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Lu Z, Ren S, Wang B, Zhang Y, Mu X, Wang Z. 3D dynamic culture of muse cells on a porous gelatin microsphere after magnetic sorting: Achieving high purity proliferation. Regen Ther 2025; 28:402-412. [PMID: 39911597 PMCID: PMC11794956 DOI: 10.1016/j.reth.2025.01.003] [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: 10/11/2024] [Revised: 12/16/2024] [Accepted: 01/04/2025] [Indexed: 02/07/2025] Open
Abstract
Muse cell has become a promising source of cells for disease treatment due to its remarkable characteristics, including stress tolerance, low tumorigenicity, effective homing ability, and differentiation into histocompatibility cells after transplantation. However, there are some obvious obstacles that need to be overcome in the efficient expansion of Muse cells. We extracted mesenchymal stem cells (MSCs) from human umbilical cord and their MSCs phenotypes were verified by flow cytometry. Then, immune magnetic sorting was performed to obtain Muse cells, and the expression of pluripotency related factors and the ability to differentiate into three germ layers were verified with sorted Muse cells. We then tested a new 3D culture method with dynamic microsphere carrier to possibly expand Muse cells more efficiently. Finally, in vivo experiments were conducted to check the homing ability of Muse cells to muscle injury. Our results showed that, the cultivation and expansion of Muse cells can be more effectively achieved through dynamic microsphere carrier; compared to non-Muse cells, Muse cells have stronger pluripotency and differentiation ability, and their homing ability in the muscle injury mice model is superior to that of non-Muse cells. Therefore, with the method of immune magnetic sorting and dynamic microsphere carrier, highly regenerative Muse cells can be more effectively sorted and expanded from MSCs.
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Affiliation(s)
| | | | - Bingjie Wang
- School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yajun Zhang
- School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiaodong Mu
- School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhihui Wang
- School of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
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Li H, Wei J, Li M, Li Y, Zhang T, Tian J, Liu X, Li K, Lin J. Biological characteristics of Muse cells derived from MenSCs and their application in acute liver injury and intracerebral hemorrhage diseases. Regen Ther 2024; 27:48-62. [PMID: 38496012 PMCID: PMC10940801 DOI: 10.1016/j.reth.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 03/19/2024] Open
Abstract
The increasing interest in multilineage differentiating stress-enduring (Muse) cells within the field of regenerative medicine is attributed to their exceptional homing capabilities, prolonged viability in adverse conditions, and enhanced three-germ-layer differentiate ability, surpassing their parent mesenchymal stem cells. Given their abundant sources, non-invasive collection procedure, and periodic availability, human menstrual blood-derived endometrium stem cells (MenSCs) have been extensively investigated as a potential resource for stem cell-based therapies. However, there is no established modality to isolate Muse cells from MenSCs and disparity in gene expression profiles between Muse cells and MenSCs remain unknown. In this study, Muse cells were isolated from MenSCs by long-time trypsin incubation method. Muse cells expressed pluripotency markers and could realize multilineage differentiation in vitro. Compared with MenSCs, Muse cells showed enhanced homing ability and superior therapeutic efficacy in animal models of acute liver injury (ALI) and intracerebral hemorrhage (ICH). Furthermore, the RNA-seq analysis offers insights into the mechanism underlying the disparity in trypsin resistance and migration ability between Muse and MenSCs cells. This research offers a significant foundation for further exploration of cell-based therapies using MenSCs-derived Muse cells in the context of various human diseases, highlighting their promising application in the field of regenerative medicine.
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Affiliation(s)
- Han Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Jinghui Wei
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Mingzhi Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Yaoqiang Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Tong Zhang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Jialu Tian
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Xuejia Liu
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Kangjia Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
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Cancedda R, Mastrogiacomo M. The Phoenix of stem cells: pluripotent cells in adult tissues and peripheral blood. Front Bioeng Biotechnol 2024; 12:1414156. [PMID: 39139297 PMCID: PMC11319133 DOI: 10.3389/fbioe.2024.1414156] [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: 04/08/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024] Open
Abstract
Pluripotent stem cells are defined as cells that can generate cells of lineages from all three germ layers, ectoderm, mesoderm, and endoderm. On the contrary, unipotent and multipotent stem cells develop into one or more cell types respectively, but their differentiation is limited to the cells present in the tissue of origin or, at most, from the same germ layer. Multipotent and unipotent stem cells have been isolated from a variety of adult tissues, Instead, the presence in adult tissues of pluripotent stem cells is a very debated issue. In the early embryos, all cells are pluripotent. In mammalians, after birth, pluripotent cells are maintained in the bone-marrow and possibly in gonads. In fact, pluripotent cells were isolated from marrow aspirates and cord blood and from cultured bone-marrow stromal cells (MSCs). Only in few cases, pluripotent cells were isolated from other tissues. In addition to have the potential to differentiate toward lineages derived from all three germ layers, the isolated pluripotent cells shared other properties, including the expression of cell surface stage specific embryonic antigen (SSEA) and of transcription factors active in the early embryos, but they were variously described and named. However, it is likely that they are part of the same cell population and that observed diversities were the results of different isolation and expansion strategies. Adult pluripotent stem cells are quiescent and self-renew at very low rate. They are maintained in that state under the influence of the "niche" inside which they are located. Any tissue damage causes the release in the blood of inflammatory cytokines and molecules that activate the stem cells and their mobilization and homing in the injured tissue. The inflammatory response could also determine the dedifferentiation of mature cells and their reversion to a progenitor stage and at the same time stimulate the progenitors to proliferate and differentiate to replace the damaged cells. In this review we rate articles reporting isolation and characterization of tissue resident pluripotent cells. In the attempt to reconcile observations made by different authors, we propose a unifying picture that could represent a starting point for future experiments.
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Affiliation(s)
- Ranieri Cancedda
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
| | - Maddalena Mastrogiacomo
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università Degli Studi di Genova, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Kushida Y, Oguma Y, Abe K, Deguchi T, Barbera FG, Nishimura N, Fujioka K, Iwatani S, Dezawa M. Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord. Cell Mol Life Sci 2024; 81:297. [PMID: 38992309 PMCID: PMC11335221 DOI: 10.1007/s00018-024-05339-4] [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: 01/31/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/13/2024]
Abstract
Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine.
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Affiliation(s)
- Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan.
| | - Yo Oguma
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Kana Abe
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Taichi Deguchi
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Federico Girolamo Barbera
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan
| | - Noriyuki Nishimura
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Sota Iwatani
- Department of Neonatology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi, 980-8575, Japan.
