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Carneiro-Pereira B, Ferreira-Antunes F, Campos J, Salgado AJ, Sampaio-Marques B. Caloric Restriction Mimetics as Priming Agents of Mesenchymal Stem Cells Secretome to Enhance Regenerative Responses to Parkinson's Disease. Molecules 2025; 30:2260. [PMID: 40509148 PMCID: PMC12156009 DOI: 10.3390/molecules30112260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 05/16/2025] [Accepted: 05/20/2025] [Indexed: 06/18/2025] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder primarily defined by the deterioration of motor function and characterized by the loss of dopaminergic neurons in the nigrostriatal system. Although it is the second most prevalent disorder of the central nervous system, current treatments primarily focus on symptom management and modestly slowing disease progression, ultimately failing to preserve the long-term quality of life of a substantial proportion of affected individuals. Innovative therapies that can restore neuronal function have emerged, such as the use of the secretome of Mesenchymal Stem Cells (MSCs) due to their rich composition of bioactive molecules. This therapy exhibits robust paracrine activity that drives most of the self-renewal capacity, differentiation potential, and immune regulation of MSCs without presenting compatibility issues often associated with stem cell-based therapies. While conceptually appealing, the clinical application of this approach is still limited by the availability and proliferation capacity of MSCs, as it impacts not only secretome production but also its quality. Various protocols have been developed to enhance secretome action by adding various compounds to cell culture media, given the high environmental plasticity of MSCs. Some of the compounds already used are Caloric Restriction Mimetics (CRMs), molecules that mimic Caloric Restriction (CR) conditions, which have been demonstrated to extend lifespan and reduce age-related diseases in various organisms. While not sufficient to cure neurodegenerative disorders, these compounds may potentiate secretome efficiency by enhancing autophagy pathways and relieving oxidative stress burden from MSCs. Therefore, in this article, we aim to explore the effects of CRMs priming on MSCs and how it may help bridge existing gaps in regenerative therapies for PD.
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Affiliation(s)
- Bárbara Carneiro-Pereira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (B.C.-P.); (F.F.-A.); (J.C.); (A.J.S.)
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Filipa Ferreira-Antunes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (B.C.-P.); (F.F.-A.); (J.C.); (A.J.S.)
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Jonas Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (B.C.-P.); (F.F.-A.); (J.C.); (A.J.S.)
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - António J. Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (B.C.-P.); (F.F.-A.); (J.C.); (A.J.S.)
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (B.C.-P.); (F.F.-A.); (J.C.); (A.J.S.)
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
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Li M, Tang Y, Zhou C, Geng Y, Zhang C, Hsu Y, Ma L, Guo W, Li M, Wang Y. The Application of Stem Cells and Exosomes in Promoting Nerve Conduits for Peripheral Nerve Repair. Biomater Res 2025; 29:0160. [PMID: 40231207 PMCID: PMC11994886 DOI: 10.34133/bmr.0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 04/16/2025] Open
Abstract
The repair of peripheral nerve injury (PNI) presents a multifaceted and protracted challenge, with current therapeutic approaches failing to achieve optimal repair outcomes, thereby not satisfying the considerable clinical demand. The advent of tissue engineering has led to a growing body of experimental evidence indicating that the synergistic application of nerve conduits, which provide structural guidance, alongside the biological signals derived from exosomes and stem cells, yields superior therapeutic results for PNI compared to isolated interventions. This combined approach holds great promise for clinical application. In this review, we present the latest advancements in the treatment of PNI through the integration of stem cells or exosomes with nerve conduits. We have addressed the inadequate efficiency of exosomes or stem cells in conjunction with nerve conduits from 3 perspectives: enhancing stem cells or exosomes, improving nerve conduits, and incorporating physical stimulation.
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Affiliation(s)
- Mengen Li
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
- Department of Orthopedics and Trauma,
Peking University People’s Hospital, Beijing 100044, China
| | - Ye Tang
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
- Department of Orthopedics and Trauma,
Peking University People’s Hospital, Beijing 100044, China
| | - Chengkai Zhou
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
| | - Yan Geng
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
| | - Chenxi Zhang
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
| | - Yuwei Hsu
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
- Emergency Department,
Peking University People’s Hospital, Beijing 100044, China
| | - Le Ma
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
| | - Wei Guo
- Emergency Department,
Peking University People’s Hospital, Beijing 100044, China
| | - Ming Li
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Trauma Medicine Center,
Peking University People’s Hospital, Beijing 100044, China
| | - Yanhua Wang
- National Center for Trauma Medicine, Beijing 100044, China
- Key Laboratory of Trauma and Neural Regeneration, Ministry of Education,
Peking University, Beijing 100044, China
- Department of Orthopedics and Trauma,
Peking University People’s Hospital, Beijing 100044, China
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Öz Bağcı F, Özgörgülü A, Çiçek G, Utlu Özen E, Duman S, Aktan TM, Reisli I. Evaluation of the Interaction Between Wharton's Jelly-Derived Mesenchymal Stem Cells and β-Mercaptoethanol. Cureus 2025; 17:e83115. [PMID: 40438831 PMCID: PMC12117518 DOI: 10.7759/cureus.83115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2025] [Indexed: 06/01/2025] Open
Abstract
PURPOSE Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are self-regenerative and able to differentiate into multipotent stem cells. There may be different sources of mesenchymal stem cells (MSCs) involved in the repair mechanism of damaged tissues in the organism. WJ-MSCs may differentiate into osteocytes, chondrocytes, adipocytes, and myocyte cells. Furthermore, MSCs show neuroprotective effects on neurons. Today, many MSC neuroregenerative treatments have been shown to be effective. Studies have shown that MSCs are more involved in paracrine effects due to their neuroprotective effect in multiple diseases such as multiple sclerosis, acute spinal cord injury and encephalomyelitis. The main aim of this study was to investigate the neuronal markers of stem cells after incubation with β-mercaptoethanol (BME). MATERIALS AND METHODS In our study, WJ-MSCs were thawed in a water bath at 37°C and cultivated in cell culture dishes. When the cell occupancy rate reached 60-70%, they were treated with 2 mM BME. At the first and third hours, MSCs were removed from the dishes, and flow cytometry and immunostaining revealed that BME's nestin, neuron filament light (NF-L), SOX1, SOX2, doublecortin (DCX), glial fibrillary acidic protein (GFAP), Ki67, and CD44 were evaluated. RESULTS Immunocytochemically, nestin and NF-L values of MSCs exposed to BME increased at the first hour. In the flow cytometric evaluation, it was observed that nestin was high in the first hour. CONCLUSION One of our aims in this study was to reduce the possible toxic side effects of BME for MSCs by exposing the BME used in previous studies at the minimum dose for neuronal differentiation. In our study, we showed first-hour changes similar to the neuronal differentiation obtained with pre- and post-induction in other studies.
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Affiliation(s)
- Fatma Öz Bağcı
- Histology and Embryology, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
| | - Aydan Özgörgülü
- Histology and Embryology, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
| | - Gülsemin Çiçek
- Histology and Embryology, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
| | - Emine Utlu Özen
- Histology and Embryology, Etlik Zübeyde Hanım Women's Health Education and Research Hospital, Ankara, TUR
| | - Selçuk Duman
- Histology and Embryology, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
| | - Tahsin Murad Aktan
- Histology and Embryology, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
| | - Ismail Reisli
- Child Health and Diseases, Faculty of Medicine, Necmettin Erbakan University, Konya, TUR
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Myers MI, Hines KJ, Gray A, Spagnuolo G, Rosenwasser R, Iacovitti L. Intracerebral Transplantation of Autologous Mesenchymal Stem Cells Improves Functional Recovery in a Rat Model of Chronic Ischemic Stroke. Transl Stroke Res 2025; 16:248-261. [PMID: 37917400 PMCID: PMC11976345 DOI: 10.1007/s12975-023-01208-7] [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: 10/18/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 11/04/2023]
Abstract
While treatments exist for the acute phase of stroke, there are limited options for patients with chronic infarcts and long-term disability. Allogenic mesenchymal stem cells (alloMSCs) show promise for the treatment of stroke soon after ischemic injury. There is, however, no information on the use of autologous MSCs (autoMSCs), delivered intracerebrally in rats with a chronic infarct. In this study, rats underwent middle cerebral artery occlusion (MCAO) to induce stroke followed by bone marrow aspiration and MSC expansion in a closed bioreactor. Four weeks later, brain MRI was obtained and autoMSCs (1 × 106, 2.5 × 106 or 5 × 106; n = 6 each) were stereotactically injected into the peri-infarct and compared to controls (MCAO only; MCAO + PBS; n = 6-9). Behavior was assessed using the modified neurological severity score (mNSS). For comparison, an additional cohort of MCAO rats were implanted with 2.5 × 106 alloMSCs generated from a healthy rat. All doses of autoMSCs produced significant improvement (54-70%) in sensorimotor function 60 days later. In contrast, alloMSCs improved only 31.7%, similar to that in PBS controls 30%. Quantum dot-labeled auto/alloMSCs were found exclusively at the implantation site throughout the post-transplantation period with no tumor formation on MRI or Ki67 staining of engrafted MSCs. Small differences in stroke volume and no differences in corpus callosum width were observed after MSC treatment. Stroke-induced glial reactivity in the peri-infarct was long-lasting and unabated by auto/alloMSC transplantation. These studies suggest that intracerebral transplantation of autoMSCs as compared to alloMSCs may be a promising treatment in chronic stroke.
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Affiliation(s)
- Max I Myers
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
| | - Kevin J Hines
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
| | - Andrew Gray
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
| | - Gabrielle Spagnuolo
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
| | - Robert Rosenwasser
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA
| | - Lorraine Iacovitti
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA.
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA.
- Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA.
- Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Suite 462, Philadelphia, PA, 19107, USA.
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Radoszkiewicz K, Rybkowska P, Szymanska M, Krzesniak NE, Sarnowska A. The influence of biomimetic conditions on neurogenic and neuroprotective properties of dedifferentiated fat cells. Stem Cells 2025; 43:sxae066. [PMID: 39576128 PMCID: PMC11811640 DOI: 10.1093/stmcls/sxae066] [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: 05/06/2024] [Accepted: 09/30/2024] [Indexed: 02/12/2025]
Abstract
In the era of a constantly growing number of reports on the therapeutic properties of dedifferentiated, ontogenetically rejuvenated cells and their use in the treatment of neurological diseases, the optimization of their derivation and long-term culture methods seem to be crucial. One of the solutions is seen in the use of dedifferentiated fat cells (DFATs) that are characterized by a greater homogeneity. Moreover, these cells seem to possess a higher expression of transcriptional factors necessary to maintain pluripotency (stemness-related transcriptional factors) as well as a greater ability to differentiate in vitro into 3 embryonic germ layers, and a high proliferative potential in comparison to adipose stem/stromal cells. However, the neurogenic and neuroprotective potential of DFATs is still insufficiently understood; hence, our research goal was to contribute to our current knowledge of the subject. To recreate the brain's physiological (biomimetic) conditions, the cells were cultured at 5% oxygen concentration. The neural differentiation capacity of DFATs was assessed in the presence of the N21 supplement containing the factors that are typically found in the natural environment of the neural cell niche or in the presence of cerebrospinal fluid and under various spatial conditions (microprinting). The neuroprotective properties of DFATs were assessed using the coculture method with the ischemically damaged nerve tissue.
