the inflammatory response following SCI in the serum of a patient with traumatic SCI. Our preliminary results encouraged that BM-MSCs with their neuroprotective and immunomodulatory effects could affect the repair process after injury.
Collapse
|
|
21
|
Liu D, Bobrovskaya L, Zhou XF. Cell Therapy for Neurological Disorders: The Perspective of Promising Cells. BIOLOGY 2021; 10:1142. [PMID: 34827135 PMCID: PMC8614777 DOI: 10.3390/biology10111142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022]
Abstract
Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.
Collapse
Affiliation(s)
| | | | - Xin-Fu Zhou
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia; (D.L.); (L.B.)
| |
Collapse
|
|
22
|
Chiu TL, Baskaran R, Tsai ST, Huang CY, Chuang MH, Syu WS, Harn HJ, Lin YC, Chen CH, Huang PC, Wang YF, Chuang CH, Lin PC, Lin SZ. Intracerebral transplantation of autologous adipose-derived stem cells for chronic ischemic stroke: A phase I study. J Tissue Eng Regen Med 2021; 16:3-13. [PMID: 34644444 DOI: 10.1002/term.3256] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/14/2021] [Accepted: 10/09/2021] [Indexed: 11/08/2022]
Abstract
Current therapy does not provide significant benefits for patients with chronic stroke. Pre-clinical studies suggested that autologous adipose-derived stem cells have benefits for the treatment of chronic stroke. This Phase I open-label study was conducted to demonstrate the safety and efficacy of autologous adipose-derived stem cells (GXNPC1) in chronic stroke. Three patients with chronic stroke were treated with stereotactic implantation of autologous adipose-derived stem cells (1 × 108 cells). The primary endpoints of safety evaluation included adverse events, over a 6 months post-implantation period. The secondary endpoints included improvements in neurological functions. Evolutional change of brain parenchyma was also followed with magnetic resonance imaging (MRI). All three participants improved significantly at 6 months follow-up. The extent of improvement from pre-treatment was: National Institutes of Health Stroke Scale improved 5-15 points, Barthel Index: 25-50 points, Berg balance scale 0-21 points and Fugl-Meyer modified sensation 3-28 points. All three patients had signal change along the implantation tract on MRI one month after surgery. There is no related safety issue through 6 months observation. Clinical measures of neurological symptoms of these patients with chronic stroke improved at 6 months without adverse effects after implantation of autologous adipose-derived stem cells (GXNPC1), which might be correlated with post-implantation changes on brain MRI. Clinical Trial Registration-URL: https://clinicaltrials.gov/ct2/show/NCT02813512?term=ADSC&cond=Stroke&cntry=TW&draw=2&rank=1 Unique identifier: NCT02813512.
Collapse
Affiliation(s)
- Tsung-Lang Chiu
- Department of Neurosurgery, Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, ROC
| | - Sheng-Tzung Tsai
- Department of Neurosurgery, Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC.,Department of Biological Science and Technology, Asia University, Taichung, Taiwan, ROC.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, ROC
| | - Ming-Hsi Chuang
- Department of Technology Management, Chung Hwa University, Hsinchu, Taiwan, ROC
| | - Wan-Sin Syu
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi foundation; Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC
| | - Yi-Chun Lin
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
| | - Chun-Hung Chen
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
| | - Pi-Chun Huang
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
| | - Yi-Fen Wang
- Department of Neurosurgery, Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC
| | | | - Po-Cheng Lin
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
| | - Shinn-Zong Lin
- Department of Neurosurgery, Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, ROC
| |
Collapse
|
|
23
|
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.
Collapse
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
| |
Collapse
|
|
24
|
Chen H, Liu O, Chen S, Zhou Y. Aging and Mesenchymal Stem Cells: Therapeutic Opportunities and Challenges in the Older Group. Gerontology 2021; 68:339-352. [PMID: 34161948 DOI: 10.1159/000516668] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/07/2021] [Indexed: 11/19/2022] Open
Abstract
With aging, a portion of cells, including mesenchymal stem cells (MSCs), become senescent, and these senescent cells accumulate and promote various age-related diseases. Therefore, the older age group has become a major population for MSC therapy, which is aimed at improving tissue regeneration and function of the aged body. However, the application of MSC therapy is often unsatisfying in the aged group. One reasonable conjecture for this correlation is that aging microenvironment reduces the number and function of MSCs. Cellular senescence also plays an important role in MSC function impairment. Thus, it is necessary to explore the relationship between senescence and MSCs for improving the application of MSCs in the elderly. Here, we present the influence of aging on MSCs and the characteristics and functional changes of senescent MSCs. Furthermore, current therapeutic strategies for improving MSC therapy in the elderly group are also discussed.