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Miotti G, De Marco L, Quaglia D, Grando M, Salati C, Spadea L, Gagliano C, Musa M, Surico PL, Parodi PC, Zeppieri M. Fat or fillers: The dilemma in eyelid surgery. World J Clin Cases 2024; 12:2951-2965. [PMID: 38898854 PMCID: PMC11185368 DOI: 10.12998/wjcc.v12.i17.2951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/22/2024] [Accepted: 05/11/2024] [Indexed: 06/04/2024] Open
Abstract
The aging of the periocular region has always aroused great interest. A fresh, young, and attractive sight determined an ever-greater attention to surgical and non-surgical techniques to obtain this result. In particular, the change in the concept of a young look, considered then "full", led to the increasing use of surgical (fat grafting) or medical (hyaluronic acid) filling techniques. Eyelid rejuvenation became increasingly popular in the field of cosmetic treatments, with a focus on achieving a youthful and refreshed appearance. Among the various techniques available, the choice between using fat grafting or fillers presented a clinical dilemma. In particular, what surgery considered of fundamental importance was a long-lasting result over time. On the other hand, aesthetic medicine considered it fundamental not to have to resort to invasive treatments. But what was the reality? Was there one path better than the other, and above all, was there a better path for patients? The minireview aims to explore the physiopathology, diagnosis, treatment options, prognosis, and future studies regarding this dilemma. We analyzed the literature produced in the last 20 years comparing the two techniques. Current literature reveals advancements in biomaterials, stem cell research and tissue engineering held promise for further enhancing the field of eyelid rejuvenation. The choice between fat grafting and fillers in eyelid cosmetic treatments presented a clinical dilemma. Understanding physiopathology, accurately diagnosing eyelid aging, exploring treatment options, assessing prognosis, and conducting future studies were essential for providing optimal care to patients seeking eyelid rejuvenation.
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Affiliation(s)
- Giovanni Miotti
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Luca De Marco
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Davide Quaglia
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Martina Grando
- Department of Internal Medicine, Azienda Sanitaria Friuli Occidentale, San Vito al Tagliamento 33078, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, “Sapienza” University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Enna 94100, Italy
- Eye Clinic Catania University San Marco Hospital, Viale Carlo Azeglio Ciampi, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | - Pier Luigi Surico
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, United States
| | - Pier Camillo Parodi
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Que H, Mai E, Hu Y, Li H, Zheng W, Jiang Y, Han F, Li X, Gong P, Gu J. Multilineage-differentiating stress-enduring cells: a powerful tool for tissue damage repair. Front Cell Dev Biol 2024; 12:1380785. [PMID: 38872932 PMCID: PMC11169632 DOI: 10.3389/fcell.2024.1380785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/08/2024] [Indexed: 06/15/2024] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are a type of pluripotent cell with unique characteristics such as non-tumorigenic and pluripotent differentiation ability. After homing, Muse cells spontaneously differentiate into tissue component cells and supplement damaged/lost cells to participate in tissue repair. Importantly, Muse cells can survive in injured tissue for an extended period, stabilizing and promoting tissue repair. In addition, it has been confirmed that injection of exogenous Muse cells exerts anti-inflammatory, anti-apoptosis, anti-fibrosis, immunomodulatory, and paracrine protective effects in vivo. The discovery of Muse cells is an important breakthrough in the field of regenerative medicine. The article provides a comprehensive review of the characteristics, sources, and potential mechanisms of Muse cells for tissue repair and regeneration. This review serves as a foundation for the further utilization of Muse cells as a key clinical tool in regenerative medicine.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Puyang Gong
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Jian Gu
- College of Pharmacy, Southwest Minzu University, Chengdu, China
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Win KHN, Kushida Y, Yamana K, Iwatani S, Yoshida M, Nino N, Mon CY, Ohsaki H, Kamoshida S, Fujioka K, Dezawa M, Nishimura N. Human Muse cells isolated from preterm- and term-umbilical cord delivered therapeutic effects in rat bleomycin-induced lung injury model without immunosuppressant. Stem Cell Res Ther 2024; 15:147. [PMID: 38773627 PMCID: PMC11110192 DOI: 10.1186/s13287-024-03763-8] [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: 01/08/2024] [Accepted: 05/15/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. METHODS Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. RESULTS Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. CONCLUSION Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.
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Affiliation(s)
- Kaung Htet Nay Win
- Department of Public Health, Kobe University Graduate School of Health Science, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Keiji Yamana
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Sota Iwatani
- Department of Neonatology, Kobe Children's Hospital, Kobe, Hyogo, Japan
| | - Makiko Yoshida
- Department of Pathology, Kobe Children's Hospital, Kobe, Hyogo, Japan
| | - Nanako Nino
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Cho Yee Mon
- Department of Public Health, Kobe University Graduate School of Health Science, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan
| | - Hiroyuki Ohsaki
- Department of Medical Biophysics, Kobe University Graduate School of Health Science, Kobe, Hyogo, Japan
| | - Shingo Kamoshida
- Department of Medical Biophysics, Kobe University Graduate School of Health Science, Kobe, Hyogo, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Noriyuki Nishimura
- Department of Public Health, Kobe University Graduate School of Health Science, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan.
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Aprile D, Patrone D, Peluso G, Galderisi U. Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications. Stem Cell Res Ther 2024; 15:139. [PMID: 38735988 PMCID: PMC11089765 DOI: 10.1186/s13287-024-03752-x] [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: 04/04/2024] [Accepted: 05/02/2024] [Indexed: 05/14/2024] Open
Abstract
The concept of "stemness" incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells.
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Affiliation(s)
- Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Deanira Patrone
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Gianfranco Peluso
- Faculty of Medicine and Surgery, Saint Camillus International, University of Health Sciences, Rome, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy.
- Genome and Stem Cell Center (GENKÖK), Erciyes University, Kayseri, Turkey.
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine Temple University, Philadelphia, PA, USA.
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Biniazan F, Stoian A, Haykal S. Adipose-Derived Stem Cells: Angiogenetic Potential and Utility in Tissue Engineering. Int J Mol Sci 2024; 25:2356. [PMID: 38397032 PMCID: PMC10889096 DOI: 10.3390/ijms25042356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Adipose tissue (AT) is a large and important energy storage organ as well as an endocrine organ with a critical role in many processes. Additionally, AT is an enormous and easily accessible source of multipotent cell types used in our day for all types of tissue regeneration. The ability of adipose-derived stem cells (ADSCs) to differentiate into other types of cells, such as endothelial cells (ECs), vascular smooth muscle cells, or cardiomyocytes, is used in tissue engineering in order to promote/stimulate the process of angiogenesis. Being a key for future successful clinical applications, functional vascular networks in engineered tissue are targeted by numerous in vivo and ex vivo studies. The article reviews the angiogenic potential of ADSCs and explores their capacity in the field of tissue engineering (TE).
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Affiliation(s)
- Felor Biniazan
- Latner Thoracic Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital Research Institute, University Health Network, 200 Elizabeth Street Suite 8N-869, Toronto, ON M5G2C4, Canada; (F.B.); (A.S.)
| | - Alina Stoian
- Latner Thoracic Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital Research Institute, University Health Network, 200 Elizabeth Street Suite 8N-869, Toronto, ON M5G2C4, Canada; (F.B.); (A.S.)
| | - Siba Haykal
- Latner Thoracic Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital Research Institute, University Health Network, 200 Elizabeth Street Suite 8N-869, Toronto, ON M5G2C4, Canada; (F.B.); (A.S.)