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Affiliation(s)
- Klaudia Radoszkiewicz
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02‐106 Warsaw, Poland
| | - Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02‐106 Warsaw, Poland
| | - Magdalena Szymanska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02‐106 Warsaw, Poland
| | - Natalia Ewa Krzesniak
- Department of Plastic and Reconstructive Surgery, Centre of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, 00‐416 Warsaw, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02‐106 Warsaw, Poland
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Trufanova N, Hubenia O, Kot Y, Trufanov O, Kovalenko I, Kot K, Petrenko O. Metabolic Mode of Alginate-Encapsulated Human Mesenchymal Stromal Cells as a Background for Storage at Ambient Temperature. Biopreserv Biobank 2024. [PMID: 39723454 DOI: 10.1089/bio.2024.0103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Introduction: Human mesenchymal stromal cells (MSCs) are attractive for both medical practice and biomedical research. Nonfreezing short-term storage may provide safe and simple transportation and promote the practical use of MSCs. Objectives: We aimed to determine the duration of efficient storage at ambient temperature (22°C) of human dermal MSCs in different three-dimensional organization and to investigate the role of cell metabolic mode in the resistance to the ambient storage damaging factors. Methods: MSCs in monolayer, suspension, and encapsulated in alginate microspheres (AMS) were stored in sealed containers at 22°С in culture medium. Viability (fluorescein diacetate /ethidium bromide) and metabolic activity (Alamar Blue assay) were assessed at 0, 3, 7, 10, and 14 days of the storage. Mitochondrial membrane potential (JC-1 test), cell cycle analysis, reactive oxygen species level, and resistance to hydrogen peroxide were analyzed under culture conditions. Results: Alginate encapsulation was shown to maintain viability (about 85%), metabolic activity, and adhesion ability during storage for 7 days. The storage of MSCs in both monolayer and suspension was less efficient. Culture of MSCs in AMS decreased basal metabolic activity, mitochondrial activity, and led to reversible cell cycle arrest compared to standard two-dimensional culture. MSCs in AMS have a lower basal level of reactive oxygen species and higher resistance to hydrogen peroxide compared with those in monolayer culture. Conclusion: Revealed shift into quiescent metabolic mode is essential for alginate-encapsulated MSCs resistance to storage at ambient temperature.
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Affiliation(s)
- Natalia Trufanova
- Institute for Problems of Cryobiology and Cryomedicine of National Academy of Sciences of Ukraine, Kharkiv, Ukraine
| | - Oleksandra Hubenia
- Institute for Problems of Cryobiology and Cryomedicine of National Academy of Sciences of Ukraine, Kharkiv, Ukraine
- Institute for Multiphase Processes, Leibniz University Hannover, Garbsen, Germany
| | - Yurii Kot
- V.N. Karazin Kharkiv National University, Kharkiv, Ukraine
| | - Oleh Trufanov
- Institute for Problems of Cryobiology and Cryomedicine of National Academy of Sciences of Ukraine, Kharkiv, Ukraine
| | - Ihor Kovalenko
- Institute for Problems of Cryobiology and Cryomedicine of National Academy of Sciences of Ukraine, Kharkiv, Ukraine
| | - Kateryna Kot
- V.N. Karazin Kharkiv National University, Kharkiv, Ukraine
| | - Oleksandr Petrenko
- Institute for Problems of Cryobiology and Cryomedicine of National Academy of Sciences of Ukraine, Kharkiv, Ukraine
- V.N. Karazin Kharkiv National University, Kharkiv, Ukraine
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Xie Y, Ma C, Zhu Q, Fu T, Bai L, Lan X, Liu L, Xiao J. Facial nerve regeneration via body-brain crosstalk: The role of stem cells and biomaterials. Neurobiol Dis 2024; 200:106650. [PMID: 39197536 DOI: 10.1016/j.nbd.2024.106650] [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: 06/24/2024] [Revised: 08/24/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024] Open
Abstract
The human body is a complex, integral whole, and disruptions in one organ can lead to dysfunctions in other parts of the organ network. The facial nerve, as the seventh cranial nerve, arises from the brainstem, controls facial expression muscles and plays a crucial role in brain-body communication. This vulnerable nerve can be damaged by trauma, inflammation, tumors, and congenital diseases, often impairing facial expression. Stem cells have gained significant attention for repairing peripheral nerve injuries due to their multidirectional differentiation potential. Additionally, various biomaterials have been used in tissue engineering for regeneration and repair. However, the therapeutic potential of stem cells and biomaterials in treating facial nerve injuries requires further exploration. In this review, we summarize the roles of stem cells and biomaterials in the regeneration and repair of damaged facial nerves, providing a theoretical basis for the recovery and reconstruction of body-brain crosstalk between the brain and facial expression muscles.
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Affiliation(s)
- Yuping Xie
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Chuan Ma
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Qiang Zhu
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Ting Fu
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Long Bai
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Xiaorong Lan
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China
| | - Lin Liu
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Jingang Xiao
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China.
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Zou XF, Zhang BZ, Qian WW, Cheng FM. Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury. World J Stem Cells 2024; 16:799-810. [PMID: 39219723 PMCID: PMC11362854 DOI: 10.4252/wjsc.v16.i8.799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.
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Affiliation(s)
- Xiong-Fei Zou
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Bao-Zhong Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
| | - Wen-Wei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Florence Mei Cheng
- College of Nursing, The Ohio State University, Ohio, OH 43210, United States
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Chrościńska-Kawczyk M, Zdolińska-Malinowska I, Boruczkowski D. The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study. Stem Cell Rev Rep 2024; 20:1636-1649. [PMID: 38877284 DOI: 10.1007/s12015-024-10742-2] [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] [Accepted: 05/27/2024] [Indexed: 06/16/2024]
Abstract
The aim of this study was to analyze the impact of human umbilical cord-derived MSCs (hUC-MSCs) on motor function in children with cerebral palsy (CP). The study enrolled 152 children with CP who received up to two courses of five hUC-MSCs injections. Children's motor functions were assessed with the Gross Motor Function Measure (GMFM), 6-Minute Walk Test (6-MWT), Timed Up and Go test (Up&Go test), and Lovett's test, and mental abilities were assessed with the Clinical Global Impression (CGI) scale. Data collected at visit 1 (baseline) and visit 5 (after four injections) were analyzed retrospectively. After four hUC-MSCs administrations, all evaluated parameters improved. The change in GMFM score, by a median of 1.9 points (IQR: 0.0-8.0), correlated with age. This change was observed in all GFMCS groups and was noticed in all assessed GMFM areas. A median increase of 75 m (IQR: 20.0-115.0) was noted on the 6-MWT, and this correlated with GMFM score change. Time on the Up&Go test was reduced by a median of 2 s (IQR: -3 to - 1) and the change correlated with age, GMFM score at baseline, and the difference observed on the 6-MWT. Results of Lovett's test indicated slight changes in muscle strength. According to the CGI, 75.5% (96/151) of children were seriously (level VI) or significantly ill (level V) at the 1st visit, with any improvement observed in 63.6% (96/151) of patients at the 5th visit, 23.8% (36/151) with improvement (level II) or great improvement (level I). In conclusion, the application of hUC-MSCs generally enhanced functional performance, but individual responses varied. The therapy also benefited children with high level of disability but not to the same extent as the initially less disabled children. Although younger patients responded better to the treatment, older children can also benefit. Trial Registration 152/2018/KB/VII and 119/2021/KB/VIII. Retrospective registration in ClinicalTrials: ongoing.
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10
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Coccini T, Caloni F, Russo LA, Villani L, Lonati D, De Simone U. 3D human stem-cell-derived neuronal spheroids for in vitro neurotoxicity testing of methylglyoxal, highly reactive glycolysis byproduct and potent glycating agent. Curr Res Toxicol 2024; 7:100176. [PMID: 38975063 PMCID: PMC11225170 DOI: 10.1016/j.crtox.2024.100176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/27/2024] [Accepted: 06/05/2024] [Indexed: 07/09/2024] Open
Abstract
Human-derived three-dimensional (3D) in vitro models are advanced human cell-based model for their complexity, relevance and application in toxicity testing. Intracellular accumulation of methylglyoxal (MGO), the most potent glycating agent in humans, mainly generated as a by-product of glycolysis, is associated with age-related diseases including neurodegenerative disorders. In our study, 3D human stem-cell-derived neuronal spheroids were set up and applied to evaluate cytotoxic effects after short-term (5 to 48 h) treatments with different MGO concentrations, including low levels, taking into consideration several biochemical endpoints. In MGO-treated neurospheroids, reduced cell growth proliferation and decreased cell viability occurred early from 5-10 μM, and their compactness diminished starting from 100 μM, apparently without affecting spheroid size. MGO markedly caused loss of the neuronal markers MAP-2 and NSE from 10-50 μM, decreased the detoxifying Glo1 enzyme from 50 μM, and activated NF-kB by nuclear translocation. The cytochemical evaluation of the 3D sections showed the presence of necrotic cells with loss of nuclei. Apoptotic cells were observed from 50 μM MGO after 48 h, and from 100 μM after 24 h. MGO (50-10 µM) also induced modifications of the cell-cell and cell-ECM interactions. These effects worsened at the higher concentrations (300-500 µM). In 3D neuronal spheroids, MGO tested concentrations comparable to human samples levels measured in MGO-associated diseases, altered neuronal key signalling endpoints relevant for the pathogenesis of neurodegenerative diseases and aging. The findings also demonstrated that the use of 3D neuronal spheroids of human origin can be useful in a strategy in vitro for testing MGO and other dicarbonyls evaluation.