Collapse
Affiliation(s)
- Huan Chen
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, and Xiangya School of Stomatology, Central South University, Changsha, China
| | - Ousheng Liu
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, and Xiangya School of Stomatology, Central South University, Changsha, China
| | - Sijia Chen
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, and Xiangya School of Stomatology, Central South University, Changsha, China
| | - Yueying Zhou
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, and Xiangya School of Stomatology, Central South University, Changsha, China
| |
Collapse
|
|
25
|
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.
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
Sungura R, Onyambu C, Mpolya E, Sauli E, Vianney JM. The extended scope of neuroimaging and prospects in brain atrophy mitigation: A systematic review. INTERDISCIPLINARY NEUROSURGERY 2021. [DOI: 10.1016/j.inat.2020.100875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
|
|
28
|
Sommer CJ, Schäbitz WR. Principles and requirements for stroke recovery science. J Cereb Blood Flow Metab 2021; 41:471-485. [PMID: 33175596 PMCID: PMC7907998 DOI: 10.1177/0271678x20970048] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 10/03/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.
Collapse
Affiliation(s)
- Clemens J Sommer
- Institute of Neuropathology, University Medical Center of the
Johannes Gutenberg-University Mainz, Mainz, Germany
| | | |
Collapse
|
|
29
|
Zhao L, Hu C, Han F, Chen D, Ma Y, Wang J, Chen J. Cellular senescence, a novel therapeutic target for mesenchymal stem cells in acute kidney injury. J Cell Mol Med 2021. [PMCID: PMC7812305 DOI: 10.1111/jcmm.16163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cellular senescence is a widespread cellular programme that is characterized by permanent cell cycle arrest. Senescent cells adopt a changed secretory phenotype that can alter cellular function. For years, cellular senescence has been thought to be a protective factor against cancer; however, it is now recognized that it has a dual effect on individuals. Co‐ordinated activation of cellular senescence provides advantages during embryogenesis, wound healing, tissue repair and inhibition of tumorigenesis. On the other hand, the aberrant generation and accumulation of abnormal senescent cells lead to the development of age‐related conditions and tissue deterioration. During acute kidney injury (AKI), the kidney faces multiple types of stressors and challenges, which can easily drive cellular senescence. How to appropriately progress through the cell cycle and minimize long‐term damage is of great importance to the acquisition of adaptive repair considering that no available therapeutic interventions can reliably limit injury, speedy recovery or improve the prognosis of this syndrome. Whether the manipulation of cellular senescence can become a novel therapeutic target in AKI and reignite clinical and research interest remains to be determined. Here, we share our current understanding of the role of cellular senescence in AKI, along with examples of the application of mesenchymal stem cells (MSCs) for targeting this disorder during its treatment.
Collapse
Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou Zhejiang China
| | - Fei Han
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Dajin Chen
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Yanhong Ma
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Junni Wang
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Jianghua Chen
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| |
Collapse
|
|
30
|
Zhang S, Lachance BB, Moiz B, Jia X. Optimizing Stem Cell Therapy after Ischemic Brain Injury. J Stroke 2020; 22:286-305. [PMID: 33053945 PMCID: PMC7568970 DOI: 10.5853/jos.2019.03048] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.
Collapse
Affiliation(s)
- Shuai Zhang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Brittany Bolduc Lachance
- Program in Trauma, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bilal Moiz
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
31
|
Meng QS, Liu J, Wei L, Fan HM, Zhou XH, Liang XT. Senescent mesenchymal stem/stromal cells and restoring their cellular functions. World J Stem Cells 2020; 12:966-985. [PMID: 33033558 PMCID: PMC7524698 DOI: 10.4252/wjsc.v12.i9.966] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/23/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have various properties that make them promising candidates for stem cell-based therapies in clinical settings. These include self-renewal, multilineage differentiation, and immunoregulation. However, recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products. Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs. This review will summarize the current knowledge on characteristics and functional changes of aged MSCs. Additionally, it will highlight cell rejuvenation strategies such as molecular regulation, non-coding RNA modifications, and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.