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, 200 Elizabeth Street Suite 8N-869, Toronto, ON M5G2C4, Canada
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Li G, Wakao S, Kitada M, Dezawa M. Tumor suppressor let-7 acts as a key regulator for pluripotency gene expression in Muse cells. Cell Mol Life Sci 2024; 81:54. [PMID: 38261036 PMCID: PMC10805825 DOI: 10.1007/s00018-023-05089-9] [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: 08/28/2023] [Revised: 12/01/2023] [Accepted: 12/12/2023] [Indexed: 01/24/2024]
Abstract
In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.
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Affiliation(s)
- Gen Li
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Masaaki Kitada
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
- Department of Anatomy, Kansai Medical University School of Medicine, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan.
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
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Nagaoki T, Kumagai G, Nitobe Y, Sasaki A, Fujita T, Fukutoku T, Saruta K, Tsukuda M, Asari T, Wada K, Dezawa M, Ishibashi Y. Comparison of the Anti-Inflammatory Effects of Mouse Adipose- and Bone-Marrow-Derived Multilineage-Differentiating Stress-Enduring Cells in Acute-Phase Spinal Cord Injury. J Neurotrauma 2023; 40:2596-2609. [PMID: 37051701 DOI: 10.1089/neu.2022.0470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023] Open
Abstract
Abstract Spinal cord injury (SCI) is a serious neurological disorder, with the consequent disabilities conferred by this disorder typically persisting for life. Multilineage-differentiating stress-enduring (Muse) cells are endogenous stem cells that can be collected from various tissues as well as from mesenchymal stem cells (MSCs); additionally, these Muse cells are currently being used in clinical trials. The anti-inflammatory effect of stem cell transplantation prevents secondary injuries of SCI; however, its effect on Muse cells remains unclear. In this study, we aimed to compare the anti-inflammatory effects of adipose (AD)- and bone marrow (BM)-Muse cells that were isolated from mice (6-week-old C57BL/6J) following intralesional administration during the acute phase of SCI. Flow cytometry was used to isolate Muse cells from AD and BM MSCs. The percentage of Muse cells was 3.9 and 2.7% for AD and BM MSCs, respectively. To examine cell viability, Muse cells were incubated under H2O2-induced oxidative stress conditions. Overall, AD-Muse cells exhibited higher viability than BM-Muse cells (p = 0.032). In enzyme-linked immunosorbent assay analysis, AD-Muse cells displayed greater secretion of brain-derived neurotrophic factor (BDNF; p = 0.008), vascular endothelial growth factor (p = 0.032), and hepatocyte growth factor (p = 0.016). DNA microarray analysis revealed higher expression of Bdnf, neurotrophin-3 (Ntf3), nerve growth factor (Ngf), pleiotrophin (Ptn), and midkine (Mdk) in AD-Muse cells than in BM-Muse cells. To assess their anti-inflammatory effects in vitro, Muse cells and macrophages were co-cultured, and the levels of cytokines (tumor necrosis factor [TNF] α and interleukin [IL] 10) were measured in the medium. Consequently, we found that TNFα levels were lower in AD-Muse cells than in BM-Muse cells (p = 0.009), and IL10 levels were higher in AD-Muse cells than in BM-Muse cells (p = 0.008). Further, we induced moderate injuries via contusion of the spinal cord at the T10 level; Muse cells were transplanted intralesionally 7 days post-SCI. The number of surviving cells, alongside the number of CD86+ (M1 inflammatory effect), and CD206+ (M2 anti-inflammatory effect) macrophages in the spinal cord were measured 7 days post-transplantation. The number of surviving AD-Muse cells was higher than the number of surviving BM-Muse cells (ratio of AD-Muse/BM-Muse = 2.5, p > 0.05). The M1/M2 ratio in the AD-Muse cell-group (0.37) was lower than that in the control (phosphate-buffered saline) group (3.60, p = 0.008). The lesion area in the AD-Muse cell group was smaller than that in the BM-non-Muse (p = 0.049) and control groups (p = 0.012). As AD-Muse cells conferred a higher cell survival and neurotrophic factor secretion ability in vitro, AD-Muse cells demonstrated reduced inflammation after SCI. Overall, intralesional AD-Muse cell therapy is a potential therapeutic candidate that is expected to exhibit anti-inflammatory effects following acute SCI.
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Affiliation(s)
- Toshihide Nagaoki
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Gentaro Kumagai
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Yohshiro Nitobe
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Ayako Sasaki
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Taku Fujita
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Tatsuhiro Fukutoku
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Kenya Saruta
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Manami Tsukuda
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Toru Asari
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Kanichiro Wada
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Yasuyuki Ishibashi
- Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
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Salvatore G, Dolci S, Camaioni A, Klinger FG, De Felici M. Reprogramming Human Female Adipose Mesenchymal Stem Cells into Primordial Germ Cell-Like Cells. Stem Cell Rev Rep 2023; 19:2274-2283. [PMID: 37338786 PMCID: PMC10579115 DOI: 10.1007/s12015-023-10561-x] [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] [Accepted: 05/15/2023] [Indexed: 06/21/2023]
Abstract
In the last two decades, considerable progress has been made in the derivation of mammalian germ cells from pluripotent stem cells such as Embryonic Stem Cells (ESCs) and induced Pluripotent Stem Cells (iPSCs). The pluripotent stem cells are generally first induced into pre-gastrulating endoderm/mesoderm-like status and then specified into putative primordial germ cells (PGCs) termed PGC-like cells (PGCLCs) which possess the potential to generate oocytes and sperms. Adipose-derived mesenchymal stromal cells (ASCs) are multipotent cells, having the capacity to differentiate into cell types such as adipocytes, osteocytes and chondrocytes. Since no information is available about the capability of female human ASCs (hASCs) to generate PGCLCs, we compared protocols to produce such cells from hASCs themselves or from hASC-derived iPSCs. The results showed that, providing pre-induction into a peri-gastrulating endoderm/mesoderm-like status, hASCs can generate PGCLCs. This process, however, shows a lower efficiency than when hASC-derived iPSCs are used as starting cells. Although hASCs possess multipotency and express mesodermal genes, direct induction into PGCLCs resulted less efficient.
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Affiliation(s)
- Giulia Salvatore
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Susanna Dolci
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Antonella Camaioni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy
| | - Francesca Gioia Klinger
- Saint Camillus International University Of Health Sciences, Via di Sant'Alessandro 8, Rome, 00131, Italy.
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy.