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Affiliation(s)
- Teresa Coccini
- Istituti Clinici Scientifici Maugeri IRCCS, Laboratory of Clinical and Experimental Toxicology, and Pavia Poison Centre-National Toxicology Information Centre, Toxicology Unit, Pavia, Italy
| | - Francesca Caloni
- Dipartimento di Scienze e Politiche Ambientali (ESP), Università degli Studi di Milano, Milan, Italy
| | | | - Laura Villani
- Istituti Clinici Scientifici Maugeri IRCCS, Pathology Unit, Pavia, Italy
| | - Davide Lonati
- Istituti Clinici Scientifici Maugeri IRCCS, Laboratory of Clinical and Experimental Toxicology, and Pavia Poison Centre-National Toxicology Information Centre, Toxicology Unit, Pavia, Italy
| | - Uliana De Simone
- Istituti Clinici Scientifici Maugeri IRCCS, Laboratory of Clinical and Experimental Toxicology, and Pavia Poison Centre-National Toxicology Information Centre, Toxicology Unit, Pavia, Italy
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11
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Bellon A. Comparing stem cells, transdifferentiation and brain organoids as tools for psychiatric research. Transl Psychiatry 2024; 14:127. [PMID: 38418498 PMCID: PMC10901833 DOI: 10.1038/s41398-024-02780-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 01/08/2024] [Accepted: 01/12/2024] [Indexed: 03/01/2024] Open
Abstract
The inaccessibility of neurons coming directly from patients has hindered our understanding of mental illnesses at the cellular level. To overcome this obstacle, six different cellular approaches that carry the genetic vulnerability to psychiatric disorders are currently available: Olfactory Neuroepithelial Cells, Mesenchymal Stem Cells, Pluripotent Monocytes, Induced Pluripotent Stem Cells, Induced Neuronal cells and more recently Brain Organoids. Here we contrast advantages and disadvantages of each of these six cell-based methodologies. Neuronal-like cells derived from pluripotent monocytes are presented in more detail as this technique was recently used in psychiatry for the first time. Among the parameters used for comparison are; accessibility, need for reprograming, time to deliver differentiated cells, differentiation efficiency, reproducibility of results and cost. We provide a timeline on the discovery of these cell-based methodologies, but, our main goal is to assist researchers selecting which cellular approach is best suited for any given project. This manuscript also aims to help readers better interpret results from the published literature. With this goal in mind, we end our work with a discussion about the differences and similarities between cell-based techniques and postmortem research, the only currently available tools that allow the study of mental illness in neurons or neuronal-like cells coming directly from patients.
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Affiliation(s)
- Alfredo Bellon
- Penn State Hershey Medical Center, Department of Psychiatry and Behavioral Health, Hershey, PA, USA.
- Penn State Hershey Medical Center, Department of Pharmacology, Hershey, PA, USA.
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12
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Nguyen QT, Thanh LN, Hoang VT, Phan TTK, Heke M, Hoang DM. Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns. Cell Mol Neurobiol 2023; 43:3211-3250. [PMID: 37356043 PMCID: PMC11410020 DOI: 10.1007/s10571-023-01377-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 06/14/2023] [Indexed: 06/27/2023]
Abstract
Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.
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Affiliation(s)
- Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam.
- College of Health Science, Vin University, Vinhomes Ocean Park, Gia Lam District, Hanoi, 12400, Vietnam.
- Vinmec International Hospital-Times City, Vinmec Healthcare System, 458 Minh Khai, Hanoi, 11622, Vietnam.
| | - Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Trang T K Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
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13
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Lin WY, Wu KH, Chen CY, Guo BC, Chang YJ, Lee TA, Lin MJ, Wu HP. Stem Cell Therapy in Children with Traumatic Brain Injury. Int J Mol Sci 2023; 24:14706. [PMID: 37834152 PMCID: PMC10573043 DOI: 10.3390/ijms241914706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Pediatric traumatic brain injury is a cause of major mortality, and resultant neurological sequelae areassociated with long-term morbidity. Increasing studies have revealed stem cell therapy to be a potential new treatment. However, much work is still required to clarify the mechanism of action of effective stem cell therapy, type of stem cell therapy, optimal timing of therapy initiation, combination of cocurrent medical treatment and patient selection criteria. This paper will focus on stem cell therapy in children with traumatic brain injury.
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Affiliation(s)
- Wen-Ya Lin
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung 40705, Taiwan;
| | - Kang-Hsi Wu
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan;
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Chun-Yu Chen
- Department of Emergency Medicine, Tung’s Taichung MetroHarbor Hospital, Taichung 433, Taiwan;
- Department of Nursing, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 79-9, Taiwan
| | - Bei-Cyuan Guo
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
| | - Yu-Jun Chang
- Laboratory of Epidemiology and Biostastics, Changhua Christian Hospital, Changhua 500, Taiwan;
| | - Tai-An Lee
- Department of Emergency Medicine, Chang Bing Show Chwan Memorial Hospital, Changhua 505, Taiwan;
| | - Mao-Jen Lin
- Division of Cardiology, Department of Medicine, Taichung Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Taichung 427413, Taiwan
- Department of Medicine, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Han-Ping Wu
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pediatrics, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
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14
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Hwang J, Jang S, Kim C, Lee S, Jeong HS. Role of Stem Cell-Derived Exosomes and microRNAs in Spinal Cord Injury. Int J Mol Sci 2023; 24:13849. [PMID: 37762150 PMCID: PMC10530823 DOI: 10.3390/ijms241813849] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/30/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Neurological disorders represent a global health problem. Current pharmacological treatments often lead to short-term symptomatic relief but have dose-dependent side effects, such as inducing orthostatic arterial hypotension due to the blockade of alpha receptors, cardiotoxic effects due to impaired repolarization, and atrioventricular block and tachycardia, including ventricular fibrillation. These challenges have driven the medical community to seek effective treatments for this serious global health threat. Mesenchymal stem cells (MSCs) are pluripotent cells with anti-inflammatory, anti-apoptotic, and immunomodulatory properties, providing a promising alternative due to their ability to differentiate, favorable culture conditions, in vitro manipulation ability, and robust properties. Although MSCs themselves rarely differentiate into neurons at the site of injury after transplantation in vivo, paracrine factors secreted by MSCs can create environmental conditions for cell-to-cell communication and have shown therapeutic effects. Recent studies have shown that the pleiotropic effects of MSCs, particularly their immunomodulatory potential, can be attributed primarily to these paracrine factors. Exosomes derived from MSCs are known to play an important role in these effects. Many studies have evaluated the potential of exosome-based therapies for the treatment of various neurological diseases. In addition to exosomes, various miRNAs derived from MSCs have been identified to regulate genes and alleviate neuropathological changes in neurodegenerative diseases. This review explores the burgeoning field of exosome-based therapies, focusing on the effects of MSC-derived exosomes and exosomal miRNAs, and summarizes recent findings that shed light on the potential of exosomes in the treatment of neurological disorders. The insights gained from this review may pave the way for innovative and effective treatments for these complex conditions. Furthermore, we suggest the therapeutic effects of exosomes and exosomal miRNAs from MSCs, which have a rescue potential in spinal cord injury via diverse signaling pathways.
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Affiliation(s)
- Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
| | - Choonghyo Kim
- Department of Neurosurgery, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea;
| | - Sungjoon Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
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15
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Ou YC, Huang CC, Kao YL, Ho PC, Tsai KJ. Stem Cell Therapy in Spinal Cord Injury-Induced Neurogenic Lower Urinary Tract Dysfunction. Stem Cell Rev Rep 2023; 19:1691-1708. [PMID: 37115409 DOI: 10.1007/s12015-023-10547-9] [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] [Accepted: 04/14/2023] [Indexed: 04/29/2023]
Abstract
Spinal cord injury (SCI) is a devastating condition that enormously affects an individual's health and quality of life. Neurogenic lower urinary tract dysfunction (NLUTD) is one of the most important sequelae induced by SCI, causing complications including urinary tract infection, renal function deterioration, urinary incontinence, and voiding dysfunction. Current therapeutic methods for SCI-induced NLUTD mainly target on the urinary bladder, but the outcomes are still far from satisfactory. Stem cell therapy has gained increasing attention for years for its ability to rescue the injured spinal cord directly. Stem cell differentiation and their paracrine effects, including exosomes, are the proposed mechanisms to enhance the recovery from SCI. Several animal studies have demonstrated improvement in bladder function using mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Human clinical trials also provide promising results in urodynamic parameters after MSC therapy. However, there is still uncertainty about the ideal treatment window and application protocol for stem cell therapy. Besides, data on the therapeutic effects regarding NSCs and stem cell-derived exosomes in SCI-related NLUTD are scarce. Therefore, there is a pressing need for further well-designed human clinical trials to translate the stem cell therapy into a formal therapeutic option for SCI-induced NLUTD.
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Affiliation(s)
- Yin-Chien Ou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chen Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lin Kao
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Chuan Ho
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
| | - Kuen-Jer Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan.
- Research Center of Clinical Medicine, National Cheng Kung University Hospital , College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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16
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Salles M, Horikawa F, Allegrini Jr S, Zangrando D, Yoshimoto M, Shinohara E. Clinical evaluation of the perception of post-trauma paresthesia in the mandible, using a biomimetic material: A preliminary study in humans. Heliyon 2023; 9:e18304. [PMID: 37520975 PMCID: PMC10382299 DOI: 10.1016/j.heliyon.2023.e18304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/03/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023] Open
Abstract
There is a great effort from numerous research groups in the development of materials and therapeutic strategies for the functional recovery of patients who have suffered peripheral nerve injuries (PNI). In an article in vivo, the formation of a nerve bridge was observed, reconnecting the distal and proximal stumps, in the sciatic nerve of rats, indicating the effective participation of the biomaterial in the recovery of peripheral nerve injuries. For the current pilot study, 15 cases of multiple fractures of the mandible, with involvement of the inferior alveolar nerve (IAN) were selected and studied: JC (control cases) n = 6 with conventional treatment, and JT (treated cases) n = 9, with the use of biomimetic biomaterial. The evaluation of the return to sensitivity was measured through a self-assessment, where the patients assigned scores from 0 to 10, where zero (0) represented the complete absence of sensitivity and ten (10) the normality of the perception of local sensitivity. Patients were evaluated from the preoperative period to the 360th day. The statistical results obtained by the t-Student, Shapiro-Wilk normality and non-parametric One-Way ANOVA tests indicated statistically significant differences (p < 0.005; 0.005 e 0.5 respectively), between the two treatments, which were reflected in the clinical results observed, we also calculate the size of the effect represented by ϵ2, calculated by Cohen's d. The results indicate a great difference between the treatments performed,ϵ2 = 1.00. In the 6 cases followed up in the JC group, four remained with a significant deficit until the end of the evaluations and two indicated the remission of the lack of sensitivity in this period. In the JT group, in 28 days, all cases indicated complete remission of the lack of sensitivity with healing concentration. In one of the cases where there was a complete rupture of the mental nerve, the (score-10) was observed in 60 days. The observed results indicate the existence of a statistical significance between the groups and an important relationship when using the biomimetic biomaterial during the recovery of the perception of sensitivity in polytraumatized patients, compatible with the results observed in laboratory animals, which may indicate its clinical feasibility in the reduction of sequelae in PNI.