Collapse
Affiliation(s)
- Qing-Shu Meng
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Jing Liu
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Lu Wei
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Hui-Min Fan
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Hui Zhou
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Ting Liang
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
| |
Collapse
|
|
32
|
Campbell JM, Mahbub S, Habibalahi A, Paton S, Gronthos S, Goldys E. Ageing human bone marrow mesenchymal stem cells have depleted NAD(P)H and distinct multispectral autofluorescence. GeroScience 2020; 43:859-868. [PMID: 32789662 PMCID: PMC8110641 DOI: 10.1007/s11357-020-00250-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/06/2020] [Indexed: 12/26/2022] Open
Abstract
Stem cell exhaustion plays a major role in the ageing of different tissues. Similarly, in vitro cell ageing during expansion prior to their use in regenerative medicine can severely compromise stem cell quality through progressive declines in differentiation and growth capacity. We utilized non-destructive multispectral assessment of native cell autofluorescence to investigate the metabolic mechanisms of in vitro mesenchymal stem cell (MSC) ageing in human bone marrow MSCs over serial passages (P2-P10). The spectral signals for NAD(P)H, flavins and protein-bound NAD(P)H were successfully isolated using Robust Dependent Component Analysis (RoDECA). NAD(P)H decreased over the course of hMSC ageing in absolute terms as well as relative to flavins (optical redox ratio). Relative changes in other fluorophore levels (flavins, protein-bound NAD(P)H) suggested that this reduction was due to nicotinamide adenine dinucleotide depletion rather than a metabolic shift from glycolysis to oxidative phosphorylation. Using multispectral features, which are determined without cell fixation or fluorescent labelling, we developed and externally validated a reliable, linear model which could accurately categorize the age of culture-expanded hMSCs. The largest shift in spectral characteristics occurs early in hMSC ageing. These findings demonstrate the feasibility of applying multispectral technology for the non-invasive monitoring of MSC health in vitro.
Collapse
Affiliation(s)
- Jared M Campbell
- ARC Centre of Excellence in Nanoscale Biophotonics, Graduate School of Biomedical Engineering, The University of New South Wales, Sydney, New South Wales, 2052, Australia. .,The University of New South Wales, Sydney, New South Wales, 2052, Australia.
| | - Saabah Mahbub
- ARC Centre of Excellence in Nanoscale Biophotonics, Graduate School of Biomedical Engineering, The University of New South Wales, Sydney, New South Wales, 2052, Australia.,The University of New South Wales, Sydney, New South Wales, 2052, Australia
| | - Abbas Habibalahi
- ARC Centre of Excellence in Nanoscale Biophotonics, Graduate School of Biomedical Engineering, The University of New South Wales, Sydney, New South Wales, 2052, Australia.,The University of New South Wales, Sydney, New South Wales, 2052, Australia
| | - Sharon Paton
- Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, 5000, Australia.,South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, 5000, Australia.,South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia
| | - Ewa Goldys
- ARC Centre of Excellence in Nanoscale Biophotonics, Graduate School of Biomedical Engineering, The University of New South Wales, Sydney, New South Wales, 2052, Australia.,The University of New South Wales, Sydney, New South Wales, 2052, Australia
| |
Collapse
|
|
33
|
Alessio N, Acar MB, Demirsoy IH, Squillaro T, Siniscalco D, Bernardo GD, Peluso G, Özcan S, Galderisi U. Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice. Aging (Albany NY) 2020; 12:12609-12621. [PMID: 32634118 PMCID: PMC7377882 DOI: 10.18632/aging.103606] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/05/2020] [Indexed: 02/07/2023]
Abstract
White adipose tissue (WAT) is distributed in several depots with distinct metabolic and inflammatory functions. In our body there are subcutaneous (sWAT), visceral (vWAT) and bone marrow (bWAT) fat depots. Obesity affects the size, function and inflammatory state of WATs. In particular, obesity may affect the activity of mesenchymal stromal cells (MSCs) present in WAT. MSCs are a heterogeneous population containing stromal cells, progenitor cells, fibroblasts and stem cells that are able to differentiate among adipocytes, chondrocytes, osteocytes and other mesodermal derivatives.In the first study of this kind, we performed a comparison of the effects of obesity on MSCs obtained from sWAT, vWAT and bWAT. Our study showed that obesity affects mainly the biological functions of MSCs obtained from bone marrow and vWAT by decreasing the proliferation rate, reducing the percentage of cells in S phase and triggering senescence. The onset of senescence was confirmed by expression of genes belonging to RB and P53 pathways.Our study revealed that the negative consequences of obesity on body physiology may also be related to impairment in the functions of the stromal compartment present in the several adipose tissues. This finding provides new insights as to the targets that should be considered for an effective treatment of obesity-related diseases.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
| | - Mustafa B. Acar
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
- Department of Biology, Faculty of Sciences, Erciyes University, Kayseri, Turkey
