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Casap N, Dvir-Ginzberg M, Jensen OT, Alterman M. The bone growing concept: A call for a paradigm shift in bone reconstruction. Br J Oral Maxillofac Surg 2025; 63:276-290. [PMID: 40199672 DOI: 10.1016/j.bjoms.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/07/2024] [Accepted: 11/29/2024] [Indexed: 04/10/2025]
Abstract
Alveolar bone reconstruction has significantly evolved over the years. The transition from bone transfer techniques to bone regeneration methods aimed to reduce morbidity, increase the available reservoir of bone, and enhance volumetric outcomes. However, current bone regeneration techniques are prolonged and yield suboptimal biological results. This is primarily because the process relies heavily on bone substitutes that lack osteoinductive or osteogenic properties, with the supply of cells and growth factors entirely dependent on endogenous sources. This article calls for a new paradigm shift, proposing a biological approach for more controlled bone growth by the incorporation of exogenous cells and growth factors into a bone-growing process, thereby enhancing biological outcomes over time. Additionally, it presents a biomorphometric clinical algorithm to tailor treatment protocols for various types of bone loss.
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Affiliation(s)
- Nardy Casap
- Faculty of Dental Medicine, Hebrew University of Jerusalem, PO Box 12272, Jerusalem 9112102, Israel; Department of Oral and Maxillofacial Surgery, Hadassah Medical Center, Jerusalem, Israel.
| | - Mona Dvir-Ginzberg
- Institute for BioMedical and Oral Research, Faculty of Dental Medicine, Hebrew University- Ein Kerem Campus, Israel.
| | - Ole T Jensen
- Department Oral Maxillofacial Surgery, School of Dentistry, University of Utah, Salt Lake City, UT, USA.
| | - Michael Alterman
- Faculty of Dental Medicine, Hebrew University of Jerusalem, PO Box 12272, Jerusalem 9112102, Israel; Department of Oral and Maxillofacial Surgery, Hadassah Medical Center, Jerusalem, Israel.
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2
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Meligy FY, Mohammed HSED, Abou Elghait AT, Mohamed HK, Ashry IESM, Abdel-Rahman Sayed A, Hussein OA, Salman A, Atia T, Mohamed AS, Behnsawy NH, Gaber SS, Sakr HI, Ahmed SF. Mesenchymal stem cells versus mesenchymal stem cells-derived exosomes as potential autophagy pathway modulators in a diabetic model. Adv Med Sci 2025; 70:152-165. [PMID: 39956208 DOI: 10.1016/j.advms.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/06/2024] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
PURPOSE This work compared the potential effects of bone marrow mesenchymal stem cells (BM-MSCs) with BM-MSCs-derived exosomes against impaired autophagy in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS Three days after STZ injection, a single dose of (3 × 10^6) BM- MSCs or BM-MSCs-derived exosomes (80 μg/rat) was administered to evaluate their effects against nondiabetic and diabetic control rats. We assessed pancreatic structure via light and electron microscopy and evaluated its staining for insulin and the autophagy marker P62 immunohistochemically. Moreover, autophagy marker LC3 gene expression was examined by PCR. RESULTS Both BM-MSCs and BM-MSCs derived exosomes showed histological restoration of pancreatic tissues. Both treatments markedly increased the amount of insulin and significantly decreased the autophagy markers P62 and LC3. CONCLUSION Our findings suggest that both BM-MSCs and BM-MSCs-derived exosomes provides a potential alternative to modulate diabetes mellitus.
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Affiliation(s)
- Fatma Y Meligy
- Department of Restorative Dentistry and Basic Medical Sciences, Faculty of Dentistry, University of Petra, Amman, Jordan; Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Amal T Abou Elghait
- Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut, Egypt; Histology and Cell Biology Department, Sphinx University, New Assiut city, Assiut, Egypt
| | - Heba K Mohamed
- Anatomy and Embryology Department, Faculty of Medicine, Assiut University, Assiut, Egypt; Anatomy and Embryology Department, Sphinx University, New Assiut city, Assiut, Egypt
| | | | - Ayat Abdel-Rahman Sayed
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt; Department of Biochemistry, Sphinx University, New Assiut city, Assiut, Egypt
| | - Ola A Hussein
- Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Salman
- Department of Anatomy and Histology, Faculty of Medicine, The University of Jordan, Amman, Jordan; Department of Anatomy, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Tarek Atia
- Department of Medical Laboratories, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Abir S Mohamed
- Department of Public Health, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Nour H Behnsawy
- Faculty of Medicine, Assiut University, Assiut, Egypt; Skilled Medical Practitioners Focus Area Coordinator 24/25, International Federation of Medical Students Association, Egypt
| | - Safy Salah Gaber
- Department of Medical Physiology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Hader I Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt; Department of Medical Physiology, General Medicine Practice Program, Batterjee Medical College, Jeddah, 21442, Saudi Arabia.
| | - Salwa Fares Ahmed
- Histology and Cell Biology Department, Faculty of Medicine, Assiut University, Assiut, Egypt; Anatomy Department, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
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Kąpa M, Koryciarz I, Kustosik N, Jurowski P, Pniakowska Z. Future Directions in Diabetic Retinopathy Treatment: Stem Cell Therapy, Nanotechnology, and PPARα Modulation. J Clin Med 2025; 14:683. [PMID: 39941353 PMCID: PMC11818668 DOI: 10.3390/jcm14030683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/16/2025] Open
Abstract
This narrative review focuses on innovative treatment approaches to diabetic retinopathy to meet the urgent demand for advancements in managing both the early and late stages of the disease. Recent studies highlight the potential of adipose stem cells and their secreted factors in mitigating the retinal complications of diabetes, with promising results in improving visual acuity and reducing inflammation and angiogenesis in diabetic retinopathy. However, caution is warranted regarding the safety and long-term therapeutic effects of adipose stem cells transplantation. Bone marrow mesenchymal stem cells can also mitigate retinal damage in diabetic retinopathy. Studies demonstrate that bone marrow mesenchymal stem cells-derived exosomes can suppress the Wnt/β-catenin pathway, reducing oxidative stress, inflammation, and angiogenesis in the diabetic retina, offering promise for future diabetic retinopathy treatments. Nanotechnology has the ability to precisely target the retina and minimize systemic side effects. Nanoparticles and nanocarriers offer improved bioavailability, sustained release of therapeutics, and potential for synergistic effects. They can be a new way of effective treatment and prevention of diabetic retinopathy. Activation and modulation of PPARα as a means for diabetic retinopathy treatment has been widely investigated in recent years and demonstrated promising effects in clinical trials. PPARα activation turned out to be a promising therapeutic method for treating dyslipidemia, inflammation, and insulin sensitivity. The combination of PPARα modulators with small molecules offers an interesting perspective for retinal diseases' therapy.
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Affiliation(s)
- Maria Kąpa
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Iga Koryciarz
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Natalia Kustosik
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Piotr Jurowski
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Zofia Pniakowska
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
- Optegra Eye Clinic, 90-127 Lodz, Poland
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Tan YL, Ju SH, Wang Q, Zhong R, Gao JH, Wang MJ, Kang YL, Xu MZ. Shuanglongjiegu pill promoted bone marrow mesenchymal stem cell osteogenic differentiation by regulating the miR-217/RUNX2 axis to activate Wnt/β-catenin pathway. J Orthop Surg Res 2024; 19:617. [PMID: 39350234 PMCID: PMC11443779 DOI: 10.1186/s13018-024-05085-0] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/14/2024] [Indexed: 10/04/2024] Open
Abstract
This study aimed to investigate the effects of Shuanglongjiegu pill (SLJGP) on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explore its mechanism based on miR-217/RUNX2 axis. Results found that drug-containing serum of SLJGP promoted BMSCs viability with a dose-dependent effect. Under osteogenic differentiation conditions, SLJGP promoted the expression of ALP, OPN, BMP2, RUNX2, and the osteogenic differentiation ability of BMSCs. In addition, SLJGP significantly reduced miR-217 expression, and miR-217 directly targeted RUNX2. After treatment with miR-217 mimic, the promoting effects of SLJGP on proliferation and osteogenic differentiation of BMSCs were significantly inhibited. MiR-217 mimic co-treated with pcDNA-RUNX2 further confirmed that the miR-217/RUNX2 axis was involved in SLJGP to promote osteogenic differentiation of BMSCs. In addition, analysis of Wnt/β-catenin pathway protein expression showed that SLJGP activated the Wnt/β-catenin pathway through miR-217/RUNX2. In conclusion, SLJGP promoted osteogenic differentiation of BMSCs by regulating miR-217/RUNX2 axis and activating Wnt/β-catenin pathway.
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Affiliation(s)
- You-Li Tan
- Department of Pharmacy, Affiliated Sport Hospital of CDSU, Chengdu Sport University, Chengdu, 610041, China.
| | - Shao-Hua Ju
- Department of Pharmacy, Affiliated Sport Hospital of CDSU, Chengdu Sport University, Chengdu, 610041, China
| | - Qiang Wang
- Department of Rehabilitation of sports medicine, Affiliated Sport Hospital of CDSU, Chengdu Sport University, Chengdu, 610041, China
| | - Rui Zhong
- Department of Orthopedics, Affiliated Sports Hospital of Chengdu Sport University, Chengdu, 610041, China
| | - Ji-Hai Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Ming-Jian Wang
- Department of Pharmacy, Affiliated Sport Hospital of CDSU, Chengdu Sport University, Chengdu, 610041, China
| | - Ya-Lan Kang
- Department of Pharmacy, Affiliated Sport Hospital of CDSU, Chengdu Sport University, Chengdu, 610041, China
| | - Meng-Zhang Xu
- Department of Neck, Shoulder, Waist, and Leg Pain, Sichuan Province Orthopedic Hospital, Chengdu, Sichuan, China
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Picazo RA, Rojo C, Rodriguez-Quiros J, González-Gil A. Current Advances in Mesenchymal Stem Cell Therapies Applied to Wounds and Skin, Eye, and Neuromuscular Diseases in Companion Animals. Animals (Basel) 2024; 14:1363. [PMID: 38731367 PMCID: PMC11083242 DOI: 10.3390/ani14091363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 04/27/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are considered a very promising alternative tool in cell therapies and regenerative medicine due to their ease of obtaining from various tissues and their ability to differentiate into different cell types. This manuscript provides a review of current knowledge on the use of MSC-based therapies as an alternative for certain common pathologies in dogs and cats where conventional treatments are ineffective. The aim of this review is to assist clinical veterinarians in making decisions about the suitability of each protocol from a clinical perspective, rather than focusing solely on research. MSC-based therapies have shown promising results in certain pathologies, such as spinal cord injuries, wounds, and skin and eye diseases. However, the effectiveness of these cell therapies can be influenced by a wide array of factors, leading to varying outcomes. Future research will focus on designing protocols and methodologies that allow more precise and effective MSC treatments for each case.