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Affiliation(s)
| | - F.K. Horikawa
- Depart. Oral and Maxillofac. Surg. Hospital Regional de Osasco SUS, São Paulo, Brazil
| | - S. Allegrini Jr
- Program in Biodentistry, Ibirapuera University (UNIB), São Paulo, SP, 04661 100, Brazil
- Católica Portuguesa University (UCP), Viseu, Portugal
| | - D. Zangrando
- Depart. Oral and Maxillofac. Surg. Hospital Regional de Osasco SUS, São Paulo, Brazil
- Department of Surgery Stomatology Pathology and Radiology of the Faculty of Dentistry of Bauru, University of São Paulo (FOB-USP) Bauru, São Paulo, Brazil
| | | | - E.H. Shinohara
- Depart. Oral and Maxillofac. Surg. Hospital Regional de Osasco SUS, São Paulo, Brazil
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Dave KM, Stolz DB, Manickam DS. Delivery of mitochondria-containing extracellular vesicles to the BBB for ischemic stroke therapy. Expert Opin Drug Deliv 2023; 20:1769-1788. [PMID: 37921194 DOI: 10.1080/17425247.2023.2279115] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/31/2023] [Indexed: 11/04/2023]
Abstract
INTRODUCTION Ischemic stroke-induced mitochondrial dysfunction in brain endothelial cells (BECs) leads to breakdown of the blood-brain barrier (BBB) causing long-term neurological dysfunction. Restoration of mitochondrial function in injured BECs is a promising therapeutic strategy to alleviate stroke-induced damage. Mounting evidence demonstrate that selected subsets of cell-derived extracellular vehicles (EVs), such as exosomes (EXOs) and microvesicles (MVs), contain functional mitochondrial components. Therefore, development of BEC-derived mitochondria-containing EVs for delivery to the BBB will (1) alleviate mitochondrial dysfunction and limit long-term neurological dysfunction in ischemic stroke and (2) provide an alternative therapeutic option for treating numerous other diseases associated with mitochondrial dysfunction. AREA COVERED This review will discuss (1) how EV subsets package different types of mitochondrial components during their biogenesis, (2) mechanisms of EV internalization and functional mitochondrial responses in the recipient cells, and (3) EV biodistribution and pharmacokinetics - key factors involved in the development of mitochondria-containing EVs as a novel BBB-targeted stroke therapy. EXPERT OPINION Mitochondria-containing MVs have demonstrated therapeutic benefits in ischemic stroke and other pathologies associated with mitochondrial dysfunction. Delivery of MV mitochondria to the BBB is expected to protect the BBB integrity and neurovascular unit post-stroke. MV mitochondria quality control, characterization, mechanistic understanding of its effects in vivo, safety and efficacy in different preclinical models, large-scale production, and establishment of regulatory guidelines are foreseeable milestones to harness the clinical potential of MV mitochondria delivery.
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Affiliation(s)
- Kandarp M Dave
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
| | - Donna B Stolz
- Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA, USA
| | - Devika S Manickam
- Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
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18
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Slovinska L, Harvanova D. The Role of Mesenchymal Stromal Cells and Their Products in the Treatment of Injured Spinal Cords. Curr Issues Mol Biol 2023; 45:5180-5197. [PMID: 37367078 DOI: 10.3390/cimb45060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023] Open
Abstract
Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.
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Affiliation(s)
- Lucia Slovinska
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, 040 01 Košice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
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Valsecchi C, Croce S, Lenta E, Acquafredda G, Comoli P, Avanzini MA. TITLE: New therapeutic approaches in pediatric diseases: Mesenchymal stromal cell and mesenchymal stromal cell-derived extracellular vesicles as new drugs. Pharmacol Res 2023; 192:106796. [PMID: 37207738 DOI: 10.1016/j.phrs.2023.106796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases.
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Affiliation(s)
- Chiara Valsecchi
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Stefania Croce
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Elisa Lenta
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Gloria Acquafredda
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Patrizia Comoli
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Maria Antonietta Avanzini
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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Jiang M, Jang SE, Zeng L. The Effects of Extrinsic and Intrinsic Factors on Neurogenesis. Cells 2023; 12:cells12091285. [PMID: 37174685 PMCID: PMC10177620 DOI: 10.3390/cells12091285] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
In the mammalian brain, neurogenesis is maintained throughout adulthood primarily in two typical niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles and in other nonclassic neurogenic areas (e.g., the amygdala and striatum). During prenatal and early postnatal development, neural stem cells (NSCs) differentiate into neurons and migrate to appropriate areas such as the olfactory bulb where they integrate into existing neural networks; these phenomena constitute the multistep process of neurogenesis. Alterations in any of these processes impair neurogenesis and may even lead to brain dysfunction, including cognitive impairment and neurodegeneration. Here, we first summarize the main properties of mammalian neurogenic niches to describe the cellular and molecular mechanisms of neurogenesis. Accumulating evidence indicates that neurogenesis plays an integral role in neuronal plasticity in the brain and cognition in the postnatal period. Given that neurogenesis can be highly modulated by a number of extrinsic and intrinsic factors, we discuss the impact of extrinsic (e.g., alcohol) and intrinsic (e.g., hormones) modulators on neurogenesis. Additionally, we provide an overview of the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to persistent neurological sequelae such as neurodegeneration, neurogenic defects and accelerated neuronal cell death. Together, our review provides a link between extrinsic/intrinsic factors and neurogenesis and explains the possible mechanisms of abnormal neurogenesis underlying neurological disorders.
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Affiliation(s)
- Mei Jiang
- Department of Human Anatomy, Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Dongguan Campus, Guangdong Medical University, Dongguan 523808, China
| | - Se Eun Jang
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore
| | - Li Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore
- Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, 11 Mandalay Road, Singapore 308232, Singapore
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21
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Maassen J, Guenther R, Hondrich TJJ, Cepkenovic B, Brinkmann D, Maybeck V, Offenhäusser A, Dittrich B, Müller A, Skazik-Voogt C, Kosel M, Baum C, Gutermuth A. In Vitro Simulated Neuronal Environmental Conditions Qualify Umbilical Cord Derived Highly Potent Stem Cells for Neuronal Differentiation. Stem Cell Rev Rep 2023:10.1007/s12015-023-10538-w. [PMID: 37093520 PMCID: PMC10390376 DOI: 10.1007/s12015-023-10538-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/25/2023]
Abstract
The healing of neuronal injuries is still an unachieved goal. Medicine-based therapies can only extend the survival of patients, but not finally lead to a healing process. Currently, a variety of stem cell-based tissue engineering developments are the subject of many research projects to bridge this gap. As yet, neuronal differentiation of induced pluripotent stem cells (iPS), embryonic cell lines, or neuronal stem cells could be accomplished and produce functional neuronally differentiated cells. However, clinical application of cells from these sources is hampered by ethical considerations. To overcome these hurdles numerous studies investigated the potential of adult mesenchymal stem cells (MSCs) as a potential stem cell source. Adult MSCs have been approved as cellular therapeutical products due to their regenerative potential and immunomodulatory properties. Only a few of these studies could demonstrate the capacity to differentiate MSCs into active firing neuron like cells. With this study we investigated the potential of Wharton's Jelly (WJ) derived stem cells and focused on the intrinsic pluripotent stem cell pool and their potential to differentiate into active neurons. With a comprehensive neuronal differentiation protocol comprised of mechanical and biochemical inductive cues, we investigated the capacity of spontaneously forming stem cell spheroids (SCS) from cultured WJ stromal cells in regard to their neuronal differentiation potential and compared them to undifferentiated spheroids or adherent MSCs. Spontaneously formed SCSs show pluripotent and neuroectodermal lineage markers, meeting the pre-condition for neuronal differentiation and contain a higher amount of cells which can be differentiated into cells whose functional phenotypes in calcium and voltage responsive electrical activity are similar to neurons. In conclusion we show that up-concentration of stem cells from WJ with pluripotent characteristics is a tool to generate neuronal cell replacement.
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Affiliation(s)
- Jessika Maassen
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Rebecca Guenther
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Timm J J Hondrich
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Bogdana Cepkenovic
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
- Department of Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany
| | - Dominik Brinkmann
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Vanessa Maybeck
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Andreas Offenhäusser
- Institute for Biological Information Processing, IBI-3, Forschungszentrum Jülich GmbH, Leo Brandtstrasse Station 71, 52425, Jülich, Germany
| | - Barbara Dittrich
- DWI-Leibniz Institute for Interactive Materials, Forckenbeckstrasse 50, 52074, Aachen, Germany
| | - Anna Müller
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Claudia Skazik-Voogt
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Maximilian Kosel
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Christoph Baum
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany
| | - Angela Gutermuth
- Department for Applied Cell Biology, Fraunhofer Institute for Production Technology, Steinbachstr. 17, 52074, Aachen, Germany.
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22
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Savitz SI, Cox CS. Cell-based therapies for neurological disorders - the bioreactor hypothesis. Nat Rev Neurol 2023; 19:9-18. [PMID: 36396913 DOI: 10.1038/s41582-022-00736-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2022] [Indexed: 11/18/2022]
Abstract
Cell-based therapies are an emerging biopharmaceutical paradigm under investigation for the treatment of a range of neurological disorders. Accumulating evidence is demonstrating that cell-based therapies might be effective, but the mechanism of action remains unclear. In this Review, we synthesize results from over 20 years of animal studies that illustrate how transdifferentiation, cell replacement and restoration of damaged tissues in the CNS are highly unlikely mechanisms. We consider the evidence for an alternative model that we refer to as the bioreactor hypothesis, in which exogenous cells migrate to peripheral organs and modulate and reprogramme host immune cells to generate an anti-inflammatory, regenerative environment. The results of clinical trials clearly demonstrate a role for immunomodulation in the effects of cell-based therapies. Greater understanding of these mechanisms could facilitate the optimization of cell-based therapies for a variety of neurological disorders.