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Smolinska A, Bzinkowska A, Rybkowska P, Chodkowska M, Sarnowska A. Promising Markers in the Context of Mesenchymal Stem/Stromal Cells Subpopulations with Unique Properties. Stem Cells Int 2023; 2023:1842958. [PMID: 37771549 PMCID: PMC10533301 DOI: 10.1155/2023/1842958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
The heterogeneity of the mesenchymal stem/stromal cells (MSCs) population poses a challenge to researchers and clinicians, especially those observed at the population level. What is more, the lack of precise evidences regarding MSCs developmental origin even further complicate this issue. As the available evidences indicate several possible pathways of MSCs formation, this diverse origin may be reflected in the unique subsets of cells found within the MSCs population. Such populations differ in specialization degree, proliferation, and immunomodulatory properties or exhibit other additional properties such as increased angiogenesis capacity. In this review article, we attempted to identify such outstanding populations according to the specific surface antigens or intracellular markers. Described groups were characterized depending on their specialization and potential therapeutic application. The reports presented here cover a wide variety of properties found in the recent literature, which is quite scarce for many candidates mentioned in this article. Even though the collected information would allow for better targeting of specific subpopulations in regenerative medicine to increase the effectiveness of MSC-based therapies.
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Affiliation(s)
- Agnieszka Smolinska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Aleksandra Bzinkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Magdalena Chodkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
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Alanazi RF, Alhwity BS, Almahlawi RM, Alatawi BD, Albalawi SA, Albalawi RA, Albalawi AA, Abdel-Maksoud MS, Elsherbiny N. Multilineage Differentiating Stress Enduring (Muse) Cells: A New Era of Stem Cell-Based Therapy. Cells 2023; 12:1676. [PMID: 37443710 PMCID: PMC10340735 DOI: 10.3390/cells12131676] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/03/2023] [Accepted: 06/17/2023] [Indexed: 07/15/2023] Open
Abstract
Stem cell transplantation has recently demonstrated a significant therapeutic efficacy in various diseases. Multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant endogenous pluripotent stem cells that were first reported in 2010. Muse cells can be found in the peripheral blood, bone marrow and connective tissue of nearly all body organs. Under basal conditions, they constantly move from the bone marrow to peripheral blood to supply various body organs. However, this rate greatly changes even within the same individual based on physical status and the presence of injury or illness. Muse cells can differentiate into all three-germ-layers, producing tissue-compatible cells with few errors, minimal immune rejection and without forming teratomas. They can also endure hostile environments, supporting their survival in damaged/injured tissues. Additionally, Muse cells express receptors for sphingosine-1-phosphate (S1P), which is a protein produced by damaged/injured tissues. Through the S1P-S1PR2 axis, circulating Muse cells can preferentially migrate to damaged sites following transplantation. In addition, Muse cells possess a unique immune privilege system, facilitating their use without the need for long-term immunosuppressant treatment or human leucocyte antigen matching. Moreover, they exhibit anti-inflammatory, anti-apoptotic and tissue-protective effects. These characteristics circumvent all challenges experienced with mesenchymal stem cells and induced pluripotent stem cells and encourage the wide application of Muse cells in clinical practice. Indeed, Muse cells have the potential to break through the limitations of current cell-based therapies, and many clinical trials have been conducted, applying intravenously administered Muse cells in stroke, myocardial infarction, neurological disorders and acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection. Herein, we aim to highlight the unique biological properties of Muse cells and to elucidate the advantageous difference between Muse cells and other types of stem cells. Finally, we shed light on their current therapeutic applications and the major obstacles to their clinical implementation from laboratory to clinic.
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Affiliation(s)
- Raghad F. Alanazi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Basma S. Alhwity
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Raghad M. Almahlawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Bashayer D. Alatawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Shatha A. Albalawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Raneem A. Albalawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Amaal A. Albalawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.F.A.); (B.S.A.); (R.M.A.); (B.D.A.); (S.A.A.); (R.A.A.); (A.A.A.)
| | - Mohamed S. Abdel-Maksoud
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Nehal Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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15
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Ossanna R, Veronese S, Quintero Sierra LA, Conti A, Conti G, Sbarbati A. Multilineage-Differentiating Stress-Enduring Cells (Muse Cells): An Easily Accessible, Pluripotent Stem Cell Niche with Unique and Powerful Properties for Multiple Regenerative Medicine Applications. Biomedicines 2023; 11:1587. [PMID: 37371682 DOI: 10.3390/biomedicines11061587] [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: 05/08/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Cell-based therapy in regenerative medicine is a powerful tool that can be used both to restore various cells lost in a wide range of human disorders and in renewal processes. Stem cells show promise for universal use in clinical medicine, potentially enabling the regeneration of numerous organs and tissues in the human body. This is possible due to their self-renewal, mature cell differentiation, and factors release. To date, pluripotent stem cells seem to be the most promising. Recently, a novel stem cell niche, called multilineage-differentiating stress-enduring (Muse) cells, is emerging. These cells are of particular interest because they are pluripotent and are found in adult human mesenchymal tissues. Thanks to this, they can produce cells representative of all three germ layers. Furthermore, they can be easily harvested from fat and isolated from the mesenchymal stem cells. This makes them very promising, allowing autologous treatments and avoiding the problems of rejection typical of transplants. Muse cells have recently been employed, with encouraging results, in numerous preclinical studies performed to test their efficacy in the treatment of various pathologies. This review aimed to (1) highlight the specific potential of Muse cells and provide a better understanding of this niche and (2) originate the first organized review of already tested applications of Muse cells in regenerative medicine. The obtained results could be useful to extend the possible therapeutic applications of disease healing.
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Affiliation(s)
- Riccardo Ossanna
- Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, 37124 Verona, Italy
| | - Sheila Veronese
- Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, 37124 Verona, Italy
| | | | - Anita Conti
- Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, 37124 Verona, Italy
| | - Giamaica Conti
- Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, 37124 Verona, Italy
| | - Andrea Sbarbati
- Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, 37124 Verona, Italy
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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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Castillo MG, Peralta TM, Locatelli P, Velazquez C, Herrero Y, Crottogini AJ, Olea FD, Cuniberti LA. Promoting early neovascularization by allotransplanted adipose-derived Muse cells in an ovine model of acute myocardial infarction. PLoS One 2023; 18:e0277442. [PMID: 36662847 PMCID: PMC9858827 DOI: 10.1371/journal.pone.0277442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/26/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Recent preclinical studies have demonstrated that bone marrow (BM)-derived Muse cells have a homing mechanism to reach damaged cardiac tissue while also being able to reduce myocardial infarct size and improve cardiac function; however, the potential of BM-Muse cells to foster new blood-vessel formation has not been fully assessed. Up to date, adipose tissue (AT)-derived Muse cells remain to be studied in acute myocardial infarction (AMI). The aim of the present study was to analyze in vitro and in vivo the neovascularization capacity of AT-Muse cells while exploring their biodistribution and differentiation potential in a translational ovine model of AMI. METHODS AND RESULTS AT-Muse cells were successfully isolated from ovine adipose tissue. In adult sheep, one or more diagonal branches of the left anterior descending coronary artery were permanently ligated for thirty minutes. Sheep were randomized in two groups and treated with intramyocardial injections: Vehicle (PBS, n = 4) and AT-Muse (2x107 AT-Muse cells labeled with PKH26 Red Fluorescent Dye, n = 4). Molecular characterization showed higher expression of angiogenic genes (VEGF, PGF and ANG) and increased number of tube formation in AT-Muse cells group compared to Adipose-derived mesenchymal stromal cells (ASCs) group. At 7 days post-IAM, the AT-Muse group showed significantly more arterioles and capillaries than the Vehicle group. Co-localization of PKH26+ cells with desmin, sarcomeric actin and troponin T implied the differentiation of Muse cells to a cardiac fate; moreover, PKH26+ cells also co-localized with a lectin marker, suggesting a possible differentiation to a vascular lineage. CONCLUSION Intramyocardially administered AT-Muse cells displayed a significant neovascularization activity and survival capacity in an ovine model of AMI.