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Affiliation(s)
- Rosa Ana Picazo
- Department of Physiology, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Concepción Rojo
- Department of Anatomy and Embryology, School of Veterinary Medicine, University Complutense of Madrid, 28040 Madrid, Spain;
| | - Jesus Rodriguez-Quiros
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Alfredo González-Gil
- Department of Physiology, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
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Cao YY, Ning J, Zhang RZ, Ge K, Huang TT. Characterization of CM-Dil-labeled Muse cells in culture and in skin wounds in rats. Cell Tissue Bank 2024; 25:285-294. [PMID: 36617377 DOI: 10.1007/s10561-022-10067-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023]
Abstract
To investigate the characteristics of multilineage-differentiating stress-enduring (Muse) cells labeled with chloromethyl dialkylcarbocyanine (CM-Dil) in culture and in skin wounds of rats. Normal human dermal fibroblasts (NHDFs) were obtained from foreskins and were confirmed by immunocytochemistry with vimentin. Muse cells were derived from NHDFs using long-term trypsinization (LTT), were confirmed using immunocytochemistry with antibodies against stage specific embryonic antigen-3 (SSEA-3) and CD105 and were expanded in suspension cultures. The Muse cells were labeled with CM-Dil and were further evaluated with respect to their biological properties using CCK-8 assays and scratch tests. One hundred µl CM-Dil-labeled Muse cells at a concentration of 5 × 103/µl were injected subcutaneously at the edges of skin wounds in adult male SD rats. At weeks 1, 3 and 5 after the injection, the distribution of CM-Dil-labeled Muse cells in skin tissues was observed using immunofluorescence microscopy. Muse cells were double-positive for CD105 and SSEA-3. ALP staining of the M-clusters were positive and they displayed orange-red fluorescence after labelling with CM-Dil, which had no adverse effects on their viability, migration or differentiation capacity. One week after the subcutaneous injection of CM-Dil-labeled Muse cells, many cells with orange-red fluorescence were observed at the edges of the skin injuries; those fluorescent spots gradually decreased over time, and only a few Muse cells with fluorescence could be detected by week 5. CM-Dil can be used to label Muse cells without affecting their proliferation, migration or differentiation, and can be used for short-term tracking of Muse cells for the treatment of skin wounds in a rat model.
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Affiliation(s)
- Yan-Yun Cao
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jing Ning
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ru-Zhi Zhang
- The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Kang Ge
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ting-Ting Huang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
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Qiu L, Ma L, Chen D, Zhang N, Cai J, Zhang Q, Wang X, Yi H, Yao H, Fan FY. Novel_circ_003686 regulates the osteogenic differentiation of MSCs in patients with myeloma bone disease through miR-142-5p/IGF1 axis. J Bone Oncol 2023; 43:100509. [PMID: 38021072 PMCID: PMC10654027 DOI: 10.1016/j.jbo.2023.100509] [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: 07/13/2023] [Revised: 10/13/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Objectives Circ_003686 is a novel_circRNA with abnormally low expression found in the samples of multiple myeloma bone disease (MBD) patients. The current research intended to investigate the effects of novel_circ_003686 in osteogenesis-induced differentiation of bone marrow mesenchymal stem cells (BMSCs) in MBD. Methods BMSCs were extracted from MBD patients and normal participants, the pcDNA3.1 encoding the circ_003686 (ov-circ_003686), miR-142-5p-mimic/inhibitor and siRNA oligonucleotides targeting insulin like growth factor 1 (IGF1, si-IGF1) were applied to intervene circ_003686, miR-142-5p and IGF1 levels, respectively. Results: Results showed that ov-circ_003686 could mediate the osteogenesis-induced differentiation of MBD-BMSC, and luciferase assay and RIP experiments confirmed that circ_003686 could bind to miR-142-5p. MiR-142-5p-inhibitor helped osteogenesis-induced differentiation, while miR-142-5p-mimic inhibited osteogenesis-induced differentiation and reversed the promoting effect of ov-circ_003686, suggesting that circ_003686/miR-142-5p axis participated in osteogenesis-induced differentiation of MBD-BMSC. In addition, miR-142-5p binds to the target gene IGF1 and negatively adjust its expression. Si-IGF1 significantly inhibited the osteogenesis-induced differentiation and reversed the promotion effects of miR-142-5p-inhibitor and ov-circ_003686. Moreover, circ_003686/miR-142-5p/IGF1 axis meaningfully regulates protein expressions in the PI3K/AKT pathway. Conclusion In conclusion, this research confirmed that circ_003686 regulated the osteogenesis-induced differentiation of MBD-BMSC by sponging miR-142-5p and mediating IGF1, and the PI3K/AKT pathway may also be involved.
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Affiliation(s)
| | | | | | - Nan Zhang
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Jiao Cai
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Qian Zhang
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Xiao Wang
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Hai Yi
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Hao Yao
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
| | - Fang-Yi Fan
- Department of Hematology and Hematopoietic Stem Cell Transplantation Center, General Hospital of the Chinese People’s Liberation Army Western Theatre, Chengdu, SiChuan, China
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Satyadev N, Rivera MI, Nikolov NK, Fakoya AOJ. Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications. Front Physiol 2023; 14:1241096. [PMID: 37745252 PMCID: PMC10515224 DOI: 10.3389/fphys.2023.1241096] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.
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Affiliation(s)
- Nihal Satyadev
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Milagros I. Rivera
- University of Medicine and Health Sciences, Basseterre, St. Kitts and Nevis
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Velasco MG, Satué K, Chicharro D, Martins E, Torres-Torrillas M, Peláez P, Miguel-Pastor L, Del Romero A, Damiá E, Cuervo B, Carrillo JM, Cugat R, Sopena JJ, Rubio M. Multilineage-Differentiating Stress-Enduring Cells (Muse Cells): The Future of Human and Veterinary Regenerative Medicine. Biomedicines 2023; 11:biomedicines11020636. [PMID: 36831171 PMCID: PMC9953712 DOI: 10.3390/biomedicines11020636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
In recent years, several studies have been conducted on Muse cells mainly due to their pluripotency, high tolerance to stress, self-renewal capacity, ability to repair DNA damage and not being tumoral. Additionally, since these stem cells can be isolated from different tissues in the adult organism, obtaining them is not considered an ethical problem, providing an advantage over embryonic stem cells. Regarding their therapeutic potential, few studies have reported clinical applications in the treatment of different diseases, such as aortic aneurysm and chondral injuries in the mouse or acute myocardial infarction in the swine, rabbit, sheep and in humans. This review aims to describe the characterization of Muse cells, show their biological characteristics, explain the differences between Muse cells and mesenchymal stem cells, and present their contribution to the treatment of some diseases.
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Affiliation(s)
- María Gemma Velasco
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Katy Satué
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Emma Martins
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Laura Miguel-Pastor
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Ayla Del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Elena Damiá
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Belén Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - José María Carrillo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Ramón Cugat
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Joaquín Jesús Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
- Correspondence:
| | - Mónica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
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Roohaninasab M, Seifadini A, Atefi N, Sadeghzadeh-Bazargan A, Goodarzi A, Hanifnia AR, Nouri M, Zare S, Moradi S, Dehghani A, Nilforoushzadeh MA, Behrangi E. Evaluating the effectiveness of stromal-vascular fraction (SVF) cells along with subcision method in the treatment of acne scars: A double-blind randomized controlled clinical trial study. J Cosmet Dermatol 2022; 21:6928-6938. [PMID: 36086927 DOI: 10.1111/jocd.15375] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/29/2022] [Accepted: 09/07/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND Subcision method is one of the main techniques for treatment of acne scars or stromal-vascular fraction (SVF) and combined therapy can improve treatment strategy. OBJECTIVE To use subcision method along with SVF for treatment of acne scar and comprised with alone subcision method. MATERIALS AND METHODS In this double-blind clinical trial study, 10 patients with acne scars were entered into the study. Subcision technique was randomly performed on one side of the face and subcision technique plus SVF on opposite side of the face. All patients were examined before treatment and after 3 months by Visioface for volume, area, and depth of scars, as well as thickness and density of the epidermis and dermis of the scars in question. In addition, doctor's and patients' satisfaction, tolerability, and safety were determined after 3 months of treatment. Finally, statistical analysis was done by SPPS, version 25. RESULTS In terms of volume and area of scars, the mean percent change was 46.55 ± 13.92 and 44.60 ± 5.76, for the case group, and 13.31 ± 9.27 and 11.28 ± 9.64 for the control group, respectively. So, combined therapy led to significant recovery compared with alone subcision method (p value < 0.001). In both interventions, the increase of density and thickness was proven after treatment, also a significant difference in complete, epidermal, and dermal thickness and epidermal density variables was observed between combined therapy and alone subcision (p value < 0.05). Mean score of doctor's and patients' satisfaction in combined therapy (7.10 ± 0.74 and 7.10 ± 0.99, respectively), was also significantly higher than subcision alone (5.50 ± 0.53 and 5.30 ± 1.25, respectively). Finally, no complications were observed in the patients. CONCLUSION According to the acquired results, combined therapy can be considered as effective and safe treatment for acne scars with significant higher efficacy compared with subcision alone.
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Affiliation(s)
- Masoumeh Roohaninasab
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Seifadini
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Najmolsadat Atefi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Sadeghzadeh-Bazargan
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Goodarzi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Hanifnia
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Nouri
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sona Zare
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Stem Cell and Regenerative Medicine Center, Sharif University of Technology, Tehran, Iran
| | - Sepideh Moradi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Dehghani
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Nilforoushzadeh
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Skin Repair Research Center, Jordan Dermatology and Hair Transplantation Center, Tehran, Iran
| | - Elham Behrangi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
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11
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Serrano A, Osei KA, Huertas-Bello M, Sabater AL. The Potential of Stem Cells as Treatment for Ocular Surface Diseases. CURRENT OPHTHALMOLOGY REPORTS 2022. [DOI: 10.1007/s40135-022-00303-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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12
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Lv Z, Duan S, Zhou M, Gu M, Li S, Wang Y, Xia Q, Xu D, Mao Y, Dong W, Jiang L. Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1. Mol Pharm 2022; 19:4254-4263. [PMID: 36173129 DOI: 10.1021/acs.molpharmaceut.2c00542] [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: 11/29/2022]
Abstract
Sepsis is a global disease burden, and approximately 40% of cases develop acute lung injury (ALI). Bone marrow mesenchymal stromal cells (BMSCs) and their exosomes are widely used in treating a variety of diseases including sepsis. As an acute phase protein, serum amyloid A1 (SAA1) regulates inflammation and immunity. However, the role of SAA1 in BMSCs-exosomes in septic lung injury remains to be elucidated. Exosomes derived from serum and BMSCs were isolated by ultracentrifugation. SAA1 was silenced or overexpressed in mouse BMSCs using lentiviral plasmids, containing either SAA1-targeting short interfering RNAs or SAA1 cDNA. Sepsis was induced by cecal ligation and puncture (CLP). LPS was used to induce ALI in mice. Mouse alveolar macrophages were isolated by flow cytometry. Levels of SAA1, endotoxin, TNF-α, and IL-6 were measured using commercial kits. LPS internalization was monitored by immunostaining. RT-qPCR or immunoblots were performed to test gene and protein expressions. Serum exosomes of patients with sepsis-induced lung injury had significantly higher levels of SAA1, endotoxin, TNF-α, and IL-6. Overexpression of SAA1 in BMSCs inhibited CLP- or LPS-induced lung injury and decreased CLP- or LPS-induced endotoxin, TNF-α, and IL-6 levels. Administration of the SAA1 blocking peptide was found to partially inhibit SAA1-induced LPS internalization by mouse alveolar macrophages and reverse the protective effect of SAA1. In conclusion, BMSCs inhibit sepsis-induced lung injury through exosomal SAA1. These results highlight the importance of BMSCs, exosomes, and SAA1, which may provide novel directions for the treatment of septic lung injury.