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Affiliation(s)
- Sean I Savitz
- Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston, TX, USA. .,Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
| | - Charles S Cox
- Department of Pediatric Surgery, University of Texas Health Science Center, Houston, TX, USA
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23
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Bone Tissue and the Nervous System: What Do They Have in Common? Cells 2022; 12:cells12010051. [PMID: 36611845 PMCID: PMC9818711 DOI: 10.3390/cells12010051] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/16/2022] [Indexed: 12/25/2022] Open
Abstract
Degenerative diseases affecting bone tissues and the brain represent important problems with high socio-economic impact. Certain bone diseases, such as osteoporosis, are considered risk factors for the progression of neurological disorders. Often, patients with neurodegenerative diseases have bone fractures or reduced mobility linked to osteoarthritis. The bone is a dynamic tissue involved not only in movement but also in the maintenance of mineral metabolism. Bone is also associated with the generation of both hematopoietic stem cells (HSCs), and thus the generation of the immune system, and mesenchymal stem cells (MSCs). Bone marrow is a lymphoid organ and contains MSCs and HSCs, both of which are involved in brain health via the production of cytokines with endocrine functions. Hence, it seems clear that bone is involved in the regulation of the neuronal system and vice versa. This review summarizes the recent knowledge on the interactions between the nervous system and bone and highlights the importance of the interaction between nerve and bone cells. In addition, experimental models that study the interaction between nerve and skeletal cells are discussed, and innovative models are suggested to better evaluate the molecular interactions between these two cell types.
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24
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The Effect of Different Routes of Xenogeneic Mesenchymal Stem Cell Transplantation on the Regenerative Potential of Spinal Cord Injury. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022. [DOI: 10.1007/s40883-022-00290-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
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25
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Bjugstad K, Sanberg P. The boundlessness of behavioral neuroscience: A look across 30 years. Neurosci Biobehav Rev 2022; 142:104910. [DOI: 10.1016/j.neubiorev.2022.104910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/06/2022] [Indexed: 11/30/2022]
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26
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Exploring the Concept of In Vivo Guided Tissue Engineering by a Single-Stage Surgical Procedure in a Rodent Model. Int J Mol Sci 2022; 23:ijms232012703. [PMID: 36293558 PMCID: PMC9604108 DOI: 10.3390/ijms232012703] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/09/2022] [Accepted: 10/15/2022] [Indexed: 11/17/2022] Open
Abstract
In severe malformations with a lack of native tissues, treatment options are limited. We aimed at expanding tissue in vivo using the body as a bioreactor and developing a sustainable single-staged procedure for autologous tissue reconstruction in malformation surgery. Autologous micro-epithelium from skin was integrated with plastically compressed collagen and a degradable knitted fabric mesh. Sixty-three scaffolds were implanted in nine rats for histological and mechanical analyses, up to 4 weeks after transplantation. Tissue integration, cell expansion, proliferation, inflammation, strength, and elasticity were evaluated over time in vivo and validated in vitro in a bladder wound healing model. After 5 days in vivo, we observed keratinocyte proliferation on top of the transplant, remodeling of the collagen, and neovascularization within the transplant. At 4 weeks, all transplants were fully integrated with the surrounding tissue. Tensile strength and elasticity were retained during the whole study period. In the in vitro models, a multilayered epithelium covered the defect after 4 weeks. Autologous micro-epithelial transplants allowed for cell expansion and reorganization in vivo without conventional pre-operative in vitro cell propagation. The method was easy to perform and did not require handling outside the operating theater.
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27
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Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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28
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Kot M, Neglur PK, Pietraszewska A, Buzanska L. Boosting Neurogenesis in the Adult Hippocampus Using Antidepressants and Mesenchymal Stem Cells. Cells 2022; 11:cells11203234. [PMID: 36291101 PMCID: PMC9600461 DOI: 10.3390/cells11203234] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/06/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
The hippocampus is one of the few privileged regions (neural stem cell niche) of the brain, where neural stem cells differentiate into new neurons throughout adulthood. However, dysregulation of hippocampal neurogenesis with aging, injury, depression and neurodegenerative disease leads to debilitating cognitive impacts. These debilitating symptoms deteriorate the quality of life in the afflicted individuals. Impaired hippocampal neurogenesis is especially difficult to rescue with increasing age and neurodegeneration. However, the potential to boost endogenous Wnt signaling by influencing pathway modulators such as receptors, agonists, and antagonists through drug and cell therapy-based interventions offers hope. Restoration and augmentation of hampered Wnt signaling to facilitate increased hippocampal neurogenesis would serve as an endogenous repair mechanism and contribute to hippocampal structural and functional plasticity. This review focuses on the possible interaction between neurogenesis and Wnt signaling under the control of antidepressants and mesenchymal stem cells (MSCs) to overcome debilitating symptoms caused by age, diseases, or environmental factors such as stress. It will also address some current limitations hindering the direct extrapolation of research from animal models to human application, and the technical challenges associated with the MSCs and their cellular products as potential therapeutic solutions.
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Affiliation(s)
- Marta Kot
- Correspondence: ; Tel.: +48-22-60-86-563
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29
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Zhang X, Lei T, Wang D, Cai S, Hang Z, Yang Y, Bi W, Xiao Z, Du H. Stem cells from human exfoliated deciduous teeth relieves Alzheimer's disease symptoms in SAMP8 mice by up-regulating the PPARγ pathway. Biomed Pharmacother 2022; 152:113169. [PMID: 35689863 DOI: 10.1016/j.biopha.2022.113169] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 11/24/2022] Open
Abstract
The pathology of Alzheimer's disease (AD) is complex and heterogeneous, and there are currently no drugs that can stop its progression. The failure of traditional chemical small-molecule drug development showed the weakness of single target and made researchers look to cell therapy with multiple regulatory effects. Stem cells from human exfoliated deciduous teeth (SHED) are a kind of neural crest-derived mesenchymal stem cells which have broad prospects in the treatment of neurodegenerative diseases. In this study, we demonstrated the therapeutic effects of SHED in AD mice, including behavioral improvement, neuronal protection, and alleviation of neuroinflammation. Tracking experiments on SHED showed that some of the transplanted cells could enter the brain. To elucidate the role played by the majority of cells transplanted into veins, blood proteomic assays were performed. Data are available via ProteomeXchange with identifier PXD030313. Among the altered proteins, the PPAR pathway related to energy metabolism was considered to be an important signaling pathway involved in regulation through gene ontology analysis and pathway analysis. Western blot showed that the transplantation of SHED improved the glucose metabolism in AD mice by increasing the PPARγ signaling pathway. These results suggested that SHED have a potential in relieving AD pathological symptoms and improving behavioral cognition. The therapeutic mechanism of SHED is related to up-regulating PPARγ signaling pathway and reducing neuronal damage.
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Affiliation(s)
- Xiaoshuang Zhang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Tong Lei
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Donghui Wang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Shanglin Cai
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Zhongci Hang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Yanjie Yang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Wangyu Bi
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Zhuangzhuang Xiao
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China
| | - Hongwu Du
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China.
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30
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Adugna DG, Aragie H, Kibret AA, Belay DG. Therapeutic Application of Stem Cells in the Repair of Traumatic Brain Injury. Stem Cells Cloning 2022; 15:53-61. [PMID: 35859889 PMCID: PMC9289752 DOI: 10.2147/sccaa.s369577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/10/2022] [Indexed: 12/03/2022] Open
Abstract
Traumatic brain injury is the main cause of injury-related deaths and disabilities throughout the world, which is characterized by a disruption of the normal physiology of the brain following trauma. It can potentially cause severe complications such as physical, cognitive, and emotional impairment. In addition to understanding traumatic brain injury pathophysiology, this review explains the therapeutic potential of stem cells following brain injury in two pathways: response of endogenous neurogenic cells and transplantation of exogenous stem cell therapy. After traumatic brain injuries, clinical evidence indicated that endogenous neural progenitor cells might play an important role in regenerative medicine to treat brain injury. This is due to an increased neurogenic regeneration ability of these cells following brain injury. Besides, exogenous stem cell transplantation has also accelerated immature neuronal development and increased endogenous cellular proliferation in the damaged brain region. Therefore, a better understanding of the endogenous neural stem cell’s regenerative ability and the effect of exogenous stem cells on proliferation and differentiation ability may help researchers to understand how to increase functional recovery and tissue repair following injury.
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Affiliation(s)
- Dagnew Getnet Adugna
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Hailu Aragie
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Anteneh Ayelign Kibret
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
| | - Daniel Gashaneh Belay
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia.,Department of Epidemiology, Institution of Public Health, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
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31
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Jafarzadeh E, Soodi M, Tiraihi T, Zarei M, Qasemian-Lemraski M. Study of lead-induced neurotoxicity in cholinergic cells differentiated from bone marrow-derived mesenchymal stem cells. Toxicol Ind Health 2022; 38:655-664. [PMID: 35838060 DOI: 10.1177/07482337221115514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The developing brain is susceptible to the neurotoxic effects of lead. Exposure to lead has main effects on the cholinergic system and causes reduction of cholinergic neuron function during brain development. Disruption of the cholinergic system by chemicals, which play important roles during brain development, causes of neurodevelopmental toxicity. Differentiation of stem cells to neural cells is recently considered a promising tool for neurodevelopmental toxicity studies. This study evaluated the toxicity of lead acetate exposure during the differentiation of bone marrow-derived mesenchyme stem cells (bone marrow stem cells, BMSCs) to cholinergic neurons. Following institutional animal care review board approval, BMSCs were obtained from adult rats. The differentiating protocol included two stages that were pre-induction with β-mercaptoethanol (BME) for 24 h and differentiation to cholinergic neurons with nerve growth factor (NGF) over 5 days. The cells were exposed to different lead acetate concentrations (0.1-100 μm) during three stages, including undifferentiated, pre-induction, and neuronal differentiation stages; cell viability was measured by MTT assay. Lead exposure (0.01-100 μg/ml) had no cytotoxic effect on BMSCs but could significantly reduce cell viability at 50 and 100 μm concentrations during pre-induction and neuronal differentiation stages. MAP2 and choline acetyltransferase (ChAT) protein expression were investigated by immunocytochemistry. Although cells treated with 100 μm lead concentration expressed MAP2 protein in the differentiation stages, they had no neuronal cell morphology. The ChAT expression was negative in cells treated with lead. The present study showed that differentiated neuronal BMSCs are sensitive to lead toxicity during differentiation, and it is suggested that these cells be used to study neurodevelopmental toxicity.