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Affiliation(s)
- Martha G. Castillo
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Tomás M. Peralta
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Paola Locatelli
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Candela Velazquez
- Instituto de Biología y Medicina Experimental—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Yamila Herrero
- Instituto de Biología y Medicina Experimental—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Alberto J. Crottogini
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Fernanda D. Olea
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
| | - Luis A. Cuniberti
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTYB)—Universidad Favaloro—CONICET, Ciudad de Buenos Aires, Buenos Aires, Argentina
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Quintero Sierra LA, Biswas R, Conti A, Busato A, Ossanna R, Zingaretti N, Parodi PC, Conti G, Riccio M, Sbarbati A, De Francesco F. Highly Pluripotent Adipose-Derived Stem Cell-Enriched Nanofat: A Novel Translational System in Stem Cell Therapy. Cell Transplant 2023; 32:9636897231175968. [PMID: 37243545 DOI: 10.1177/09636897231175968] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2023] Open
Abstract
Fat graft is widely used in plastic and reconstructive surgery. The size of the injectable product, the unpredictable fat resorption rates, and subsequent adverse effects make it tricky to inject untreated fat into the dermal layer. Mechanical emulsification of fat tissue, which Tonnard introduced, solves these problems, and the product obtained was called nanofat. Nanofat is widely used in clinical and aesthetic settings to treat facial compartments, hypertrophic and atrophic scars, wrinkle attenuation, skin rejuvenation, and alopecia. Several studies demonstrate that the tissue regeneration effects of nanofat are attributable to its rich content of adipose-derived stem cells. This study aimed to characterize Hy-Tissue Nanofat product by investigating morphology, cellular yield, adipose-derived stem cell (ASC) proliferation rate and clonogenic capability, immunophenotyping, and differential potential. The percentage of SEEA3 and CD105 expression was also analyzed to establish the presence of multilineage-differentiating stress-enduring (MUSE) cell. Our results showed that the Hy-Tissue Nanofat kit could isolate 3.74 × 104 ± 1.31 × 104 proliferative nucleated cells for milliliter of the treated fat. Nanofat-derived ASC can grow in colonies and show high differentiation capacity into adipocytes, osteocytes, and chondrocytes. Moreover, immunophenotyping analysis revealed the expression of MUSE cell antigen, making this nanofat enriched of pluripotent stem cell, increasing its potential in regenerative medicine. The unique characteristics of MUSE cells give a simple, feasible strategy for treating a variety of diseases.
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Affiliation(s)
| | - Reetuparna Biswas
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
| | - Anita Conti
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
| | - Alice Busato
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
- Safety Assessment Department, Aptuit (Verona) S.r.l., an Evotec Company, Verona, Italy
| | - Riccardo Ossanna
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
| | - Nicola Zingaretti
- Department of Medical Area (DAME), Clinic of Plastic and Reconstructive Surgery, Academic Hospital of Udine, University of Udine, Udine, Italy
| | - Pier Camillo Parodi
- Department of Medical Area (DAME), Clinic of Plastic and Reconstructive Surgery, Academic Hospital of Udine, University of Udine, Udine, Italy
- Research and Training Center in Regenerative Surgery, Accademia del Lipofilling, Montelabbate, Italy
| | - Giamaica Conti
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
| | - Michele Riccio
- Research and Training Center in Regenerative Surgery, Accademia del Lipofilling, Montelabbate, Italy
- Department of General and Specialties Surgery, SOD of Reconstructive Surgery and Hand Surgery, Azienda Ospedaliera Universitaria delle Marche, Ancona, Italy
| | - Andrea Sbarbati
- Human Anatomy and Histology Section, Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy
- Research and Training Center in Regenerative Surgery, Accademia del Lipofilling, Montelabbate, Italy
| | - Francesco De Francesco
- Department of General and Specialties Surgery, SOD of Reconstructive Surgery and Hand Surgery, Azienda Ospedaliera Universitaria delle Marche, Ancona, Italy
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Fluidic Device System for Mechanical Processing and Filtering of Human Lipoaspirate Enhances Recovery of Mesenchymal Stem Cells. Plast Reconstr Surg 2023; 151:72e-84e. [PMID: 36205654 PMCID: PMC10156086 DOI: 10.1097/prs.0000000000009798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Adipose tissue is an easily accessible source of stem and progenitor cells that offers exciting promise as an injectable autologous therapeutic for regenerative applications. Mechanical processing is preferred over enzymatic digestion, and the most common method involves shuffling lipoaspirate between syringes and filtering to produce nanofat. Although nanofat has shown exciting clinical results, the authors hypothesized that new device designs could enhance recovery of stem/progenitor cells through optimization of fluid dynamics principles, integration, and automation. METHODS The authors designed and fabricated the emulsification and micronization device (EMD) and the filtration device (FD) to replace the manual nanofat procedures. Using human lipoaspirate samples, the EMD and the FD were optimized and compared to traditional nanofat using ex vivo measurements of cell number, viability, and percentage of mesenchymal stem cells and endothelial progenitor cells. RESULTS The EMD produced results statistically similar to nanofat, and these findings were confirmed for a cohort of diabetic patients. Combining the FD with the EMD was superior to manually filtered nanofat in terms of both recovered cell percentages (>1.5-fold) and numbers (two- to three-fold). Differences were statistically significant for total mesenchymal stem cells and a DPP4 + /CD55 + subpopulation linked to improved wound healing in diabetes. CONCLUSIONS The new EMD and the FD improved mechanical processing of human lipoaspirate in terms of mesenchymal stem cell enrichment and number compared to traditional nanofat. Future work will seek to investigate the wound healing response both in vitro and in vivo, and to refine the technology for automated operation within clinical settings. CLINICAL RELEVANCE STATEMENT The new devices improved mechanical processing of human lipoaspirate in terms of stem cell enrichment and number compared to traditional methods. Future work will seek to validate wound healing response and refine the technology for automated operation within clinical settings.