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Affiliation(s)
- Zhou Lv
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Shuxian Duan
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Miao Zhou
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Minglu Gu
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Siyuan Li
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Yan Wang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Qin Xia
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Dunfeng Xu
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Yanfei Mao
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Wenwen Dong
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai 200092, China
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13
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TGF-β1-induced bone marrow mesenchymal stem cells (BMSCs) migration via histone demethylase KDM6B mediated inhibition of methylation marker H3K27me3. Cell Death Dis 2022; 8:339. [PMID: 35902563 PMCID: PMC9334584 DOI: 10.1038/s41420-022-01132-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/09/2022] [Accepted: 07/15/2022] [Indexed: 01/02/2023]
Abstract
Mesenchymal stem cells (MSCs) are widely used in clinical research and therapy. Since the number of MSCs migration is extremely crucial at the lesion site, exploring the mechanisms to enhance the migration of MSCs is necessary. Therefore, this study focused on the epigenetic mechanisms in MSCs migration. TGF-β1 stimulated bone marrow mesenchymal stem cells (BMSCs) to promote cell migration at lesion sites in vitro and in vivo. The mRNA and protein levels of several migration-related genes (N cadherin, CXCR4, FN1) were enhanced. The trimethylation marker H3K27me3 recruitment on the promoter of these genes were studied to dissect the epigenetic mechanisms. TGF-β1 elevated the levels of KDM6B leading to removal of repression marker H3K27me3 in the promoter region of N cadherins and FN1. Congruently, knockdown of demethylase KDM6B substantially affected the TGF-β1 induced BMSCs migration. This promoted the down-regulation of various migration-related genes. Collectively, epigenetic regulation played an important role in BMSCs migration, and H3K27me3 was at least partially involved in the migration of BMSCs induced by TGF-β1.
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14
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Furuta A, Kuroda Y, Yamamoto T, Egawa S, Dezawa M, Yoshimura N. Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model. Int Urogynecol J 2022; 33:1293-1301. [PMID: 35333929 DOI: 10.1007/s00192-022-05166-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/25/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION AND HYPOTHESIS We investigated the effects of locally administered human multilineage-differentiating stress enduring (Muse) cells, nontumorigenic pluripotent-like endogenous stem cells, on bladder tissues, function, and nociceptive behavior in a chemically induced Hunner-type interstitial cystitis (HIC)-like rat model without immunosuppressant. METHODS Chemical cystitis was induced by intravesical instillation of 0.2 N hydrochloride (HCl) for 15 min in female F344 rats. SSEA-3+ Muse cells, SSEA-3- non-Muse cells or Hanks' balanced salt solution (HBSS; vehicle) were injected into the anterior and posterior bladder wall at each 1×104 cells/10 μl 6 h after HCl application. The sham group received HBSS without HCl instillation. Urinary frequency was assessed using metabolic cages, cystometrograms, nociceptive behavior, and histological analysis of the bladder and L6 spinal cord. RESULTS Increases in urinary frequency and decreases in bladder capacity compared with the sham group were observed in the vehicle and non-Muse groups, but not in the Muse group, at 1 week. Significant increases in nociceptive behavior compared with the sham group and the expression of TNFα in the bladder and c-Fos in the bilateral dorsal horns of L6 spinal cord were also observed in the vehicle and non-Muse groups, whereas these changes were not seen in the Muse group at 1 week. Histological analysis exhibited a higher proportion of injected Muse cells remaining in the urothelial basal layer and lamina propria of the bladder than non-Muse cells until 4 weeks. CONCLUSIONS Muse cell therapy could be a promising modality for treating HIC.
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Affiliation(s)
- Akira Furuta
- Department of Urology, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Yasumasa Kuroda
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tokunori Yamamoto
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shin Egawa
- Department of Urology, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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15
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Jiang J, Xin J, Ding W, Shi D, Sun S, Guo B, Zhou X, Zheng C, Li J. MicroRNA Profile of Human Bone Marrow Mesenchymal Stem Cells during Hepatic Differentiation and Therapy. Int J Med Sci 2022; 19:152-163. [PMID: 34975309 PMCID: PMC8692113 DOI: 10.7150/ijms.67639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 11/26/2021] [Indexed: 12/05/2022] Open
Abstract
Background and Aims: MicroRNAs (miRNAs) play important roles in hepatocyte differentiation from human bone marrow mesenchymal stem cells (hBMSCs) and the therapeutic application in vivo. However, the mechanisms of miRNA regulation are still unknown. This study aimed to profile the miRNA basis for improving the function of hBMSC-differentiated hepatocyte-like cells (hBMSC-Heps). Methods: Characteristic miRNAs of hBMSC-Heps were identified by transcriptome sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). An in vivo hBMSC transplantation model was used to assess the regulatory effects of miRNAs on liver regeneration during hBMSC therapy in pigs with fulminant hepatic failure (FHF). The biological functions of significant miRNA molecules were confirmed by transfection of miRNA activators or inhibitors into hBMSCs during hepatogenic differentiation. Results: The transcriptome of hBMSC-Heps showed characteristics distinct from those of undifferentiated hBMSCs. A total of 77 miRNAs were significantly differentially expressed in hBMSC-Heps at day 10 and day 20 after hBMSC differentiation that were directly related to the functions of hepatocytes. Among the top 10 significantly differentially expressed and the top 10 most abundant miRNAs, nine miRNAs that exhibited a pattern of gradual change were chosen for further analysis. The expression of nine miRNAs was confirmed by qRT-PCR in vitro and showed the same changing trends in vivo in an hBMSC transplantation model in pigs. Functional experiments with these miRNAs showed that activators of hsa-miR-26b-5p and hsa-miR-148a-3p and an inhibitor of hsa-miR-423-3p were sufficient to improve the differentiation of hBMSCs into hepatocyte-like cells. Conclusions: Transcriptome profiles of miRNA revealed the basis of the differentiation and development of hBMSC-Heps. Manipulation of three miRNAs (hsa-miR-26b-5p, hsa-miR-148a-3p and hsa-miR-423-3p) significantly improved hepatocyte generation and liver regeneration, indicating the potential of these miRNAs for future clinical applications.
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Affiliation(s)
- Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Wenchao Ding
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Suwan Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Xingping Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Chufan Zheng
- Hangzhou No.14 High School, 580 Fengqi Rd, Gongshu District, Hangzhou, 310006, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
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16
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Sato T, Wakao S, Kushida Y, Tatsumi K, Kitada M, Abe T, Niizuma K, Tominaga T, Kushimoto S, Dezawa M. A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood. Cell Transplant 2021; 29:963689720923574. [PMID: 32525407 PMCID: PMC7586270 DOI: 10.1177/0963689720923574] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Peripheral blood (PB) contains several types of stem/progenitor cells, including hematopoietic stem and endothelial progenitor cells. We identified a population positive for both the pluripotent surface marker SSEA-3 and leukocyte common antigen CD45 that comprises 0.04% ± 0.003% of the mononuclear cells in human PB. The average size of the SSEA-3(+)/CD45(+) cells was 10.1 ± 0.3 µm and ∼22% were positive for CD105, a mesenchymal marker; ∼85% were positive for CD19, a B cell marker; and ∼94% were positive for HLA-DR, a major histocompatibility complex class II molecule relevant to antigen presentation. These SSEA-3(+)/CD45(+) cells expressed the pluripotency markers Nanog, Oct3/4, and Sox2, as well as sphingosine-1-phosphate (S1P) receptor 2, and migrated toward S1P, although their adherence and proliferative activities in vitro were low. They expressed NeuN at 7 d, Pax7 and desmin at 7 d, and alpha-fetoprotein and cytokeratin-19 at 3 d when supplied to mouse damaged tissues of the brain, skeletal muscle and liver, respectively, suggesting the ability to spontaneously differentiate into triploblastic lineages compatible to the tissue microenvironment. Multilineage-differentiating stress enduring (Muse) cells, identified as SSEA-3(+) in tissues such as the bone marrow and organ connective tissues, express pluripotency markers, migrate to sites of damage via the S1P-S1P receptor 2 system, and differentiate spontaneously into tissue-compatible cells after homing to the damaged tissue where they participate in tissue repair. After the onset of acute myocardial infarction and stroke, patients are reported to have an increase in the number of SSEA-3(+) cells in the PB. The SSEA-3(+)/CD45(+) cells in the PB showed similarity to tissue-Muse cells, although with difference in surface marker expression and cellular properties. Thus, these findings suggest that human PB contains a subset of cells that are distinct from known stem/progenitor cells, and that CD45(+)-mononuclear cells in the PB comprise a novel subpopulation of cells that express pluripotency markers.
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Affiliation(s)
- Tetsuya Sato
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuki Tatsumi
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Regenerative Medicine Division, Life Science Institute, Inc., Tokyo, Japan
| | - Masaaki Kitada
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takatsugu Abe
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kuniyasu Niizuma
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Neurosurgical Engineering and Translational Neuroscience, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan
| | - Teiji Tominaga
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigeki Kushimoto
- Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
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17
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Liu D, Zheng W, Pan S, Liu Z. Concise review: current trends on applications of stem cells in diabetic nephropathy. Cell Death Dis 2020; 11:1000. [PMID: 33221823 PMCID: PMC7680458 DOI: 10.1038/s41419-020-03206-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy, with high prevalence, is the main cause of renal failure in diabetic patients. The strategies for treating DN are limited with not only high cost but an unsatisfied effect. Therefore, the effective treatment of DN needs to be explored urgently. In recent years, due to their self-renewal ability and multi-directional differentiation potential, stem cells have exerted therapeutic effects in many diseases, such as graft-versus-host disease, autoimmune diseases, pancreatic diseases, and even acute kidney injury. With the development of stem cell technology, stem cell-based regenerative medicine has been tried to be applied to the treatment of DN. Related stem cells include embryonic stem cells, induced pluripotent stem cells, mesenchymal cells, and endothelial progenitor cells. Undoubtedly, stem cell transplantation has achieved certain results in the treatment of DN animal models. However, stem cell therapy still remains certain thorny issues during treatment. For instance, poor engraftment and limited differentiation of stem cells caused by the diabetic microenvironment, differentiation into unwanted cell lineages, and malignant transformation or genetic aberrations of stem cells. At present, various researches on the therapeutic effects of stem cells in DN with different opinions are reported and the specific mechanism of stem cells is still unclear. We review here the potential mechanism of stem cells as new therapeutic agents in the treatment of DN. Also, we review recent findings and updated information about not only the utilization of stem cells on DN in both preclinical and clinical trials but limitations and future expectations of stem cell-based therapy for DN.