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Affiliation(s)
- Emad Jafarzadeh
- Department of Toxicology, Faculty of Medical Sciences, 48503Tarbiat Modares University, Tehran, Iran
| | - Maliheh Soodi
- Department of Toxicology, Faculty of Medical Sciences, 48503Tarbiat Modares University, Tehran, Iran
| | - Taki Tiraihi
- Department of Anatomical Sciences, Faculty of Medical Sciences, 41616Tarbiat Modares University, Tehran, Iran
| | - Mohammadhadi Zarei
- Medical Plants Research Center, 154205Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mehdi Qasemian-Lemraski
- Department of Toxicology, Faculty of Medical Sciences, 48503Tarbiat Modares University, Tehran, Iran
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32
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Borah R, Das JM, Upadhyay J. Surface Functionalized Polyaniline Nanofibers:Chitosan Nanocomposite for Promoting Neuronal-like Differentiation of Primary Adipose Derived Mesenchymal Stem Cells and Urease Activity. ACS APPLIED BIO MATERIALS 2022; 5:3193-3211. [PMID: 35775198 DOI: 10.1021/acsabm.2c00171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Bioscaffolds having electrically conducting polymers (CPs) have become increasingly relevant in tissue engineering (TE) because of their ability to regulate conductivity and promote biological function. With this in mind, the current study shows a conducting polyaniline nanofibers (PNFs) dispersed chitosan (Ch) nanocomposites scaffold with a simple one-step surface functionalization approach using glutaraldehyde for potential neural regeneration applications. According to the findings, 4 wt % PNFs dispersion in Ch matrix is an optimal concentration for achieving desirable biological functions while maintaining required physicochemical properties as evidenced by SEM, XRD, current-voltage (I-V) measurement, mechanical strength test, and in vitro biodegradability test. Surface chemical compositional analysis using XPS and ATR FT-IR confirms the incorporation of aldehyde functionality after functionalization, which is corroborated by surface energy calculations following the Van Oss-Chaudhury-Good method. Surface functionalization induced enhancement in surface hydrophilicity in terms of the polar component of surface energy (γiAB) from 6.35 to 12.54 mN m-1 along with an increase in surface polarity from 13.61 to 22.54%. Functionalized PNF:Ch scaffolds demonstrated improvement in enzyme activity from 67 to 94% and better enzyme kinetics with a reduction of Michaelis constants (Km) from 21.55 to 13.81 mM, indicating favorable protein-biomaterial interactions and establishing them as biologically perceptible materials. Surface functionalization mediated improved cell-biomaterial interactions led to improved viability, adhesion, and spreading of primary adipose derived mesenchymal stem cells (ADMSCs) as well as improved immunocompatibility. Cytoskeletal architecture assessment under differentiating media containing 10 ng/mL of each basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) revealed significant actin remodeling with neurite-like projections on the functionalized scaffolds after 14 days. Immunocytochemistry results showed that more than 85% of cells expressed early neuron specific β III tubulin protein on the functionalized scaffolds, whereas glial fibrillary acidic protein (GFAP) expression was limited to approximately 40% of cells. The findings point to the functionalized nanocomposites' potential as a smart scaffold for electrically stimulated neural regeneration, as they are flexible enough to be designed into microchanneled or conduit-like structures that mimic the microstructures and mechanical properties of peripheral nerves.
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Affiliation(s)
- Rajiv Borah
- Seri-Biotechnology Laboratory, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati 781035, India
| | - Jitu Mani Das
- Seri-Biotechnology Laboratory, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati 781035, India
| | - Jnanendra Upadhyay
- Department of Physics, Dakshin Kamrup College, Kamrup, Assam 781125, India
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33
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Xie JL, Wang XR, Li MM, Tao ZH, Teng WW, Saijilafu. Mesenchymal Stromal Cell Therapy in Spinal Cord Injury: Mechanisms and Prospects. Front Cell Neurosci 2022; 16:862673. [PMID: 35722621 PMCID: PMC9204037 DOI: 10.3389/fncel.2022.862673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.
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Affiliation(s)
- Ji-Le Xie
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Xing-Ran Wang
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Mei-Mei Li
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Zi-Han Tao
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Wen-Wen Teng
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Saijilafu
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China,*Correspondence: Saijilafu,
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Derkus B, Isik M, Eylem CC, Ergin I, Camci CB, Bilgin S, Elbuken C, Arslan YE, Akkulak M, Adali O, Kiran F, Okesola BO, Nemutlu E, Emregul E. Xenogenic Neural Stem Cell-Derived Extracellular Nanovesicles Modulate Human Mesenchymal Stem Cell Fate and Reconstruct Metabolomic Structure. Adv Biol (Weinh) 2022; 6:e2101317. [PMID: 35347890 DOI: 10.1002/adbi.202101317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/02/2022] [Indexed: 01/27/2023]
Abstract
Extracellular nanovesicles, particularly exosomes, can deliver their diverse bioactive biomolecular content, including miRNAs, proteins, and lipids, thus providing a context for investigating the capability of exosomes to induce stem cells toward lineage-specific cells and tissue regeneration. In this study, it is demonstrated that rat subventricular zone neural stem cell-derived exosomes (rSVZ-NSCExo) can control neural-lineage specification of human mesenchymal stem cells (hMSCs). Microarray analysis shows that the miRNA content of rSVZ-NSCExo is a faithful representation of rSVZ tissue. Through immunocytochemistry, gene expression, and multi-omics analyses, the capability to use rSVZ-NSCExo to induce hMSCs into a neuroglial or neural stem cell phenotype and genotype in a temporal and dose-dependent manner via multiple signaling pathways is demonstrated. The current study presents a new and innovative strategy to modulate hMSCs fate by harnessing the molecular content of exosomes, thus suggesting future opportunities for rSVZ-NSCExo in nerve tissue regeneration.
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Affiliation(s)
- Burak Derkus
- Stem Cell Research Lab, Department of ChemistryFaculty of Science, Ankara University, Ankara, 06560, Turkey.,Interdisciplinary Research Unit for Advanced Materials (INTRAM) Department of Chemistry, Faculty of Science, Ankara University, Ankara, 06560, Turkey
| | - Melis Isik
- Interdisciplinary Research Unit for Advanced Materials (INTRAM) Department of Chemistry, Faculty of Science, Ankara University, Ankara, 06560, Turkey
| | - Cemil Can Eylem
- Analytical Chemistry Division, Faculty of Pharmacy, Hacettepe University, Ankara, 06530, Turkey
| | - Irem Ergin
- Department of Surgery, Faculty of Veterinary Medicine, Ankara University, Turkey
| | - Can Berk Camci
- Interdisciplinary Research Unit for Advanced Materials (INTRAM) Department of Chemistry, Faculty of Science, Ankara University, Ankara, 06560, Turkey
| | - Sila Bilgin
- Interdisciplinary Research Unit for Advanced Materials (INTRAM) Department of Chemistry, Faculty of Science, Ankara University, Ankara, 06560, Turkey
| | - Caglar Elbuken
- UNAM-National Nanotechnology Research Center, Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, 06800, Turkey.,Faculty of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland
| | - Yavuz Emre Arslan
- Regenerative Biomaterials Laboratory, Department of Bioengineering, Engineering Faculty, Canakkale Onsekiz Mart University, Canakkale, 17100, Turkey
| | - Merve Akkulak
- Department of Biological Sciences, Faculty of Science, Middle East Technical University, Ankara, 06800, Turkey
| | - Orhan Adali
- Department of Biological Sciences, Faculty of Science, Middle East Technical University, Ankara, 06800, Turkey
| | - Fadime Kiran
- Department of Biology, Faculty of Science, Ankara University, Ankara, 06560, Turkey
| | - Babatunde O Okesola
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, L7 8TX, UK
| | - Emirhan Nemutlu
- Analytical Chemistry Division, Faculty of Pharmacy, Hacettepe University, Ankara, 06530, Turkey.,Bioanalytic and Omics Laboratory, Faculty of Pharmacy, Hacettepe University, Ankara, 06530, Turkey
| | - Emel Emregul
- Interdisciplinary Research Unit for Advanced Materials (INTRAM) Department of Chemistry, Faculty of Science, Ankara University, Ankara, 06560, Turkey
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Wang J, Wang T, Zhang F, Zhang Y, Guo Y, Jiang X, Yang B. Roles of circular RNAs in osteogenic differentiation of bone marrow mesenchymal stem cells (Review). Mol Med Rep 2022; 26:227. [PMID: 35593273 PMCID: PMC9178710 DOI: 10.3892/mmr.2022.12743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/10/2022] [Indexed: 11/06/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts, chondrocytes, adipocytes and even myoblasts, and are therefore defined as pluripotent cells. BMSCs have become extremely important seed cells in gene therapy, tissue engineering, cell replacement therapy and regenerative medicine due to their potential in multilineage differentiation, self‑renewal, immune regulation and other fields. Circular RNAs (circRNAs) are a class of non‑coding RNAs that are widely present in eukaryotic cells. Unlike standard linear RNAs, circRNAs form covalently closed continuous loops with no 5' or 3' polarity. circRNAs are abundantly expressed in cells and tissues, and are highly conserved and relatively stable during evolution. Numerous studies have shown that circRNAs play an important role in the osteogenic differentiation of BMSCs. Further studies on the role of circRNAs in the osteogenic differentiation of BMSCs can provide a new theoretical and experimental basis for bone tissue engineering and clinical treatment.
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Affiliation(s)
- Jicheng Wang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Tengyun Wang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Fujie Zhang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Yangyang Zhang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Yongzhi Guo
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Xin Jiang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Bo Yang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
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Che H, Selig M, Rolauffs B. Micro-patterned cell populations as advanced pharmaceutical drugs with precise functional control. Adv Drug Deliv Rev 2022; 184:114169. [PMID: 35217114 DOI: 10.1016/j.addr.2022.114169] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Human cells are both advanced pharmaceutical drugs and 'drug deliverers'. However, functional control prior to or after cell implantation remains challenging. Micro-patterning cells through geometrically defined adhesion sites allows controlling morphogenesis, polarity, cellular mechanics, proliferation, migration, differentiation, stemness, cell-cell interactions, collective cell behavior, and likely immuno-modulatory properties. Consequently, generating micro-patterned therapeutic cells is a promising idea that has not yet been realized and few if any steps have been undertaken in this direction. This review highlights potential therapeutic applications, summarizes comprehensively the many cell functions that have been successfully controlled through micro-patterning, details the established micro-pattern designs, introduces the available fabrication technologies to the non-specialized reader, and suggests a quality evaluation score. Such a broad review is not yet available but would facilitate the manufacturing of therapeutically patterned cell populations using micro-patterned cell-instructive biomaterials for improved functional control as drug delivery systems in the context of cells as pharmaceutical products.