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Single-cell RNA sequencing reveals different signatures of mesenchymal stromal cell pluripotent-like and multipotent populations. iScience 2022; 25:105395. [PMID: 36339265 PMCID: PMC9633745 DOI: 10.1016/j.isci.2022.105395] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 07/22/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022] Open
Abstract
Somatic stem cells are advantageous research targets for understanding the properties required to maintain stemness. Human bone marrow-mesenchymal stromal cells (BM-MSCs) were separated into pluripotent-like SSEA-3(+) Muse cells (Muse-MSCs) and multipotent SSEA-3(−) MSCs (MSCs) and were subjected to single-cell RNA sequencing analysis. Compared with MSCs, Muse-MSCs exhibited higher expression levels of the p53 repressor MDM2; signal acceptance-related genes EGF, VEGF, PDGF, WNT, TGFB, INHB, and CSF; ribosomal protein; and glycolysis and oxidative phosphorylation. Conversely, MSCs had higher expression levels of FGF and ANGPT; Rho family and caveola-related genes; amino acid and cofactor metabolism; MHC class I/II, and lysosomal enzyme genes than Muse-MSCs. Unsupervised clustering further divided Muse-MSCs into two clusters stratified by the expression of cell cycle-related genes, and MSCs into three clusters stratified by the expression of cell cycle-, cytoskeleton-, and extracellular matrix-related genes. This study evaluating the differentiation ability of BM-MSC subpopulations provides intriguing insights for understanding stemness.
MSCs were separated into pluripotent-like Muse-MSCs and multipotent MSCs Gene expressions of Muse-MSCs and MSCs were analyzed by single-cell RNA sequencing p53 suppressor, ribosomal protein, and energy metabolism were higher in Muse-MSCs Genes related to the cytoskeleton, amino acid metabolism, and MHC were higher in MSCs
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Kuroda Y, Oguma Y, Hall K, Dezawa M. Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation. Front Pharmacol 2022; 13:1027961. [PMID: 36339573 PMCID: PMC9627303 DOI: 10.3389/fphar.2022.1027961] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/05/2022] [Indexed: 11/21/2022] Open
Abstract
Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.
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Affiliation(s)
| | | | | | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
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22
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Ogawa E, Oguma Y, Kushida Y, Wakao S, Okawa K, Dezawa M. Naïve pluripotent-like characteristics of non-tumorigenic Muse cells isolated from human amniotic membrane. Sci Rep 2022; 12:17222. [PMID: 36241699 PMCID: PMC9568515 DOI: 10.1038/s41598-022-22282-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 10/12/2022] [Indexed: 01/06/2023] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic pluripotent-like stem cells that exhibit triploblastic differentiation and self-renewability at the single-cell level, and are collectable as pluripotent surface marker SSEA-3(+) from the bone marrow (BM), peripheral blood, and organ connective tissues. SSEA-3(+) cells from human amniotic membrane mesenchymal stem cells (hAMSCs) were compared with hBM-Muse cells. Similar to hBM-Muse cells, hAMSC-SSEA-3(+) cells expressed pluripotency genes (OCT3/4, NANOG, and SOX2), differentiated into triploblastic cells from a single cell, self-renewed, and exhibited non-tumorigenicity. Notably, however, they exhibited unique characteristics not seen in hBM-Muse cells, including higher expression of genes related to germline- and extraembryonic cell-lineages compared with those in hBM-Muse cells in single-cell RNA-sequencing; and enhanced expression of markers relevant to germline- (PRDM14, TFAP2C, and NANOS3) and extraembryonic cell- (CDX2, GCM1, and ID2) lineages when induced by cytokine subsets, suggesting a broader differentiation potential similar to naïve pluripotent stem cells. t-SNE dimensionality reduction and Gene ontology analysis visualized hAMSC-SSEA-3(+) cells comprised a large undifferentiated subpopulation between epithelial- and mesenchymal-cell states and a small mesenchymal subpopulation expressing genes relevant to the placental formation. The AM is easily accessible by noninvasive approaches. These unique cells are a potentially interesting target naïve pluripotent stem cell-like resource without tumorigenicity.
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Affiliation(s)
- Eiji Ogawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Yo Oguma
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Yoshihiro Kushida
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Shohei Wakao
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Kana Okawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
| | - Mari Dezawa
- grid.69566.3a0000 0001 2248 6943Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Sendai, 980-8575 Japan
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Wakao S, Oguma Y, Kushida Y, Kuroda Y, Tatsumi K, Dezawa M. Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame. Cell Mol Life Sci 2022; 79:542. [PMID: 36203068 PMCID: PMC9537123 DOI: 10.1007/s00018-022-04555-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/29/2022]
Abstract
Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing ‘model cells’ (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.
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Affiliation(s)
- Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan.
| | - Yo Oguma
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan
| | - Yasumasa Kuroda
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan
| | - Kazuki Tatsumi
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan.,Regenerative Medicine Division, Analytical Research Department, Technology Development Unit, Life Science Institute, Inc., Tokyo, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan.
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Hatabi K, Hirohara Y, Kushida Y, Kuroda Y, Wakao S, Trosko J, Dezawa M. Inhibition of Gap Junctional Intercellular Communication Upregulates Pluripotency Gene Expression in Endogenous Pluripotent Muse Cells. Cells 2022; 11:2701. [PMID: 36078111 PMCID: PMC9455024 DOI: 10.3390/cells11172701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Gap junctions (GJ) are suggested to support stem cell differentiation. The Muse cells that are applied in clinical trials are non-tumorigenic pluripotent-like endogenous stem cells, can be collected as stage-specific embryonic antigen 3 (SSEA-3+) positive cells from multiple tissues, and show triploblastic differentiation and self-renewability at a single cell level. They were reported to up-regulate pluripotency gene expression in suspension. We examined how GJ inhibition affected pluripotency gene expression in adherent cultured-Muse cells. Muse cells, mainly expressing gap junction alpha-1 protein (GJA1), reduced GJ intercellular communication from ~85% to 5-8% after 24 h incubation with 120 μM 18α-glycyrrhetinic acid, 400 nM 12-O-tetradecanoylphorbol-13-acetate, and 90 μM dichlorodiphenyltrichloroethane, as confirmed by a dye-transfer assay. Following inhibition, NANOG, OCT3/4, and SOX2 were up-regulated 2-4.5 times more; other pluripotency-related genes, such as KLF4, CBX7, and SPRY2 were elevated; lineage-specific differentiation-related genes were down-regulated in quantitative-PCR and RNA-sequencing. Connexin43-siRNA introduction also confirmed the up-regulation of NANOG, OCT3/4, and SOX2. YAP, a co-transcriptional factor in the Hippo signaling pathway that regulates pluripotency gene expression, co-localized with GJA1 (also known as Cx43) in the cell membrane and was translocated to the nucleus after GJ inhibition. Adherent culture is usually more suitable for the stable expansion of cells than is a suspension culture. GJ inhibition is suggested to be a simple method to up-regulate pluripotency in an adherent culture that involves a Cx43-YAP axis in pluripotent stem cells, such as Muse cells.