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Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Wen Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China. .,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China.
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18
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Salerno A, Brady K, Rikkers M, Li C, Caamaño-Gutierrez E, Falciani F, Blom AW, Whitehouse MR, Hollander AP. MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis. Stem Cells 2020; 38:1438-1453. [PMID: 32652878 DOI: 10.1002/stem.3255] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 06/11/2020] [Indexed: 01/01/2023]
Abstract
Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale-up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo-cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow-derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13+ , TIMP1-secretinghigh MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13- , TIMP1-secretinghigh MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair.
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Affiliation(s)
- Anna Salerno
- Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Kyla Brady
- Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Margot Rikkers
- Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK.,Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Chao Li
- Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Eva Caamaño-Gutierrez
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.,Computational Biology Facility, University of Liverpool, Liverpool, UK
| | - Francesco Falciani
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.,Computational Biology Facility, University of Liverpool, Liverpool, UK
| | - Ashley W Blom
- Musculoskeletal Research Unit, University of Bristol, Bristol, UK.,National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
| | - Michael R Whitehouse
- Musculoskeletal Research Unit, University of Bristol, Bristol, UK.,National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
| | - Anthony P Hollander
- Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK
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19
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Kemilew J, Sobczyńska-Rak A, Żylińska B, Szponder T, Nowicka B, Urban B. The Use of Allogenic Stromal Vascular Fraction (SVF) Cells in Degenerative Joint Disease of the Spine in Dogs. In Vivo 2019; 33:1109-1117. [PMID: 31280199 DOI: 10.21873/invivo.11580] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/20/2019] [Accepted: 06/24/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM Stem cells are widely used in regenerative medicine and in clinical practice for the treatment of damaged nerve tissue, myocytes, tendons, and ligaments. The aim of the study was to monitor VEGF levels after the administration of allogenic cellular material (SVF) in the course of treatment of dogs suffering from degenerative joint disease in the spinal region. MATERIALS AND METHODS The study was conducted on 10 dogs of both genders, aged between 6 and 13 years in which allogenic stromal vascular fraction of stem cells (SVF) was administered intravenously. The control group was composed of 10 clinically healthy dogs. Before treatment and after 2- and 8-week intervals blood samples were obtained from the study group dogs in order to determine VEGF levels via immunoenzymatic test. RESULTS in a few days after the therapy, alleviation of pain symptoms and reduction of lameness were noticed. The VEGF level in 2 weeks after the therapy was significantly elevated (median: 38.77 pg/ml), while in 8 weeks a decrease was observed (median: 18.37 pg/ml). Conlusion: Administration of allogenic stem cells has a positive influence on elevation of the VEGF levels in the blood serum of affected animals as well as their regeneration capacity.
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Affiliation(s)
- Jerzy Kemilew
- "Kemilew Stem Cells for Animals" Company, Warsaw, Poland
| | - Aleksandra Sobczyńska-Rak
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Beata Żylińska
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Tomasz Szponder
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Beata Nowicka
- Department and Clinic of Animal Surgery, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
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20
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Use of Mesenchymal Stem/Stromal Cells for Pediatric Orthopedic Applications. Tech Orthop 2019. [DOI: 10.1097/bto.0000000000000351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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21
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Sun Z, Li X, Zheng X, Cao P, Yu B, Wang W. Stromal cell-derived factor-1/CXC chemokine receptor 4 axis in injury repair and renal transplantation. J Int Med Res 2019; 47:5426-5440. [PMID: 31581874 PMCID: PMC6862890 DOI: 10.1177/0300060519876138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Stem cell therapy has shown promise in treating a variety of pathologies, such as myocardial infarction, ischaemic stroke and organ transplantation. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) axis plays a key role in stem cell mobilization. This review describes the important role of SDF-1 in tissue injury and how it works in tissue revascularization and regeneration via CXCR4. Furthermore, factors influencing the SDF-1/CXCR4 axis and its clinical potential in ischaemia reperfusion injury, such as renal transplantation, are discussed. Exploring signalling pathways of the SDF-1/CXCR4 axis will contribute to the development of stem cell therapy so that more clinical problems can be solved. Controlling directional homing of stem cells through the SDF-1/CXCR4 axis is key to improving the efficacy of stem cell therapy for tissue injury. CXCR4 antagonists may also be effective in increasing circulating levels of adult stem cells, thereby exerting beneficial effects on damaged or inflamed tissues in diseases that are currently not treated by standard approaches.
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Affiliation(s)
- Zejia Sun
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Xin Li
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Xiang Zheng
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Peng Cao
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Baozhong Yu
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
| | - Wei Wang
- Institute of Urology, Capital Medical University, Department of Urology, Capital Medical University Beijing Chaoyang Hospital, Beijing, China
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22
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Identification and characterization of two morphologically distinct stem cell subpopulations from human urine samples. SCIENCE CHINA-LIFE SCIENCES 2019; 63:712-723. [PMID: 31515730 DOI: 10.1007/s11427-018-9543-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 05/06/2019] [Indexed: 02/05/2023]
Abstract
Urine-derived stem cells (USCs) have shown potentials for the treatment of skeletal and urological disorders. Based on published literature and our own data, USCs consist of heterogeneous populations of cells. In this paper, we identify and characterize two morphologically distinct subpopulations of USCs from human urine samples, named as spindle-shaped USCs (SS-USCs) and rice-shaped USCs (RS-USCs) respectively. The two subpopulations showed similar clone-forming efficiency, while SS-USCs featured faster proliferation, higher motility, and greater potential for osteogenic and adipogenic differentiation, RS-USCs showed greater potential for chondrogenic differentiation. POU5F1 was strongly expressed in both subpopulations, but MYC was weakly expressed. Both subpopulations showed similar patterns of CD24, CD29, CD34, CD44, CD73, CD90 and CD105 expression, while a higher percentage of RS-USCs were positive for CD133. SS-USCs were positive for VIM, weakly positive for SLC12A1 and UMOD, and negative for KRT18, NPHS1, AQP1 and AQP2, indicating a renal mesenchyme origin; while RS-USCs are positive for VIM, partially positive for KRT18, NPHS1, AQP1, SLC12A1 and UMOD, and negative for AQP2, indicating a nephron tubule origin. The above results can facilitate understanding of the biological characteristics of subpopulations of USCs, and provide a basis for further research and applications of such cells.
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23
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Abdelaziz MH, Salah El-Din EY, El-Dakdoky MH, Ahmed TA. The impact of mesenchymal stem cells on doxorubicin-induced testicular toxicity and progeny outcome of male prepubertal rats. Birth Defects Res 2019; 111:906-919. [PMID: 31210400 DOI: 10.1002/bdr2.1535] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 05/07/2019] [Accepted: 05/29/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Many therapies to treat cancer are gonadotoxic and can lead to infertility. New strategies to diminish the side effects and protective plans during and after chemotherapy are needed. Therefore, bone marrow mesenchymal stem cells (BM-MSCs) as a novel solution were investigated against doxorubicin (Dox)-induced toxicity in rat testes. METHODS Forty male albino prepubertal rats were divided into four groups, 10 rats per each group. The first was injected intraperitoneally with saline as control. The second group was injected intravenously with a single dose of BM-MSCs (2 × 106 cells). The third was injected intraperitoneally with a single dose of Dox (5 mg/kg b.wt). The fourth was injected with both Dox and BM-MSCs as previously mentioned. Rats were cohabited each separately with an untreated adult female after 8 weeks of treatment to examine Dox effects on male's fertility. RESULTS BM-MSCs counteract the deleterious effects of Dox on body, testicular weight as well as sperm quality by increasing sperm concentration and reducing the rate of abnormal sperm. BM-MSCs reduced significantly the testicular oxidative stress by reducing the elevated level of malondialdehyde and increasing the antioxidant capacity. Histologically, the testicular atrophy, severe damage of spermatogenesis and the significant reduction of the diameter and germinative cell layer thickness of the seminiferous tubules caused by Dox were significantly recovered after administration of the BM-MSCs. CONCLUSION BM-MSCs have a significant role in restoring the structural efficiency of male reproductive system in rats after Dox treatment.
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Affiliation(s)
| | | | - Mai H El-Dakdoky
- Zoology Department, Women College for Arts, Science and Education, Ain Shams University, Cairo, Egypt
| | - Tawfik A Ahmed
- Faculty of Science, Zoology Department, Cairo University, Giza, Egypt
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24
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Kidoaki S. Frustrated differentiation of mesenchymal stem cells. Biophys Rev 2019; 11:377-382. [PMID: 31102200 DOI: 10.1007/s12551-019-00528-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 04/22/2019] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are one of the most useful cell resources for clinical application in regenerative medicine. However, standardization and quality assurance of MSCs are still essential problems because the stemness of MSCs depends on such factors as the collection method, individual differences associated with the source, and cell culture history. As such, the establishment of culture techniques which assure the stemness of MSCs is of vital importance. One important factor affecting MSCs during culture is the effect of the mechanobiological memory of cultured MSCs built up by their encounter with particular mechanical properties of the extracellular mechanical milieu. How can we guarantee that MSCs will remain in an undifferentiated state? Procedures capable of eliminating effects related to the history of the mechanical dose for cultured MSCs are required. For this problem, we have tried to establish the design of microelastically patterned cell-culture matrix which can effectively induce mechanical oscillations during the period of nomadic migration of cells among different regions of the matrix. We have previously observed before that the MSCs exposed to such a growth regimen during nomadic culture keep their undifferentiated state-with this maintenance of stemness believed due to lack of a particular regular mechanical dosage that is likely to determine a specific lineage. We have termed this situation as "frustrated differentiation". In this minireview, I introduce the concept of frustrated differentiation of MSCs and show possibility of purposeful regulation of this phenomenon.
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Affiliation(s)
- Satoru Kidoaki
- Laboratory of Biomedical and Biophysical Chemistry, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, 819-0395, Japan.
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25
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Leng Z, Sun D, Huang Z, Tadmori I, Chiang N, Kethidi N, Sabra A, Kushida Y, Fu YS, Dezawa M, He X, Young W. Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting. Cell Transplant 2019; 28:907-923. [PMID: 30997834 PMCID: PMC6719495 DOI: 10.1177/0963689719844260] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are a population of pluripotent stage-specific embryonic antigen 3 (SSEA3)+ mesenchymal stem cells first described by Mari Dezawa in 2010. Although some investigators have reported SSEA3+ mesenchymal cells in umbilical cord tissues, none have quantitatively compared SSEA3+ cells isolated from Wharton’s jelly (WJ) and the cord lining (CL) of human umbilical cords (HUCs). We separated WJ and the CL from HUCs, cultured mesenchymal stromal cells (MSCs) isolated from these two tissues with collagenase, and quantified the percentage of SSEA3+ cells over three passages. The first passage had 5.0% ± 4.3% and 5.3% ± 5.1% SSEA3+ cells from WJ and the CL, respectively, but the percentage of SSEA3+ cells decreased significantly (P < 0.05) between P0 and P2 in the CL group and between P0 and P1 in the WJ group. Magnetic-activated cell sorting (MACS) markedly enriched SSEA3+ cells to 91.4% ± 3.2%. Upon culture of the sorted population, we found that the SSEA3+ percentage ranged from 62.5% to 76.0% in P2–P5 and then declined to 42.0%–54.7% between P6 and P9. At P10, the cultures contained 37.4% SSEA3+ cells. After P10, we resorted the cells and achieved 89.4% SSEA3+ cells in culture. The procedure for MACS-based enrichment of SSEA3+ cells, followed by expansion in culture and a re-enrichment step, allows the isolation of many millions of SSEA3+ cells in relatively pure culture. When cultured, the sorted SSEA3+ cells differentiated into embryoid spheres and survived 4 weeks after transplant into a contused Sprague-Dawley rat spinal cord. The transplanted SSEA3+ cells migrated into the injury area from four injection points around the contusion site and did not produce any tumors. The umbilical cord is an excellent source of fetal Muse cells, and our method allows the practical and efficient isolation and expansion of relatively pure populations of SSEA3+ Muse cells that can be matched by human leukocyte antigen for transplantation in human trials.