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Affiliation(s)
- Hui Che
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; Orthopedics and Sports Medicine Center, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215006, China
| | - Mischa Selig
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany
| | - Bernd Rolauffs
- G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center-Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany.
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The Effect of Oral Mucosal Mesenchymal Stem Cells on Pathological and Long-Term Outcomes in Experimental Traumatic Brain Injury. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4065118. [PMID: 35528162 PMCID: PMC9071883 DOI: 10.1155/2022/4065118] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/26/2022] [Accepted: 04/09/2022] [Indexed: 01/10/2023]
Abstract
Background Neuroprotective effects of stem cells have been shown in some neurologic diseases. In this study, the effect of oral mucosal mesenchymal stem cells (OMSCs) on traumatic brain injury (TBI) was evaluated in long term. Materials and Methods TBI was induced by Marmarou's method. The number of 2 × 106 OMSCs was intravenously injected 1 and 24 h after the injury. Brain edema and pathological outcome were assessed at 24 h and 21 days after the injury. Besides, long-term neurological, motor, and cognitive outcomes were evaluated at days 3, 7, 14, and 21 after the injury. Results OMSCs administration could significantly inhibit microglia proliferation, and reduce brain edema and neuronal damage, at 24 h and 21 days after the injury. Neurological function improvement was observed in the times evaluated in OMSCs group. Cognitive and motor function dysfunction and anxiety-like behavior were prevented especially at 14 and 21 days after the injury in the treatment group. Conclusion According to the results of this study, OMSCs administration after TBI reduced brain edema and neuronal damage, improved neurologic outcome, and prevented memory and motor impairments and anxiety-like behavior in long term.
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Holzer AK, Suciu I, Karreman C, Goj T, Leist M. Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro. Int J Mol Sci 2022; 23:ijms23073734. [PMID: 35409095 PMCID: PMC8998302 DOI: 10.3390/ijms23073734] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 12/18/2022] Open
Abstract
Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca2+-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50−200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.
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Affiliation(s)
- Anna-Katharina Holzer
- In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany; (A.-K.H.); (I.S.); (C.K.); (T.G.)
| | - Ilinca Suciu
- In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany; (A.-K.H.); (I.S.); (C.K.); (T.G.)
- Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, 78457 Konstanz, Germany
| | - Christiaan Karreman
- In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany; (A.-K.H.); (I.S.); (C.K.); (T.G.)
| | - Thomas Goj
- In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany; (A.-K.H.); (I.S.); (C.K.); (T.G.)
| | - Marcel Leist
- In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany; (A.-K.H.); (I.S.); (C.K.); (T.G.)
- CAAT-Europe, University of Konstanz, 78457 Konstanz, Germany
- Correspondence: ; Tel.: +49-(0)-7531-88-5037
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Monsour M, Ebedes D, Borlongan CV. A review of the pathology and treatment of TBI and PTSD. Exp Neurol 2022; 351:114009. [PMID: 35150737 DOI: 10.1016/j.expneurol.2022.114009] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/25/2021] [Accepted: 02/05/2022] [Indexed: 02/07/2023]
Abstract
This literature review focuses on the underlying pathophysiology of TBI and PTSD symptoms, while also examining the plethora of stem cell treatment options to ameliorate these neuronal and functional changes. As more veterans return suffering from TBI and/or PTSD, it is vital that researchers discover novel therapies to mitigate the detrimental symptoms of both diagnoses. A variety of stem cell treatments have been studied and offer hopeful options for TBI and PTSD recovery.
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Affiliation(s)
- Molly Monsour
- Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Dominique Ebedes
- Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA
| | - Cesario V Borlongan
- Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA.
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40
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Identification of circRNA Expression Profiles in BMSCs from Glucocorticoid-Induced Osteoporosis Model. Stem Cells Int 2022; 2022:3249737. [PMID: 35154330 PMCID: PMC8837445 DOI: 10.1155/2022/3249737] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 01/09/2022] [Indexed: 02/07/2023] Open
Abstract
Background. Circular RNAs (circRNAs) contribute to the regulation of many diseases. However, little is known about the role of circRNAs in the development of glucocorticoid-induced osteoporosis (GIOP). The present study is aimed at systematically characterizing the circRNA expression profiles in GIOP and predict the potential functions of the associated regulatory networks. Methods. A small animal GIOP model was developed in Sprague-Dawley rats given daily intraperitoneal doses of the synthetic glucocorticoid dexamethasone. Micro-CT and bone histomorphometry were performed to characterize the bone loss. Alizarin red S (ARS) staining and alkaline phosphatase (ALP) activity were assessed to determine the osteogenic differentiation potential of BMSCs. RNA sequencing was performed to identify differentially expressed circRNAs in BMSCs between the GIOP and normal groups, which were validated by qRT-PCR. siRNA interference experiments were used to demonstrate their function. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the functions of differentially expressed circRNAs. The microRNA (miRNA) targets of the circRNAs and circRNA-miRNA interactions were predicted. Results. Micro-CT and bone histomorphometry confirmed the rat GIOP model. Both ARS intensity and ALP activity were decreased in GIOP BMSCs. Seventeen circRNAs were identified by
,
, and
, of which 7 were upregulated and 10 were downregulated. The qRT-PCR results of the selected circRNAs were consistent with the RNA-seq results and showed that circARSB and circAKT3 were significantly upregulated, while circPTEN and circTRPM7 were downregulated in the GIOP group. Further functional experiments found that downregulation of circARSB and circPTEN expression resulted in a corresponding change in osteogenic differentiation, suggesting that circARSB negatively, while circPTEN positively, regulates BMSC osteogenic differentiation. Analysis of circRNA-targeted miRNAs predicted that miR-135a-5p was associated with circARSB and circAKT3, and miR-881-3p was associated with circPTEN and circTRPM7. Furthermore, the signalling pathways associated with these differentially expressed circRNAs were predicted. Conclusions. The present study identified circARSB, circAKT3, circPTEN, and circTRPM7 as being associated with osteogenic differentiation during GIOP through a circRNA-targeted miRNA-mRNA axis, which might provide insight into the pathophysiological mechanism of GIOP.
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Yoshimi R, Nakajima H. Current State and Issues of Regenerative Medicine for Rheumatic Diseases. Front Med (Lausanne) 2022; 9:813952. [PMID: 35155499 PMCID: PMC8831787 DOI: 10.3389/fmed.2022.813952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/05/2022] [Indexed: 12/15/2022] Open
Abstract
The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.
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Rahman MM, Islam MR, Islam MT, Harun-Or-Rashid M, Islam M, Abdullah S, Uddin MB, Das S, Rahaman MS, Ahmed M, Alhumaydhi FA, Emran TB, Mohamed AAR, Faruque MRI, Khandaker MU, Mostafa-Hedeab G. Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives. BIOLOGY 2022; 11:147. [PMID: 35053145 PMCID: PMC8772847 DOI: 10.3390/biology11010147] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases are a global health issue with inadequate therapeutic options and an inability to restore the damaged nervous system. With advances in technology, health scientists continue to identify new approaches to the treatment of neurodegenerative diseases. Lost or injured neurons and glial cells can lead to the development of several neurological diseases, including Parkinson's disease, stroke, and multiple sclerosis. In recent years, neurons and glial cells have successfully been generated from stem cells in the laboratory utilizing cell culture technologies, fueling efforts to develop stem cell-based transplantation therapies for human patients. When a stem cell divides, each new cell has the potential to either remain a stem cell or differentiate into a germ cell with specialized characteristics, such as muscle cells, red blood cells, or brain cells. Although several obstacles remain before stem cells can be used for clinical applications, including some potential disadvantages that must be overcome, this cellular development represents a potential pathway through which patients may eventually achieve the ability to live more normal lives. In this review, we summarize the stem cell-based therapies that have been explored for various neurological disorders, discuss the potential advantages and drawbacks of these therapies, and examine future directions for this field.
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Affiliation(s)
- Mohammad Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Touhidul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Harun-Or-Rashid
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mahfuzul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sabirin Abdullah
- Space Science Center, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia;
| | - Mohammad Borhan Uddin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Sumit Das
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Mohammad Saidur Rahaman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Muniruddin Ahmed
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.T.I.); (M.H.-O.-R.); (M.I.); (M.B.U.); (S.D.); (M.S.R.); (M.A.)
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia;
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | | | | | - Mayeen Uddin Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Bandar Sunway 47500, Selangor, Malaysia;
| | - Gomaa Mostafa-Hedeab
- Pharmacology Department & Health Sciences Research Unit, Medical College, Jouf University, Sakaka 72446, Saudi Arabia;
- Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62521, Egypt
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Belkozhayev AM, Al-Yozbaki M, George A, Niyazova RY, Sharipov KO, Byrne LJ, Wilson CM. Extracellular Vesicles, Stem Cells and the Role of miRNAs in Neurodegeneration. Curr Neuropharmacol 2022; 20:1450-1478. [PMID: 34414870 PMCID: PMC9881087 DOI: 10.2174/1570159x19666210817150141] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/16/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022] Open
Abstract
There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington's disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.
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Affiliation(s)
- Ayaz M. Belkozhayev
- Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Republic of Kazakhstan
- Structural and Functional Genomics Laboratory of M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, Almaty, Republic of Kazakhstan
| | - Minnatallah Al-Yozbaki
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
| | - Alex George
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
- Jubilee Centre for Medical Research, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala, India
| | - Raigul Ye Niyazova
- Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Republic of Kazakhstan
| | - Kamalidin O. Sharipov
- Structural and Functional Genomics Laboratory of M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, Almaty, Republic of Kazakhstan
| | - Lee J. Byrne
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
| | - Cornelia M. Wilson
- Canterbury Christ Church University, School of Human and Life Sciences, Life Sciences Industry Liaison Lab, Sandwich, UK
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Kim GU, Sung SE, Kang KK, Choi JH, Lee S, Sung M, Yang SY, Kim SK, Kim YI, Lim JH, Seo MS, Lee GW. Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury. Int J Mol Sci 2021; 22:13672. [PMID: 34948463 PMCID: PMC8703906 DOI: 10.3390/ijms222413672] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date.