| | - Ibrahim H. Demirsoy
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
| | - Tiziana Squillaro
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
| | - Dario Siniscalco
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
| | | | - Servet Özcan
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
- Department of Biology, Faculty of Sciences, Erciyes University, Kayseri, Turkey
| | - Umberto Galderisi
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Luigi Vanvitelli Campania University, Naples, Italy
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| |
Collapse
|
|
34
|
Taguchi T, Borjesson DL, Osmond C, Griffon DJ. Influence of Donor's Age on Immunomodulatory Properties of Canine Adipose Tissue-Derived Mesenchymal Stem Cells. Stem Cells Dev 2019; 28:1562-1571. [PMID: 31588862 DOI: 10.1089/scd.2019.0118] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis challenges traditional therapies and remains a leading cause of lameness in older dogs. Regenerative medicine offers new strategies, typically involving the injection of autologous adipose-derived mesenchymal stem cells (MSCs). Conversely, allogenic MSCs are appealing candidates to palliate patient morbidity and cell preparation time. Regardless of the source of cells, identifying critical donor characteristics, such as age, is essential to obtain the most competent MSCs. The objectives of this study were to determine the influence of donor's age on proliferation, gene expression, and immunomodulatory properties of MSCs in dogs. Canine adipose tissue-derived MSCs (cAD-MSCs) were isolated from the falciform-ligament adipose tissues of nine pairs of gender-matched young (<2 years) or old (>7 years) client-owned dogs undergoing abdominal surgery. Growth kinetics, transcriptome before and after stimulation by tumor necrosis factor alpha and interferon gamma, MSC-induced lymphocyte suppression assay, and secretion of prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO) were compared between cells obtained from young or old dogs. The doubling times at passages 2 and 3 were shorter when MSCs were isolated from young (34.8 ± 1.8 h and 46.3 ± 2.3 h) rather than old dogs (56.5 ± 8.0 h and 123.8 ± 46.7 h, P < 0.05). The MSC transcriptomes from both populations were similar without stimulation, while stimulation resulted in a 3-fold greater expression of osteogenic gene, fibroblast growth factor 10, in cells from old dogs. cAD-MSCs from young dogs suppressed proliferation of activated T cells more strongly (P < 0.05), although secretion of PGE2 and IDO did not differ between groups. In conclusion, donors' age affected proliferation, immunomodulatory properties of cAD-MSCs, and increased expression of osteogenic gene under proinflammatory conditions in our population of dogs. Collectively, our results provide evidence to support further evaluation of allogenic MSC therapies derived from young donors as alternatives to autologous MSC therapy in older dogs.
Collapse
Affiliation(s)
- Takashi Taguchi
- College of Veterinary Medicine, Western University of Health Sciences, Pomona, California
| | - Dori L Borjesson
- Department of Pathology, Microbiology and Immunology, Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Christian Osmond
- VCA California Veterinary Specialists (Carlsbad), Carlsbad, California
| | - Dominique J Griffon
- College of Veterinary Medicine, Western University of Health Sciences, Pomona, California
| |
Collapse
|
|
35
|
Stem cell therapy for perianal Crohn's. Curr Opin Gastroenterol 2019; 35:311-320. [PMID: 33216484 DOI: 10.1097/mog.0000000000000545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW Perianal Crohn's disease is a morbid and disabling condition, notoriously difficult to successfully treat with conventional medical and surgical therapies. Mesenchymal stem cells (MSCs) are an emerging novel therapy for perianal Crohn's disease. RECENT FINDINGS Over 300 patients with perianal Crohn's disease have now been treated with MSCs in the context of clinical trials. All trials have demonstrated safety, and efficacy superior to conventional therapy with biologics and surgical intervention. This was consistent despite the heterogeneity in study protocols including variability in cell dosing, mode of delivery, repeat dosing, and allogeneic versus autologous donors. Sustained healing to 1 year has also been demonstrated in a recent extension of the largest phase III study confirming superior efficacy of MSCs to placebo at 1-year follow-up. However, several outstanding questions regarding the use of MSCs for perianal Crohn's disease remain, which, if answered, could enhance MSCs' treatment efficacy. These include defining the optimal MSC donor, optimal MSC source (e.g., bone marrow versus adipose tissue), investigating a potential alloimmune response following allogeneic cellular delivery, and determining the optimal mode for MSC delivery. In addition to these unanswered questions, significant challenges in the required infrastructure and cost required for cell-based therapies may drive future research toward identifying novel acellular therapies. SUMMARY Novel regenerative therapies offer promising new treatment options for perianal Crohn's disease, without the risk of opportunistic infection seen with biologics and incontinence with surgical techniques. Future research will help define the optimal MSC product and treatment protocol, and may even expand our horizon of regenerative medicine into acellular therapy as well as cell-based therapies.