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Affiliation(s)
- Zikuan Leng
- 1 Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Dongming Sun
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Zihao Huang
- 3 Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei
| | - Iman Tadmori
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Ning Chiang
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Nikhit Kethidi
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Ahmed Sabra
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
| | - Yoshihiro Kushida
- 4 Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yu-Show Fu
- 3 Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei
| | - Mari Dezawa
- 4 Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Xijing He
- 1 Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wise Young
- 2 W.M. Keck Center for Collaborative Neuroscience, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA
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26
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Konari N, Nagaishi K, Kikuchi S, Fujimiya M. Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo. Sci Rep 2019; 9:5184. [PMID: 30914727 PMCID: PMC6435708 DOI: 10.1038/s41598-019-40163-y] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 02/04/2019] [Indexed: 12/11/2022] Open
Abstract
The underlying therapeutic mechanism of renal tubular epithelium repair of diabetic nephropathy (DN) by bone marrow-derived mesenchymal stem cells (BM-MSCs) has not been fully elucidated. Recently, mitochondria (Mt) transfer was reported as a novel action of BM-MSCs to rescue injured cells. We investigated Mt transfer from systemically administered BM-MSCs to renal proximal tubular epithelial cells (PTECs) in streptozotocin (STZ)-induced diabetic animals. BM-MSCs also transferred their Mt to impaired PTECs when co-cultured in vitro, which suppressed apoptosis of impaired PTECs. Additionally, BM-MSC-derived isolated Mt enhanced the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression and inhibited reactive oxygen species (ROS) production in vitro. Isolated Mt also inhibited nuclear translocation of PGC-1α and restored the expression of megalin and SGLT2 under high glucose condition (HG) in PTECs. Moreover, isolated Mt directly injected under the renal capsule of STZ rats improved the cellular morphology of STZ-PTECs, and the structure of the tubular basement membrane and brush border in vivo. This study is the first to show Mt transfer from systemically administered BM-MSCs to damaged PTECs in vivo, and the first to investigate mechanisms underlying the potential therapeutic effects of Mt transfer from BM-MSCs in DN.
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Affiliation(s)
- Naoto Konari
- Second Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan
| | - Kanna Nagaishi
- Second Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan.
| | - Shin Kikuchi
- First Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan
| | - Mineko Fujimiya
- Second Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan
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27
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Kitada M, Murakami T, Wakao S, Li G, Dezawa M. Direct conversion of adult human skin fibroblasts into functional Schwann cells that achieve robust recovery of the severed peripheral nerve in rats. Glia 2019; 67:950-966. [PMID: 30637802 DOI: 10.1002/glia.23582] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 12/03/2018] [Accepted: 12/11/2018] [Indexed: 12/12/2022]
Abstract
Direct conversion is considered a promising approach to obtain tissue-specific cells for cell therapies; however, this strategy depends on exogenous gene expression that may cause undesired adverse effects such as tumorigenesis. By optimizing the Schwann cell induction system, which was originally developed for trans-differentiation of bone marrow mesenchymal stem cells into Schwann cells, we established a system to directly convert adult human skin fibroblasts into cells comparable to authentic human Schwann cells without gene introduction. Serial treatments with beta-mercaptoethanol, retinoic acid, and finally a cocktail of basic fibroblast growth factor, forskolin, platelet-derived growth factor-AA, and heregulin-β1 (EGF domain) converted fibroblasts into cells expressing authentic Schwann cell markers at an efficiency of approximately 75%. Genome-wide gene expression analysis suggested the conversion of fibroblasts into the Schwann cell-lineage. Transplantation of induced Schwann cells into severed peripheral nerve of rats facilitated axonal regeneration and robust functional recovery in sciatic function index comparable to those of authentic human Schwann cells. The contributions of induced Schwann cells to myelination of regenerated axons and re-formation of neuromuscular junctions were also demonstrated. Our data clearly demonstrated that cells comparable to functional Schwann cells feasible for the treatment of neural disease can be induced from adult human skin fibroblasts without gene introduction. This direct conversion system will be beneficial for clinical applications to peripheral and central nervous system injuries and demyelinating diseases.
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Affiliation(s)
- Masaaki Kitada
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Murakami
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Gen Li
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
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28
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Dall'Oca C, Breda S, Elena N, Valentini R, Samaila EM, Magnan B. Mesenchymal Stem Cells injection in hip osteoarthritis: preliminary results. ACTA BIO-MEDICA : ATENEI PARMENSIS 2019; 90:75-80. [PMID: 30715002 PMCID: PMC6503401 DOI: 10.23750/abm.v90i1-s.8084] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 01/10/2019] [Indexed: 12/18/2022]
Abstract
Background and aim of the work: Osteoarthritis will become even more common in the near future since the average life span is steadily growing. Pain and loss of function are the main complaints reported by patients, inevitably leading towards a worsened daily life performance. New modern techniques have been developed with advanced cell based therapies. Mesenchymal stem cells (MSC) have the inner ability to mature into different types of cells depending on the stimuli they undergo. This technique has already been proven successful in the knee and, with this retrospective study, we would like to assess its feasibility in the hip joint. Methods:6 consecutive patients affected by hip osteoarthritis were treated by intra-articular injection of autologous adipose-derived MSC between June 2017 and June 2018. Our study included only patients with constant hip pain resistant conservative treatment and OA graded 0-2 on the Tonnis grading scale. All 6 patients were evaluated in the preoperative setting and at the 6 months post-operative mark. Results: The HHS showed an improvement from the pre-operative baseline mean value of 67.2±3.4 to the 84.6±6.3 post-operative value. Moreover, the WOMAC score dropped from a baseline score of 36.3±4.7 to 19.8±3.4 at 6 months’ post-op follow up visit. Conclusions: MSC Lipogems is a fairly easy technique. No adverse effects were recorded in our experience. Preliminary results showed a positive outcome according to all the grading systems used in this study even though a longer follow up is needed to validate this technique. (www.actabiomedica.it)
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Affiliation(s)
- Carlo Dall'Oca
- Azienda Ospedaliera Universitaria Integrata Verona, Ortopedia e Traumatologia B, Verona, Italy.
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29
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Gong B, Dong Y, He C, Jiang W, Shan Y, Zhou BY, Li W. Intravenous Transplants of Human Adipose-Derived Stem Cell Protect the Rat Brain From Ischemia-Induced Damage. J Stroke Cerebrovasc Dis 2018; 28:595-603. [PMID: 30482485 DOI: 10.1016/j.jstrokecerebrovasdis.2018.10.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/24/2018] [Accepted: 10/31/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Survival following cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR), to a great extent, depends on brain damage. Adipose-derived stem cells (ADSCs), as a source of paracrine growth factors and the capacity of neural differentiation may reduce this brain damage. OBJECTIVE The purpose of this study is to evaluate the protection of ADSCs to brain damage following CPR. METHODS Rats were divided into 3 groups, sham, CA, and ADSCs group. Rats in sham group went through sham surgery. Rats in CA group went through CA, CPR, and injection PBS (phosphate buffer saline). Rats in ADSCs group went through CA, CPR, and intravenous injection of ADSCs. Rats in sham group were sacrificed immediately after operation. At 24, 72, and 168 hours after return of spontaneous circulation operation, rats in CA and ADSCs group were randomly selected and sacrificed. Brain damage was evaluated by using Neurological Deficit Scale (NDS) score, hippocampal pathology, serum level of S100β, and apoptosis ratio of hippocampal neurons. Protein of brain derived neurotrophic factor (BDNF) and IL-6 (interleukin-6) in the hippocampus were detected. RESULTS Compared with sham group, CA and ADSCs group showed a decrease in NDS score, an increased apoptosis ratio of hippocampal nerve cells, increased serum level of S100-β, and a significant increase in neuroprotective IL-6 and BDNF. In comparison to CA group, ADSCs group had a mild degree of brain damage and higher expression of IL-6 and BDNF. CONCLUSIONS In the acute stage of cerebral injury following CA, ADSCs might improve the prognosis of brain damage by stimulating the expression of neuroprotective IL-6 and BDNF.
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Affiliation(s)
- Bo Gong
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China; Deparment of emergency, Hankou Branch of Central Theater General Hospital, Wuhan, PR China
| | - Yongpin Dong
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China
| | - Chao He
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China
| | - Weiwei Jiang
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China
| | - Yi Shan
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China
| | - Betty Y Zhou
- Shenzhen Alpha-biotechnology Inc. Shenzhen, PR China.
| | - Wenfang Li
- Department of Emergency, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China.
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30
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Li H, Rong P, Ma X, Nie W, Chen C, Yang C, Zhang J, Dong Q, Wang W. Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life Sci 2018; 215:113-118. [PMID: 30399376 DOI: 10.1016/j.lfs.2018.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/25/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022]
Abstract
Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM) and the main reason for end-stage renal diseases (ESRD). Based on the role of mesenchymal stem cells (MSCs) in regenerative medicine, the MSC therapy has been considered a promising strategy to ameliorate the progression of DN. In this article, we review the therapeutic potential of MSCs in DN, mainly involving MSC paracrine mechanism based on trophic factors and extracellular vesicles. Knowledge of mechanism underlying the therapeutic action of MSCs on DN can provide much needed new drug targets for this disease.