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Affiliation(s)
- Gang-Un Kim
- Department of Orthopedic Surgery, Hanil General Hospital, 308 Uicheon-ro, Dobong-gu, Seoul 01450, Korea;
| | - Soo-Eun Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Kyung-Ku Kang
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Joo-Hee Choi
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Sijoon Lee
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Minkyoung Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Seung Yun Yang
- Department of Biomaterials Science, Life and Industry Convergence Institute, Pusan National University, Miryang 50463, Korea;
| | - Seul-Ki Kim
- Efficacy Evaluation Team, Food Science R&D Center, KolmarBNH CO., LTD, 61Heolleungro 8-gil, Seocho-gu, Seoul 06800, Korea;
| | | | - Ju-Hyeon Lim
- New Drug Development Center, Osong Medical Innovation Foundation, Chungbuk 28160, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
| | - Min-Soo Seo
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Gun Woo Lee
- Cellexobio, Co. Ltd., Daegu 42415, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
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Gupta A, Singh S. Potential Role of Growth Factors Controlled Release in Achieving Enhanced Neuronal Trans-differentiation from Mesenchymal Stem Cells for Neural Tissue Repair and Regeneration. Mol Neurobiol 2021; 59:983-1001. [PMID: 34816381 DOI: 10.1007/s12035-021-02646-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
With an increase in the incidence of neurodegenerative diseases, a need to replace incapable conventional methods has arisen. To overcome this burden, stem cells therapy has emerged as an efficient treatment option. Endeavours to accomplish this have paved the path to neural regeneration through efficient neuronal transdifferentiation. Despite their potential, the use of stem cells still entails several limitations, such as low differentiation efficiency and difficulties in guiding differentiation. The process of neural differentiation through the stem cells is achieved through the use of chemical inducers or growth factors and their direct introduction reduces their bioavailability in the system. To address these limitations, neural regeneration ventures require growth factors to be effectively implemented on stem cells in order to produce functional neuronal precursor cells. An efficient technique to achieve it is through the delivery of growth factors via microcarriers for their sustained release. It ensures the presence of commensurable concentration even at later stages of neuronal transdifferentiation. Nanofibers and nanoparticles, along with liposomes and such, have been used to implement this. The interaction between such carriers and the growth factors is mainly electrostatic. Such interaction enables them to form a stable assembly through immobilisation of the growth factor either onto their surfaces or within the core of their structures. The rate of sustained release depends upon the release kinetics associated with the polymeric structure employed and its interaction with the encapsulated growth factor. The sustained release ensures that the stem cells immerse under the effect of the growth factors for a prolonged period, ultimately aiding in the formation of cells showing ample characteristics of neuron precursors. This review analyses the various carriers that have been employed for the release of growth factors in an orderly fashion and their constituents, along with the advantages and the limitations they pose in delivering the growth factors for facilitating the process of neuronal transdifferentiation.
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Affiliation(s)
- Ayushi Gupta
- Applied Science Department, Indian Institute of Information Technology, Allahabad, UP, India
| | - Sangeeta Singh
- Applied Science Department, Indian Institute of Information Technology, Allahabad, UP, India.
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Assunção Silva RC, Pinto L, Salgado AJ. Cell transplantation and secretome based approaches in spinal cord injury regenerative medicine. Med Res Rev 2021; 42:850-896. [PMID: 34783046 DOI: 10.1002/med.21865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023]
Abstract
The axonal growth-restrictive character of traumatic spinal cord injury (SCI) makes finding a therapeutic strategy a very demanding task, due to the postinjury events impeditive to spontaneous axonal outgrowth and regeneration. Considering SCI pathophysiology complexity, it has been suggested that an effective therapy should tackle all the SCI-related aspects and provide sensory and motor improvement to SCI patients. Thus, the current aim of any therapeutic approach for SCI relies in providing neuroprotection and support neuroregeneration. Acknowledging the current SCI treatment paradigm, cell transplantation is one of the most explored approaches for SCI with mesenchymal stem cells (MSCs) being in the forefront of many of these. Studies showing the beneficial effects of MSC transplantation after SCI have been proposing a paracrine action of these cells on the injured tissues, through the secretion of protective and trophic factors, rather than attributing it to the action of cells itself. This manuscript provides detailed information on the most recent data regarding the neuroregenerative effect of the secretome of MSCs as a cell-free based therapy for SCI. The main challenge of any strategy proposed for SCI treatment relies in obtaining robust preclinical evidence from in vitro and in vivo models, before moving to the clinics, so we have specifically focused on the available vertebrate and mammal models of SCI currently used in research and how can SCI field benefit from them.
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Affiliation(s)
- Rita C Assunção Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Wu SH, Liao YT, Huang CH, Chen YC, Chiang ER, Wang JP. Comparison of the Confluence-Initiated Neurogenic Differentiation Tendency of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells. Biomedicines 2021; 9:biomedicines9111503. [PMID: 34829732 PMCID: PMC8615071 DOI: 10.3390/biomedicines9111503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/27/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs), which tended to neurogenically differentiate spontaneously after achieving high confluence, were observed. Human ADSCs reaching 80% confluence were cultured in DMEM without an inducing factor for 24 h and then maintained in DMEM plus 1% FBS medium for 7 days. The neurogenic, adipogenic, and osteogenic genes of the factor-induced and confluence-initiated differentiation of the ADSCs and bone marrow-derived mesenchymal stem cells (BMSCs) at passages 3 to 5 were determined and compared using RT-qPCR, and the neurogenic differentiation was confirmed using immunofluorescent staining. In vitro tests revealed that the RNA and protein expression of neuronal markers, including class III β-tubulin (TUBB3), microtubule-associated protein 2 (MAP2), neurofilament medium polypeptide (NEFM), neurofilament heavy polypeptide (NEFH), and neurofilament light polypeptide (NEFL), had been enhanced in the confluence-initiated differentiation of the ADSCs. In addition, the expressions of neurotrophins, such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), were also elevated in the confluence-initiated differentiation of the ADSCs. However, the confluent ADSCs did not show a tendency toward spontaneous adipogenic and osteogenic differentiation. Moreover, compared with the confluent ADSCs, the tendency of spontaneous neurogenic, adipogenic, and osteogenic differentiation of the confluent human bone marrow mesenchymal stem cells (BMSCs) was not observed. The results indicated that ADSCs had the potential to spontaneously differentiate into neuron-like cells during the confluent culture period; however, this tendency was not observed in BMSCs.
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Affiliation(s)
- Szu-Hsien Wu
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 112, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Chi-Han Huang
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
| | - Yi-Chou Chen
- Department of Orthopedics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan;
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- Correspondence: ; Tel.: +886-2-2875-7557; Fax: +886-2-2875-7657
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Ma Y, Zhang Q, Yang K, Ma J, Pan R, Lu G. Ultra-structural morphology analysis of human cranial bone marrow mesenchymal stromal cells during neural differentiation. Neurosci Lett 2021; 763:136179. [PMID: 34416344 DOI: 10.1016/j.neulet.2021.136179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/31/2021] [Accepted: 08/15/2021] [Indexed: 10/20/2022]
Abstract
Neural differentiation of mesenchymal stromal cells has been widely studied. However, a comparative characterization of ultrastructural changes during neural differentiation has not been performed. In this study, we conducted scanning electron microscopy and transmission electron microscopy analysis to show the morphological changes in mesenchymal stromal cells upon induction of neural differentiation. In addition, transmission electron microscopy results demonstrated ultrastructural differences between human cranial bone marrow mesenchymal stromal cells and iliac crest bone marrow mesenchymal stromal cells. We propose that enriched microvesicles in cranial bone marrow mesenchymal stromal cells may be responsible for the increased efficiency of neural differentiation.
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Affiliation(s)
- Yuyuan Ma
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China
| | - Qulin Zhang
- Department of Neurosurgery, Nanxun People's Hospital, Huzhou 313009, PR China
| | - Kaichuang Yang
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China
| | - Jie Ma
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, P R China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou 311121, PR China; Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou 311121, PR China.
| | - Gang Lu
- Department of Neurosurgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, PR China.
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MILI BHABESH, DAS KINSUK, P MADHUSOODANA, KUMAR KULDEEP, SAXENA AC, BAG SADHAN. Transdifferentiation of canine mesenchymal stem cells into neuron-like cells by induction with β-mercaptoethanol. THE INDIAN JOURNAL OF ANIMAL SCIENCES 2021. [DOI: 10.56093/ijans.v91i7.115900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The objective of this study was to check whether β- mercaptoethanol in a culture medium can induce the neuronal differentiation of canine MSCs. The canine bonemarrow derived MSCs were first pre-inducted with 1 mM BME for 24 hrs followed by induction in a serum-free medium supplemented with 4 mM BME without FBS for another 6 days. Morphological changes in MSCs from spindle-shaped to neuron-like branching from the edges of the cells were noticed at the end of induction. These neuronlike cells were found positive for the immunophenotypic expression of different neural cell markers β-tubulin III, MAP-2 and Nestin. In RT-PCR analysis, it was also evident that the relative expressions of these representative genes were significantly higher in the differentiated cells. On the basis of our observations, it can be summarized that the BME induction of canine MSCs resulted in morphological changes that resembled neuron-like cells which were found to express the representative neuronal markers. Therefore, inducing canine MSCs with BME resulted in the generation of neuron-like cells that might be utilized for the prospective therapeutic applications in veterinary medicine.
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Strategies to Improve the Efficiency of Transplantation with Mesenchymal Stem Cells for the Treatment of Ischemic Stroke: A Review of Recent Progress. Stem Cells Int 2021; 2021:9929128. [PMID: 34490053 PMCID: PMC8418553 DOI: 10.1155/2021/9929128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022] Open
Abstract
Cerebral ischemia is a common global disease that is characterized by a loss of neurological function and a poor prognosis in many patients. However, only a limited number of treatments are available for this condition at present. Given that the efficacies of these treatments tend to be poor, cerebral ischemia can create a significant burden on patients, families, and society. Mesenchymal stem cell (MSC) transplantation treatment has shown significant potential in animal models of ischemic stroke; however, the specific mechanisms underlying this effect have yet to be elucidated. Furthermore, clinical trials have yet to yield promising results. Consequently, there is an urgent need to identify new methods to improve the efficiency of MSC transplantation as an optimal treatment for ischemic stroke. In this review, we provide an overview of recent scientific reports concerning novel strategies that promote MSC transplantation as an effective therapeutic approach, including physical approaches, chemical agents, traditional Chinese medicines and extracts, and genetic modification. Our analyses showed that two key factors need to be considered if we are to improve the efficacy of MSC transplantation treatments: survival ability and homing ability. We also highlight the importance of other significant mechanisms, including the enhanced activation of MSCs to promote neurogenesis and angiogenesis, and the regulation of permeability in the blood-brain barrier. Further in-depth investigations of the specific mechanisms underlying MSC transplantation treatment will help us to identify effective methods that improve the efficiency of MSC transplantation for ischemic stroke. The development of safer and more effective methods will facilitate the application of MSC transplantation as a promising adjuvant therapy for the treatment of poststroke brain damage.
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