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Affiliation(s)
- Khaled Hatabi
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
| | - Yukari Hirohara
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
- Regenerative Medicine Division, Life Science Institute, Inc., Tokyo 135-0004, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
| | - Yasumasa Kuroda
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
| | - James Trosko
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai 980–8575, Japan
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Li H, Wei J, Liu X, Zhang P, Lin J. Muse cells: ushering in a new era of stem cell-based therapy for stroke. Stem Cell Res Ther 2022; 13:421. [PMID: 35986359 PMCID: PMC9389783 DOI: 10.1186/s13287-022-03126-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/07/2022] [Indexed: 11/10/2022] Open
Abstract
AbstractStem cell-based regenerative therapies have recently become promising and advanced for treating stroke. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) have received the most attention for treating stroke because of the outstanding paracrine function of MSCs and the three-germ-layer differentiation ability of iPSCs. However, the unsatisfactory homing ability, differentiation, integration, and survival time in vivo limit the effectiveness of MSCs in regenerative medicine. The inherent tumorigenic property of iPSCs renders complete differentiation necessary before transplantation, which is complicated and expensive and affects the consistency among cell batches. Multilineage differentiating stress-enduring (Muse) cells are natural pluripotent stem cells in the connective tissues of nearly every organ and thus are considered nontumorigenic. A single Muse cell can differentiate into all three-germ-layer, preferentially migrate to damaged sites after transplantation, survive in hostile environments, and spontaneously differentiate into tissue-compatible cells, all of which can compensate for the shortcomings of MSCs and iPSCs. This review summarizes the recent progress in understanding the biological properties of Muse cells and highlights the differences between Muse cells and other types of stem cells. Finally, we summarized the current research progress on the application of Muse cells on stroke and challenges from bench to bedside.
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Cao J, Shen Y, Yang Z, Pan B, Liu Z. Unique hypoxia-tolerant subpopulations of adipose-derived stem cells: ITGB3 + cells. J Plast Reconstr Aesthet Surg 2022; 75:3586-3594. [PMID: 35643597 DOI: 10.1016/j.bjps.2022.04.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/26/2022] [Accepted: 04/12/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND We found by accident that stem cells could still be isolated from adipose tissue stored for 14 days in sealed tubes, which was distinct from previous protocols. The morphology of these hypoxia-tolerant stem cells also differs from that of conventional adipose-derived stem cells (ADSCs). In this study, we aim to define the newly found subsets. MATERIALS AND METHODS Stem cells were isolated from adipose tissue that was aspirated immediately or stored for 14 days. The stem cells were then harvested for flowcytometric analysis and differentiation potentials. The expression of hypoxia-inducible factor 1 alpha (HIF-1α) was assayed to confirm the hypoxia-tolerant ability. RNA sequencing (RNA-seq) was performed to find the common signatures of the hypoxia-tolerant cells. The result of bioinformatics was tested by quantitative real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. RESULTS Certain subsets of ADSCs can be isolated from adipose tissue stored for 14 days. These survived cells were positive for CD90, CD105, and CD73 and showed multilineage differentiation potentials. The hypoxic condition was evidenced by up-regulation of HIF-1α for 2.0-fold changes (p < 0.05). The hypoxia-tolerant stem cells were distinct from multilineage-differentiating stress-enduring (Muse) cells, previously found stress-enduring stromal cells. RNA-seq suggested that integrin beta 3 (ITGB3) was highly expressed in hypoxia-tolerant subpopulations. The result was further confirmed at transcription and translation levels by qPCR and western blotting (mRNA: 2.9 ± 0.4, p < 0.05; protein: 1.5 ± 0.2, p < 0.05; respectively). The conventional ADSCs are positive for ITGB3, which implies that ITGB3+ cells are subpopulations of heterogeneous ADSCs. CONCLUSIONS Our study reveals the ITGB3+ subsets with potent hypoxia tolerance, which has significant implications for improving fat retention rates and curing obesity-related diseases.
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Affiliation(s)
- Jiankun Cao
- Department of Burns and Plastic Surgery, Beijing Jishuitan Hospital, Forth Medical College of Peking University, Beijing, China; Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuming Shen
- Department of Burns and Plastic Surgery, Beijing Jishuitan Hospital, Forth Medical College of Peking University, Beijing, China
| | - Zhigang Yang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Pan
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Zhenzhong Liu
- Department of Burns and Plastic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
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Kaminska A, Radoszkiewicz K, Rybkowska P, Wedzinska A, Sarnowska A. Interaction of Neural Stem Cells (NSCs) and Mesenchymal Stem Cells (MSCs) as a Promising Approach in Brain Study and Nerve Regeneration. Cells 2022; 11:cells11091464. [PMID: 35563770 PMCID: PMC9105617 DOI: 10.3390/cells11091464] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 11/16/2022] Open
Abstract
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous system still remain a challenge for the regenerative medicine. Neural stem cells (NSCs) are the optimal cells for the central nervous system restoration as they can differentiate into mature cells and, most importantly, functional neurons and glial cells. However, their application is limited by multiple factors such as difficult access to source material, limited cells number, problematic, long and expensive cultivation in vitro, and ethical considerations. On the other hand, according to the available clinical databases, most of the registered clinical trials involving cell therapies were carried out with the use of mesenchymal stem/stromal/signalling cells (MSCs) obtained from afterbirth or adult human somatic tissues. MSCs are the multipotent cells which can also differentiate into neuron-like and glia-like cells under proper conditions in vitro; however, their main therapeutic effect is more associated with secretory and supportive properties. MSCs, as a natural component of cell niche, affect the environment through immunomodulation as well as through the secretion of the trophic factors. In this review, we discuss various therapeutic strategies and activated mechanisms related to bilateral MSC–NSC interactions, differentiation of MSCs towards the neural cells (subpopulation of crest-derived cells) under the environmental conditions, bioscaffolds, or co-culture with NSCs by recreating the conditions of the neural cell niche.