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Affiliation(s)
- Hongde Li
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Cheng Chen
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Cejun Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Juan Zhang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qiong Dong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
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Wang L, Xiao L, Zhang RZ, Qiu LZ, Zhang R, Shi HX. Effects of acrylate/acrylamide polymers on the adhesion, growth and differentiation of Muse cells. ACTA ACUST UNITED AC 2018; 14:015003. [PMID: 30277887 DOI: 10.1088/1748-605x/aae5cb] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Acrylate/acrylamide copolymers have excellent optical properties and biocompatibility and are ideal biomaterials that have been widely used in tissue engineering. Multilineage-differentiating stress-enduring cells (Muse cells) are a specific subset of mesenchymal stem cells that have an excellent potential for the regenerative medicine. OBJECTIVE This study was designed to investigate the effects of acrylate/acrylamide copolymers on the adhesion, proliferation and pluripotent-like properties of Muse cells, which were derived from normal human dermal fibroblasts by long-term trypsin incubation. METHODS In an initial experiment, Muse cells were seeded on primary microarrays containing micro-spots of 275 different mixtures of acrylate/acrylamide. Each mixture was composed of two of 11 different monomers in various proportions, and was replicated in four micro-spots each. According to the adhesion and growth characteristics of Muse cells on those substrates, specific polymer candidates for Muse cells were selected and secondary microarrays were prepared. We then observed the effects of those specific polymer candidates on the adherence, proliferation and differentiation of Muse cells and suitable candidates for their optimal culture were identified. RESULTS According to the adhesion and growth patterns of Muse cells on the primary microarrays, ten suitable mixtures of acrylate/acrylamide copolymers were identified. Muse cells grew well on six of those combinations and around the four other combinations of those polymer mixtures. Muse cells cultured on three of those combinations proliferated and differentiated into long spindle-shaped cells that looked like fibroblasts, while Muse cells cultured on one combination formed clusters that were ring-shaped. Muse cells cultured on some of those combinations of acrylate/acrylamide proliferated and formed clusters that appeared to be very healthy, whereas Muse cells cultured on other combinations formed clusters that expanded outwards. CONCLUSIONS These results identified a polymer combination that was optimum for the adhesion, proliferation and maintenance of Muse cells in an undifferentiated state.
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Affiliation(s)
- Li Wang
- Department of Dermatology and Venereology, the Third Affiliated Hospital of Soochow University, Changzhou 213000, People's Republic of China. Department of Dermatology and Venereology, First Affiliated Hospital of Bengbu Medical College, Anhui 233000, People's Republic of China
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Yamazato M, Ishida A, Yamazato Y, Nakamura T, Ohya Y. Intracerebroventricular administration of bone marrow-derived cells attenuates angiotensin II-initiated neurogenic hypertension in rats. Hypertens Res 2018; 41:828-838. [DOI: 10.1038/s41440-018-0088-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 03/24/2018] [Accepted: 03/26/2018] [Indexed: 11/09/2022]
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Fiore EJ, Domínguez LM, Bayo J, García MG, Mazzolini GD. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol 2018; 24:2427-2440. [PMID: 29930465 PMCID: PMC6010941 DOI: 10.3748/wjg.v24.i23.2427] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/08/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs' stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSCderived EVs as intercellular mediators and therapeutic tools in liver diseases.
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Affiliation(s)
- Esteban Juan Fiore
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Luciana María Domínguez
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Juan Bayo
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Mariana Gabriela García
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Guillermo Daniel Mazzolini
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
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Hao Y, Ran Y, Lu B, Li J, Zhang J, Feng C, Fang J, Ma R, Qiao Z, Dai X, Xiong W, Liu J, Zhou Q, Hao J, Li R, Dai J. Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on Canine Radiation-Induced Lung Injury. Int J Radiat Oncol Biol Phys 2018; 102:407-416. [PMID: 30191872 DOI: 10.1016/j.ijrobp.2018.05.068] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 05/02/2018] [Accepted: 05/25/2018] [Indexed: 12/27/2022]
Abstract
PURPOSE To investigate the effect of human umbilical cord-derived mesenchymal stem cell (MSC) transplantation on canine radiation-induced lung injury. METHODS AND MATERIALS Beagle dogs received localized 15-Gy x-ray radiation to the right lower lung to establish the model of radiation-induced lung injury. After 180 days, dogs were divided into 2 groups (4 per group). The MSC group received intratracheal MSC transplantation, and the saline group received the same volume of normal saline by lavage. The effect of MSC transplantation on lung injury was then evaluated 180 days after transplantation. RESULTS At 180 days after 15-Gy radiation, canine arterial blood oxygen partial pressure was significantly decreased, and the levels of hydroxyproline and transforming growth factor (TGF)-β in peripheral blood were significantly increased, whereas that of TGF-α was significantly decreased. Computed tomography evaluation revealed visible honeycomb shadows in the right middle and lower pulmonary pleurae. Blood oxygen partial pressure of the MSC group gradually increased over time, whereas the levels of hydroxyproline and TGF-β in the peripheral blood showed a decreasing trend; TGF-α levels gradually increased, which differed significantly from the results observed in the saline group. In addition, computed tomography and pathologic examination showed that the degree of lung injury in the MSC group was milder. The MSC group also showed significantly increased pulmonary superoxide dismutase levels and significantly decreased tumor necrosis factor-α, Interleukein-1, and hyaluronic acid levels. Further study confirmed that MSC transplantation inhibited the activation of TGF-β-Smad2/3 in lung tissues, and in vitro experiments showed that medium conditioned with MSCs effectively inhibited the increase in Smad2 and 3 levels induced by TGF-β1. CONCLUSION Canine radiation-induced lung injury could be observed at 180 days after radiation at 15 Gy. MSC transplantation can reduce oxidative stress, inflammatory reactions, and TGF-β-Smad2/3 pathway activation, thereby reducing lung injury.
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Affiliation(s)
- Yuhui Hao
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
| | - Yonghong Ran
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Binghui Lu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Jiayin Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Jiaojiao Zhang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Chunjing Feng
- Institute of Animals, Chinese Academy of Sciences, Beijing, China
| | - Jinhui Fang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Ruoyu Ma
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Zhihui Qiao
- Department of Respiratory Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiaotian Dai
- Department of Respiratory Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Wei Xiong
- Department of Respiratory Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jing Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Qi Zhou
- Institute of Animals, Chinese Academy of Sciences, Beijing, China
| | - Jie Hao
- Institute of Animals, Chinese Academy of Sciences, Beijing, China
| | - Rong Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Jianwu Dai
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
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Yabuki H, Wakao S, Kushida Y, Dezawa M, Okada Y. Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model. Cell Transplant 2018; 27:979-993. [PMID: 29707971 PMCID: PMC6050908 DOI: 10.1177/0963689718761657] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 01/29/2018] [Indexed: 12/26/2022] Open
Abstract
Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.
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Affiliation(s)
- Hiroshi Yabuki
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
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Li DW, He J, He FL, Liu YL, Liu YY, Ye YJ, Deng X, Yin DC. Silk fibroin/chitosan thin film promotes osteogenic and adipogenic differentiation of rat bone marrow-derived mesenchymal stem cells. J Biomater Appl 2018; 32:1164-1173. [PMID: 29471713 DOI: 10.1177/0885328218757767] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
As a biodegradable polymer thin film, silk fibroin/chitosan composite film overcomes the defects of pure silk fibroin and chitosan films, respectively, and shows remarkable biocompatibility, appropriate hydrophilicity and mechanical properties. Silk fibroin/chitosan thin film can be used not only as metal implant coating for bone injury repair, but also as tissue engineering scaffold for skin, cornea, adipose, and other soft tissue injury repair. However, the biocompatibility of silk fibroin/chitosan thin film for mesenchymal stem cells, a kind of important seed cell of tissue engineering and regenerative medicine, is rarely reported. In this study, silk fibroin/chitosan film was prepared by solvent casting method, and the rat bone marrow-derived mesenchymal stem cells were cultured on the silk fibroin/chitosan thin film. Osteogenic and adipogenic differentiation of rat bone marrow-derived mesenchymal stem cells were induced, respectively. The proliferation ability, osteogenic and adipogenic differentiation abilities of rat bone marrow-derived mesenchymal stem cells were systematically compared between silk fibroin/chitosan thin film and polystyrene tissue culture plates. The results showed that silk fibroin/chitosan thin film not only provided a comparable environment for the growth and proliferation of rat bone marrow-derived mesenchymal stem cells but also promoted their osteogenic and adipogenic differentiation. This work provided information of rat bone marrow-derived mesenchymal stem cells behavior on silk fibroin/chitosan thin film and extended the application of silk fibroin/chitosan thin film. Based on the results, we suggested that the silk fibroin/chitosan thin film could be a promising material for tissue engineering of bone, cartilage, adipose, and skin.
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Affiliation(s)
- Da-Wei Li
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Jin He
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Feng-Li He
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Ya-Li Liu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Yang-Yang Liu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Ya-Jing Ye
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Xudong Deng
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
| | - Da-Chuan Yin
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, 26487 Northwestern Polytechnical University , Xi'an, P.R. China
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The Muse Cell Discovery, Thanks to Wine and Science. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1103:1-11. [PMID: 30484221 DOI: 10.1007/978-4-431-56847-6_1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Multilineage-differentiating stress-enduring (Muse) cells, identified as cells positive for the pluripotent marker stage-specific embryonic antigen (SSEA-3+), were discovered as stress-tolerant pluripotent stem cells from among mesenchymal stem cells (MSCs) and fibroblasts, as well as from the adult human bone marrow mononucleated fraction. MSCs are a crude population of cells that differentiate into multiple cell types covering all three germ layers in low proportion and were thus deduced to contain a genuine pluripotent stem cell subpopulation. Muse cells constitute several percent of MSCs and 1 of ~3000 bone marrow mononucleated cells. They exhibit pluripotent gene expression as well as trilineage differentiation and self-renewal capabilities at the single-cell level, while, in contrast, MSC cells other than Muse cells do not exhibit these characteristics. These characteristics indicate that Muse cells correspond to the subpopulation of MSC cells responsible for the pluripotent aspect of MSCs. In addition to their pluripotency, Muse cells play an important role in vivo as endogenous stem cells that contribute to tissue homeostasis through daily reparative maintenance and to tissue reconstruction through their unique reparative functions following serious tissue damage. This chapter describes how my research team discovered Muse cells.