Collapse
|
|
36
|
Nguyen H, Zarriello S, Coats A, Nelson C, Kingsbury C, Gorsky A, Rajani M, Neal EG, Borlongan CV. Stem cell therapy for neurological disorders: A focus on aging. Neurobiol Dis 2019; 126:85-104. [PMID: 30219376 PMCID: PMC6650276 DOI: 10.1016/j.nbd.2018.09.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/04/2018] [Accepted: 09/11/2018] [Indexed: 02/07/2023] Open
Abstract
Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.
Collapse
Affiliation(s)
- Hung Nguyen
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Sydney Zarriello
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Alexandreya Coats
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Cannon Nelson
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Chase Kingsbury
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Anna Gorsky
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Mira Rajani
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Elliot G Neal
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
| |
Collapse
|
|
37
|
Aboutaleb N, Faezi M, Nasseri Maleki S, Nazarinia D, Razavi Tousi SMT, Hashemirad N. Conditioned medium obtained from mesenchymal stem cells attenuates focal cerebral ischemia reperfusion injury through activation of ERK1/ERK2-BDNF signaling pathway. J Chem Neuroanat 2019; 97:87-98. [DOI: 10.1016/j.jchemneu.2019.02.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 02/13/2019] [Accepted: 02/17/2019] [Indexed: 12/23/2022]
|
|
38
|
Yamaguchi S, Horie N, Morikawa M, Tateishi Y, Hiu T, Morofuji Y, Izumo T, Hayashi K, Matsuo T. Assessment of veins in T2*-weighted MR angiography predicts infarct growth in hyperacute ischemic stroke. PLoS One 2018; 13:e0195554. [PMID: 29617449 PMCID: PMC5884555 DOI: 10.1371/journal.pone.0195554] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 03/23/2018] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND AND PURPOSE T2*-weighted magnetic resonance angiography (SWAN) detects hemodynamic insufficiency as hypointense areas in medullary or cortical veins. We therefore investigated whether SWAN can help predict ischemic penumbra-like lesions in patients with acute ischemic stroke (AIS). MATERIALS AND METHODS Magnetic resonance imaging (MRI) records-including SWAN, diffusion-weighted imaging (DWI), and magnetic resonance angiography (MRA)-of consecutive patients with major vessel occlusion within 6 h from AIS onset were analyzed. Acute recanalization was defined as an arterial occlusive lesion score of 2-3. A modified Alberta Stroke Program Early CT Score (mASPECTS) was used to evaluate ischemic areas revealed by SWAN and DWI. SWAN- and DWI-based mASPECTSs were calculated, and correlations between DWI-SWAN mismatches with final infarct lesions or clinical outcomes were evaluated. RESULTS Among the 35 patients included in this study, we confirmed cardioembolic stroke in 26, atherothrombotic stroke in 4, and unknown stroke etiology in 5. Overall, recanalization was achieved in 23 patients, who showed a higher follow-up DWI-based mASPECTS and lower modified Rankin Scale (mRS) score at 90 days than patients without recanalization. Initial SWAN- and follow-up DWI-based mASPECTSs were significantly higher for atherothrombotic stroke than for cardioembolic stroke. Of 12 patients without recanalization, DWI-SWAN mismatch was significantly correlated with infarct growth. Patients with recanalization showed no such correlation. In the assessment of clinical outcome, follow-up DWI-based mASPECTS and patient's age were significantly correlated with mRS at 90 days after stroke. A multivariate logistic regression analysis revealed that the follow-up DWI-based mASPECTS was independently associated with a favorable outcome 90 days after stroke. CONCLUSIONS For patients with AIS, DWI-SWAN mismatch might show penumbra-like lesions that would predict infarct growth without acute recanalization. Assessment of ischemic lesions from the venous side appears to be useful for considering the etiology and revascularization therapy.
Collapse
Affiliation(s)
- Susumu Yamaguchi
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- * E-mail:
| | - Nobutaka Horie
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Minoru Morikawa
- Department of Radiological Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yohei Tateishi
- Department of Neurology and Strokology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takeshi Hiu
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoichi Morofuji
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tsuyoshi Izumo
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kentaro Hayashi
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takayuki Matsuo
- Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| |
Collapse
|