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Zamani Mazdeh D, Mirshokraei P, Emami M, Mirshahi A, Karimi I. 17β-estradiol improves the efficacy of exploited autologous bone marrow-derived mesenchymal stem cells in non-union radial defect healing: A rabbit model. Res Vet Sci 2017; 118:11-18. [PMID: 29334646 DOI: 10.1016/j.rvsc.2017.12.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/14/2017] [Accepted: 12/27/2017] [Indexed: 12/11/2022]
Abstract
Exploiting mesenchymal stem cells (MSCs) appears to be an appealing alternative to the traditional clinical approach in the treatment of non-union bone defects. It has been shown that 17β-estradiol improves the osteogenesis and proliferation potential of the MSCs via estrogen receptors. We investigated the effect of 17β-estradiol on exploiting autologous BMSCs (bone marrow-derived MSCs) for the purpose of healing of radial non-union segmental defect in rabbit. Twenty rabbits were divided into 4 experimental groups: 1. Control group; 2. MSC treatment group; 3. 17β-estradiol (E2) treatment group; and 4. E2+MSC treatment group. Isolated BMSCs were seeded in a critical-sized defect on radial mid-diaphysis that was filled with autologous fibrin clot differently in 4 groups: 1. intact fibrin clot (control); 2. Fibrin clot containing MSCs; 3. Estradiol; and 4. E2 and MSCs. Defect healing was assessed by radiological (week 0, 2, 4, 6, 8 and 10) and histopathological evaluation (week 10). Radiological evaluation data demonstrated that quantities for the E2+MSC group were significantly the greatest in comparison with the other groups at week 4 to 10 inclusive. Moreover, Histopathological evaluation indicated that the E2+MSC group had the highest score which was significantly greater than the E2 group and the control group (P<0.05). In-vivo application of in situ 17β-estradiol provides the seeded BMSCs with improved osteogenic capacity in tandem with an accelerated rate of bone healing. This obviously more qualified approach that yields in a shorter time appears to be promising for the future cell-based clinical treatments of the non-union bone fractures. Exploiting mesenchymal stem cells (MSCs) appears to be an appealing alternative to the traditional clinical approach in the treatment of non-union bone defects. It has been shown that 17β-estradiol improves the osteogenesis and proliferation potential of the MSCs via estrogen receptors. We investigated the effect of 17β-estradiol on exploiting autologous BMSCs (bone marrow-derived MSCs) for the purpose of healing of radial non-union segmental defect in rabbit. Twenty rabbits were divided into 4 experimental groups: 1. Control group; 2. MSC treatment group; 3. 17β-estradiol (E2) treatment group; and 4. E2+MSC treatment group. Isolated BMSCs were seeded in a critical-sized defect on the radial mid-diaphysis that was filled with autologous fibrin clot differently in 4 groups: 1. intact fibrin clot (control); 2. Fibrin clot containing MSCs; 3. Estradiol; and 4. E2 and MSCs. Defect healing was assessed by radiological (week 0, 2, 4, 6, 8 and 10) and histopathological evaluation (week 10). Radiological evaluation data demonstrated that quantities for the E2+MSC group were significantly the greatest in comparison with the other groups at week 4 to 10 inclusive. Moreover, Histopathological evaluation indicated that the E2+MSC group had the highest score which was significantly greater than the E2 group and the control group (P<0.05). In-vivo application of in situ 17β-estradiol provides the seeded BMSCs with improved osteogenic capacity in tandem with an accelerated rate of bone healing. This obviously more efficient approach that yields in a shorter time appears to be promising for future cell-based clinical treatments of the non-union bone fractures.
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Affiliation(s)
- Delaram Zamani Mazdeh
- Department of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Pezhman Mirshokraei
- Department of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran; Center of Excellence in Ruminant Abortion and Neonatal Mortality, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Mohammadreza Emami
- Department of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ali Mirshahi
- Department of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Iraj Karimi
- Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
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Li DW, Lei X, He FL, He J, Liu YL, Ye YJ, Deng X, Duan E, Yin DC. Silk fibroin/chitosan scaffold with tunable properties and low inflammatory response assists the differentiation of bone marrow mesenchymal stem cells. Int J Biol Macromol 2017. [DOI: dx.doi.org/10.1016/j.ijbiomac.2017.07.080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Li DW, Lei X, He FL, He J, Liu YL, Ye YJ, Deng X, Duan E, Yin DC. Silk fibroin/chitosan scaffold with tunable properties and low inflammatory response assists the differentiation of bone marrow mesenchymal stem cells. Int J Biol Macromol 2017; 105:584-597. [DOI: 10.1016/j.ijbiomac.2017.07.080] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 01/27/2023]
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Therapeutic Potential of Multilineage-Differentiating Stress-Enduring Cells for Osteochondral Repair in a Rat Model. Stem Cells Int 2017; 2017:8154569. [PMID: 29312455 PMCID: PMC5682088 DOI: 10.1155/2017/8154569] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 09/27/2017] [Accepted: 09/28/2017] [Indexed: 12/25/2022] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are stage-specific embryonic antigen-3 (SSEA-3) positive cells existing in mesenchymal stem cell (MSC) populations. Muse cells have the pluripotency to differentiate into all germ layers as embryonic stem cells. In this study, we aimed to investigate the efficacy of Muse cell transplantation for osteochondral defect repair. Muse cells were isolated from human bone marrow MSCs. An osteochondral defect was created in the patellar groove of immunodeficient rats. After this, cell injection was performed, whereby rats were divided into 3 groups: the control group, the rats of which were given a PBS injection; the non-Muse group, which comprised 5 × 104 SSEA-3 negative non-Muse cells; and the Muse group, which comprised 5 × 104 SSEA-3 positive Muse cells. The white repaired tissue had a mostly smooth homogenous surface at 12 weeks after treatment in the Muse group, while no repair tissue was detected in the control and non-Muse groups. Histological assessments showed better repair at the cartilage defect sites in the Muse group compared to the other groups at 4 and 12 weeks after treatment. Muse cells could be a new promising cell source for the treatment of osteochondral defects.
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Shan Z, Hirai Y, Nakayama M, Hayashi R, Yamasaki T, Hasebe R, Song CH, Horiuchi M. Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease. J Gen Virol 2017; 98:2615-2627. [PMID: 28874230 DOI: 10.1099/jgv.0.000907] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Prion diseases are fatal neurodegenerative disorders of humans and animals and no effective treatments are currently available. Allogenic transplantation of immortalized human mesenchymal stem cells (MSCs) can prolong the survival of mice infected with prions. However, autologous transplantation is an appropriate model for evaluating the effects of MSCs on prion diseases. Therefore, we isolated and purified MSCs from the femur and tibia of mice as compact bone-derived MSCs (CB-MSCs). Flow cytometric analysis showed that CB-MSCs were negative for myeloid stem cell-derived cell markers CD11b and CD45, but positive for molecules such as Sca-1, CD105 and CD90.2, which are reported to be expressed on MSCs. The ability of CB-MSCs to migrate to brain extracts from prion-infected mice was confirmed by an in vitro migration assay. Intra-hippocampus transplantation of CB-MSCs at 120 days post-inoculation marginally but significantly prolonged the survival of mice infected with the Chandler prion strain. The transplantation of CB-MSCs did not influence the accumulation of disease-specific prion protein. However, the CB-MSC transplantation enhanced microglial activation, which appeared to be polarized to the M2-type activation state. These results suggest that autologous MSC transplantation is a possible treatment for prion diseases, while the modification of microglial activation may be a therapeutic target for neurodegenerative diseases.
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Affiliation(s)
- Zhifu Shan
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Yuji Hirai
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Momoko Nakayama
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Ryo Hayashi
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Takeshi Yamasaki
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Rie Hasebe
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
| | - Chang-Hyun Song
- Department of Anatomy and Histology, College of Oriental Medicine, Daegue Haany University, Gyeongsan, 712-715, Republic of Korea
| | - Motohiro Horiuchi
- Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
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Dickinson SC, Sutton CA, Brady K, Salerno A, Katopodi T, Williams RL, West CC, Evseenko D, Wu L, Pang S, Ferro de Godoy R, Goodship AE, Péault B, Blom AW, Kafienah W, Hollander AP. The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation. Stem Cells 2017; 35:2280-2291. [PMID: 28833807 PMCID: PMC5707440 DOI: 10.1002/stem.2691] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 07/07/2017] [Accepted: 07/23/2017] [Indexed: 12/24/2022]
Abstract
Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase‐like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2–ve or unfractionated MSCs. In a sheep cartilage‐repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis‐derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells2017;35:2280–2291
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Affiliation(s)
- Sally C Dickinson
- Institute of Integrative Biology, University of Liverpool, United Kingdom
| | - Catherine A Sutton
- School of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Sciences, University of Bristol, United Kingdom
| | - Kyla Brady
- Institute of Integrative Biology, University of Liverpool, United Kingdom
| | - Anna Salerno
- Institute of Integrative Biology, University of Liverpool, United Kingdom
| | - Theoni Katopodi
- Institute of Integrative Biology, University of Liverpool, United Kingdom
| | - Rhys L Williams
- School of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Sciences, University of Bristol, United Kingdom
| | - Christopher C West
- The University of Edinburgh, MRC Center for Regenerative Medicine, Scotland, United Kingdom
| | - Denis Evseenko
- Department of Orthopaedic Surgery, University of Southern California (USC), Los Angeles, California, USA.,Department of Stem Cell Research and Regenerative Medicine, University of Southern California (USC), Los Angeles, California, USA
| | - Ling Wu
- Department of Orthopaedic Surgery, University of Southern California (USC), Los Angeles, California, USA.,Department of Stem Cell Research and Regenerative Medicine, University of Southern California (USC), Los Angeles, California, USA
| | - Suzanna Pang
- School of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Sciences, University of Bristol, United Kingdom
| | - Roberta Ferro de Godoy
- Royal National Orthopaedic Hospital, Institute of Orthopaedics and Musculoskeletal Science, University College London, Brockley Hill, Stanmore, United Kingdom
| | - Allen E Goodship
- Royal National Orthopaedic Hospital, Institute of Orthopaedics and Musculoskeletal Science, University College London, Brockley Hill, Stanmore, United Kingdom
| | - Bruno Péault
- The University of Edinburgh, MRC Center for Regenerative Medicine, Scotland, United Kingdom.,The University of Edinburgh, Center for Cardiovascular Science, Scotland, United Kingdom.,David Geffen School of Medicine and Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California, Los Angeles, California, USA
| | - Ashley W Blom
- School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, United Kingdom
| | - Wael Kafienah
- School of Cellular and Molecular Medicine, Faculty of Medical and Veterinary Sciences, University of Bristol, United Kingdom
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44
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Dhivya V, Balachandar V. Cell replacement therapy is the remedial solution for treating Parkinson's disease. Stem Cell Investig 2017; 4:59. [PMID: 28725655 DOI: 10.21037/sci.2017.06.08] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/25/2017] [Indexed: 01/14/2023]
Abstract
The selective degeneration of dopaminergic (DA) neurons in Parkinson's disease (PD) has made an idol target for cell replacement therapies and other emerging surgical treatments. Certainly, by transplantation method, the therapeutic regimens such as human fetal ventral midbrain (hfVM) cells, human embryonic stem cells (hESCs), human neural stem/precursor/ progenitor cells (hNSCs/hNPCs), human mesenchymal stem cells (hMSCs), human induced neural stem cells (hiNSCs), and human induced pluripotent stem cells (hiPSCs) have been used into DA deficient striatum. In recent decades, surgical methods such as deep brain stimulation (DBS) and gene therapies have been used with the aim of treating PD. Though the technology has improved and many treating options arise, the permanent source for curing PD has not been identified yet. In this review, we examine how stem cell therapies have made advancement as a therapeutic source for PD when compared with surgical treatments.
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Affiliation(s)
- Venkatesan Dhivya
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
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45
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Aqmasheh S, Shamsasanjan K, Akbarzadehlaleh P, Pashoutan Sarvar D, Timari H. Effects of Mesenchymal Stem Cell Derivatives on Hematopoiesis and Hematopoietic Stem Cells. Adv Pharm Bull 2017; 7:165-177. [PMID: 28761818 PMCID: PMC5527230 DOI: 10.15171/apb.2017.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 04/08/2017] [Accepted: 04/18/2017] [Indexed: 12/11/2022] Open
Abstract
Hematopoiesis is a balance among quiescence, self-renewal, proliferation, and differentiation, which is believed to be firmly adjusted through interactions between hematopoietic stem and progenitor cells (HSPCs) with the microenvironment. This microenvironment is derived from a common progenitor of mesenchymal origin and its signals should be capable of regulating the cellular memory of transcriptional situation and lead to an exchange of stem cell genes expression. Mesenchymal stem cells (MSCs) have self-renewal and differentiation capacity into tissues of mesodermal origin, and these cells can support hematopoiesis through release various molecules that play a crucial role in migration, homing, self-renewal, proliferation, and differentiation of HSPCs. Studies on the effects of MSCs on HSPC differentiation can develop modern solutions in the treatment of patients with hematologic disorders for more effective Bone Marrow (BM) transplantation in the near future. However, considerable challenges remain on realization of how paracrine mechanisms of MSCs act on the target tissues, and how to design a therapeutic regimen with various paracrine factors in order to achieve optimal results for tissue conservation and regeneration. The aim of this review is to characterize and consider the related aspects of the ability of MSCs secretome in protection of hematopoiesis.
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Affiliation(s)
- Sara Aqmasheh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasanjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamze Timari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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46
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Liu Q, Zhang RZ, Li D, Cheng S, Yang YH, Tian T, Pan XR. Muse Cells, a New Type of Pluripotent Stem Cell Derived from Human Fibroblasts. Cell Reprogram 2016; 18:67-77. [PMID: 27055628 DOI: 10.1089/cell.2015.0085] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
A new type of mesenchymal stem cells (MSCs) that expresses stage-specific embryonic antigen 3 (SSEA-3) and the mesenchymal cell marker CD105 are known as multilineage-differentiating stress-enduring (Muse) cells. Studies have shown that stem cells in suspension cultures are more likely to generate embryoid body-like stem cell spheres and maintain an undifferentiated phenotype and pluripotency. We separated Muse cells derived from human dermal fibroblasts by long-term trypsin incubation (LTT) through suspension cultures in methylcellulose. The Muse cells obtained expressed several pluripotency markers, including Nanog, Oct4, Sox2, and SSEA-3, and could differentiate in vitro into cells of the three germ layers, such as hepatocytes (endodermal), neural cells (ectodermal) and adipocytes, and osteocytes (mesodermal cells). These cells showed a low level of DNA methylation and a high nucleo-cytoplasmic ratio. Our study provides an innovative and exciting platform for exploring the potential cell-based therapy of various human diseases using Muse cells as well as their great possibility for regenerative medicine.
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Affiliation(s)
- Qi Liu
- 1 Department of Dermatology, The Third Affiliated Hospital of Suzhou University , Changzhou, 213003, China
| | - Ru-zhi Zhang
- 1 Department of Dermatology, The Third Affiliated Hospital of Suzhou University , Changzhou, 213003, China
| | - Di Li
- 1 Department of Dermatology, The Third Affiliated Hospital of Suzhou University , Changzhou, 213003, China
| | - Sai Cheng
- 2 Department of Dermatology, The First Affiliated Hospital of Bengbu Medical College , Anhui, 213003, China
| | - Yu-hua Yang
- 1 Department of Dermatology, The Third Affiliated Hospital of Suzhou University , Changzhou, 213003, China
| | - Ting Tian
- 1 Department of Dermatology, The Third Affiliated Hospital of Suzhou University , Changzhou, 213003, China
| | - Xiao-ru Pan
- 2 Department of Dermatology, The First Affiliated Hospital of Bengbu Medical College , Anhui, 213003, China
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47
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Nagaishi K, Mizue Y, Chikenji T, Otani M, Nakano M, Konari N, Fujimiya M. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep 2016; 6:34842. [PMID: 27721418 PMCID: PMC5056395 DOI: 10.1038/srep34842] [Citation(s) in RCA: 195] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 08/18/2016] [Indexed: 01/11/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have contributed to the improvement of diabetic nephropathy (DN); however, the actual mediator of this effect and its role has not been characterized thoroughly. We investigated the effects of MSC therapy on DN, focusing on the paracrine effect of renal trophic factors, including exosomes secreted by MSCs. MSCs and MSC-conditioned medium (MSC-CM) as renal trophic factors were administered in parallel to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. Both therapies showed approximately equivalent curative effects, as each inhibited the exacerbation of albuminuria. They also suppressed the excessive infiltration of BMDCs into the kidney by regulating the expression of the adhesion molecule ICAM-1. Proinflammatory cytokine expression (e.g., TNF-α) and fibrosis in tubular interstitium were inhibited. TGF-β1 expression was down-regulated and tight junction protein expression (e.g., ZO-1) was maintained, which sequentially suppressed the epithelial-to-mesenchymal transition of tubular epithelial cells (TECs). Exosomes purified from MSC-CM exerted an anti-apoptotic effect and protected tight junction structure in TECs. The increase of glomerular mesangium substrate was inhibited in HFD-diabetic mice. MSC therapy is a promising tool to prevent DN via the paracrine effect of renal trophic factors including exosomes due to its multifactorial action.
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Affiliation(s)
- Kanna Nagaishi
- Second Department of Anatomy, Sapporo Medical University, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan
| | - Yuka Mizue
- Second Department of Anatomy, Sapporo Medical University, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan
| | - Takako Chikenji
- Second Department of Anatomy, Sapporo Medical University, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan
| | - Miho Otani
- Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan
| | - Masako Nakano
- Second Department of Anatomy, Sapporo Medical University, Japan
| | - Naoto Konari
- Second Department of Anatomy, Sapporo Medical University, Japan
| | - Mineko Fujimiya
- Second Department of Anatomy, Sapporo Medical University, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan
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48
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Chen D, Fu W, Zhuang W, Lv C, Li F, Wang X. Therapeutic effects of intranigral transplantation of mesenchymal stem cells in rat models of Parkinson's disease. J Neurosci Res 2016; 95:907-917. [PMID: 27617772 DOI: 10.1002/jnr.23879] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/13/2016] [Accepted: 07/18/2016] [Indexed: 12/13/2022]
Abstract
Stem cell transplantation is a promising tool for the treatment of neurodegenerative disorders, including Parkinson's disease (PD); however, the therapeutic routes and mechanisms of mechanical approaches to stem cell transplantation must be explored. This study tests the therapeutic effect of transplantation of rat bone marrow mesenchymal stem cells (MSCs) into the substantia nigra (SN) of the PD rat. 5-Bromo-2-deoxyuridine-labeled rat MSCs were transplanted into the SN of the 6-hydroxydopamine-injected side of PD rat brains. The behavioral changes in PD rats were examined before and 4 and 8 weeks after MSC transplantation. The expression of tyrosine hydroxylase (TH) in the SN and the striatum and the survival and differentiation of MSCs were assessed by immunohistochemical and double immunofluorescence techniques. Abnormal behavior of PD rats was significantly improved by the administration of bone marrow MSCs, and the number of TH-positive cells in the SN and the optical density of TH-positive fibers in the striatum were markedly increased. Transplanted MSCs can survive and migrate in the brain and differentiate into nestin-, neuron-specific enolase-, and GFAP-positive cells. Our findings suggest that transplantation of rat bone marrow MSCs into the SN of PD rats may provide therapeutic effects. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Dandan Chen
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China.,Department of Anatomy, Shandong College of Traditional Chinese Medicine, Yantai, Shandong, People's Republic of China
| | - Wenyu Fu
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China
| | - Wenxin Zhuang
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China
| | - Cui Lv
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China.,Stem Cell Research and Transplantation Center, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People's Republic of China
| | - Fengjie Li
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China
| | - Xin Wang
- Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, People's Republic of China
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49
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Shen Y, Huang J, Liu L, Xu X, Han C, Zhang G, Jiang H, Li J, Lin Z, Xiong N, Wang T. A Compendium of Preparation and Application of Stem Cells in Parkinson's Disease: Current Status and Future Prospects. Front Aging Neurosci 2016; 8:117. [PMID: 27303288 PMCID: PMC4885841 DOI: 10.3389/fnagi.2016.00117] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Parkinson's Disease (PD) is a progressively neurodegenerative disorder, implicitly characterized by a stepwise loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and explicitly marked by bradykinesia, rigidity, resting tremor and postural instability. Currently, therapeutic approaches available are mainly palliative strategies, including L-3,4-dihydroxy-phenylalanine (L-DOPA) replacement therapy, DA receptor agonist and deep brain stimulation (DBS) procedures. As the disease proceeds, however, the pharmacotherapeutic efficacy is inevitably worn off, worse still, implicated by side effects of motor response oscillations as well as L-DOPA induced dyskinesia (LID). Therefore, the frustrating status above has propeled the shift to cell replacement therapy (CRT), a promising restorative therapy intending to secure a long-lasting relief of patients' symptoms. By far, stem cell lines of multifarious origins have been established, which can be further categorized into embryonic stem cells (ESCs), neural stem cells (NSCs), induced neural stem cells (iNSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). In this review, we intend to present a compendium of preparation and application of multifarious stem cells, especially in relation to PD research and therapy. In addition, the current status, potential challenges and future prospects for practical CRT in PD patients will be elaborated as well.
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Affiliation(s)
- Yan Shen
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jinsha Huang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Ling Liu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Xiaoyun Xu
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Chao Han
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Guoxin Zhang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Haiyang Jiang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Jie Li
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Zhicheng Lin
- Department of Psychiatry, Harvard Medical School, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital Belmont, MA, USA
| | - Nian Xiong
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
| | - Tao Wang
- Department of Neurology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology Wuhan, China
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50
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Bajek A, Gurtowska N, Olkowska J, Kazmierski L, Maj M, Drewa T. Adipose-Derived Stem Cells as a Tool in Cell-Based Therapies. Arch Immunol Ther Exp (Warsz) 2016; 64:443-454. [PMID: 27178663 PMCID: PMC5085986 DOI: 10.1007/s00005-016-0394-x] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/20/2016] [Indexed: 02/06/2023]
Abstract
Recent development in stem cell isolation methods and expansion under laboratory conditions create an opportunity to use those aforementioned cells in tissue engineering and regenerative medicine. Particular attention is drawn towards mesenchymal stem cells (MSCs) being multipotent progenitors exhibiting several unique characteristics, including high proliferation potential, self-renewal abilities and multilineage differentiation into cells of mesodermal and non-mesodermal origin. High abundance of MSCs found in adipose tissue makes it a very attractive source of adult stem cells for further use in regenerative medicine applications. Despite immunomodulating properties of adipose-derived stem cells (ASCs) and a secretion of a wide variety of paracrine factors that facilitate tissue regeneration, effectiveness of stem cell therapy was not supported by the results of clinical trials. Lack of a single, universal stem cell marker, patient-to-patient variability, heterogeneity of ASC population combined with multiple widely different protocols of cell isolation and expansion hinder the ability to precisely identify and analyze biological properties of stem cells. The above issues contribute to conflicting data reported in literature. We will review the comprehensive information concerning characteristic features of ASCs. We will also review the regenerative potential and clinical application based on various clinical trials.
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Affiliation(s)
- Anna Bajek
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland.
| | - Natalia Gurtowska
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Joanna Olkowska
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Lukasz Kazmierski
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Malgorzata Maj
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Tomasz Drewa
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland.,Department of Urology, Nicolaus Copernicus Hospital, Torun, Poland
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