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Fukase M, Sakata N, Kushida Y, Wakao S, Unno M, Dezawa M. Intravenous injection of human multilineage-differentiating stress-enduring cells alleviates mouse severe acute pancreatitis without immunosuppressants. Surg Today 2022; 52:603-615. [PMID: 34687364 DOI: 10.1007/s00595-021-02382-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/16/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION We examined the effect of intravenously injected human multilineage-differentiating stress-enduring (Muse) cells, non-tumorigenic endogenous reparative stem cells already used in clinical trials, on a severe acute pancreatitis (SAP) mouse model without immunosuppressants. METHODS Human Muse cells (1.0 × 105 cells) collected from mesenchymal stem cells (MSCs) as SSEA-3(+) were injected into a C57BL/6 mouse model via the jugular vein 6 h after SAP-induction with taurocholate. The control group received saline or the same number of SSEA-3(-)-non-Muse MSCs. RESULTS Edematous parameters, F4/80(+) macrophage infiltration and terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity was the lowest and the number of proliferating endogenous pancreatic progenitors (CK18(+)/Ki67(+) cells) the highest in the Muse group among the three groups, with statistical significance, at 72 h. An enzyme-linked immunosorbent assay and quantitative polymerase chain reaction demonstrated that in vitro production of VEGF, HGF, IGF-1, and MMP-2, which are relevant to tissue protection, anti-inflammation, and anti-fibrosis, were higher in Muse cells than in non-Muse MSCs, particularly when cells were cultured in SAP mouse serum. Consistently, the pancreas of animals in the Muse group contained higher amounts of those factors according to Western blotting at 18 h than that in the non-Muse MSCs and control groups. CONCLUSIONS Intravenous injection of human Muse cells was suggested to be effective for attenuating edema, inflammation and apoptosis in the acute phase of SAP.
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Affiliation(s)
- Masahiko Fukase
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
| | - Naoaki Sakata
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
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Yamada Y, Minatoguchi S, Baba S, Shibata S, Takashima S, Wakao S, Okura H, Dezawa M, Minatoguchi S. Human Muse cells reduce myocardial infarct size and improve cardiac function without causing arrythmias in a swine model of acute myocardial infarction. PLoS One 2022; 17:e0265347. [PMID: 35324926 PMCID: PMC8947423 DOI: 10.1371/journal.pone.0265347] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/28/2022] [Indexed: 11/26/2022] Open
Abstract
Background We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product. Method and result Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed. Conclusion Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI.
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Affiliation(s)
- Yoshihisa Yamada
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shingo Minatoguchi
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | | | - Sanae Shibata
- Animal Teaching Hospital (Anesthesiology) Faculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Satoshi Takashima
- Animal Teaching Hospital (Anesthesiology) Faculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hiroyuki Okura
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shinya Minatoguchi
- Gifu Municipal Hospital, Gifu, Japan
- Department of Circulatory and Respiratory Advanced Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- * E-mail:
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Wu SH, Yu JH, Liao YT, Liu KH, Chiang ER, Chang MC, Wang JP. Comparison of the Infant and Adult Adipose-Derived Mesenchymal Stem Cells in Proliferation, Senescence, Anti-oxidative Ability and Differentiation Potential. Tissue Eng Regen Med 2022; 19:589-601. [PMID: 35247199 PMCID: PMC9130449 DOI: 10.1007/s13770-022-00431-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/26/2021] [Accepted: 01/05/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Infant adipose-derived mesenchymal stem cells (ADSCs) collected from excised polydactyly fat tissue, which was surgical waste, could be cultured and expanded in vitro in this study. In addition, the collecting process would not cause pain in the host. In this study, the proliferation, reduction of senescence, anti-oxidative ability, and differentiation potential in the infant ADSCs were compared with those in the adult ADSCs harvested from thigh liposuction to determine the availability of infant ADSCs. METHODS Proliferation was determined by detecting the fold changes in cell numbers and doubling time periods. Senescence was analyzed by investigating the age-related gene expression levels and the replicative stress. The superoxide dismutase (SOD) gene expression, adipogenic, neurogenic, osteogenic, and tenogenic differentiation were compared by RT-qPCR. The chondrogenic differentiation efficiency was also determined using RT-qPCR and immunohistochemical staining. RESULTS The proliferation, SOD (SOD1, SOD2 and SOD3) gene expression, the stemness-related gene (c-MYC) and telomerase reverse transcriptase of the infant ADSCs at early passages were enhanced compared with those of the adults'. Cellular senescence related genes, including p16, p21 and p53, and replicative stress were reduced in the infant ADSCs. The adipogenic genes (PPARγ and LPL) and neurogenic genes (MAP2 and NEFH) of the infant ADSC differentiated cells were significantly higher than those of the adults' while the expression of the osteogenic genes (OCN and RUNX) and tenogenic genes (TNC and COL3A1) of both demonstrated opposite results. The chondrogenic markers (SOX9, COL2 and COL10) were enhanced in the infant ADSC differentiated chondrogenic pellets, and the expression levels of SODs were decreased during the differentiation process. CONCLUSION Cultured infant ADSCs demonstrate less cellular senescence and replicative stress, higher proliferation rates, better antioxidant defense activity, and higher potential of chondrogenic, adipogenic and neurogenic differentiation.
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Affiliation(s)
- Szu-Hsien Wu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 112 Taiwan ,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Jin-Huei Yu
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, 33004 Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Kuo-Hao Liu
- Department of Orthopaedics, National Yang Ming Chiao Tung University Hospital, Yilan, 260 Taiwan
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Ming-Chau Chang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
| | - Jung-pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112 Taiwan ,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, 112 Taiwan
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Wang R, Wang X, Yang S, Xiao Y, Jia Y, Zhong J, Gao Q, Zhang X. Umbilical cord-derived mesenchymal stem cells promote myeloid-derived suppressor cell enrichment by secreting CXCL1 to prevent graft-versus-host disease after hematopoietic stem cell transplantation. Cytotherapy 2021; 23:996-1006. [PMID: 34465514 DOI: 10.1016/j.jcyt.2021.07.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND AIMS Human mesenchymal stem cells (MSCs) from various tissues have emerged as attractive candidates for the prevention and treatment of graft-versus-host disease (GVHD). However, the molecular machinery that defines and channels the behavior of these cells remains poorly understood. METHODS In this study, the authors compared the efficacy of four tissue-derived MSC types in controlling GVHD in a murine model and investigated their immunomodulatory effects. RESULTS Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) effectively decreased the incidence and severity of GVHD, which was mediated by the enrichment of myeloid-derived suppressor cells in GVHD target tissues. RNA sequencing results showed that hUCMSCs highly expressed CXCL1. CONCLUSIONS These results suggest a novel prophylactic application of hUCMSCs for controlling GVHD after allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
- Rui Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yunshuo Xiao
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yanhui Jia
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiangfan Zhong
- Department of Cell Biology, College of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qiangguo Gao
- Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China.
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Rohani Ivari J, Mahdipour E. Adipose tissue versus stem cell-derived small extracellular vesicles to enhance the healing of acute burns. Regen Med 2021; 16:629-641. [PMID: 34259030 DOI: 10.2217/rme-2020-0199] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Aim: Proper healing of extensive burns remains a healthcare challenge. In the present study, we proposed a distinct therapeutic application of adipose tissue and small extracellular vesicles isolated from human menstrual blood-derived mesenchymal stem cells (MenSC) small extracellular vesicles (sEVs) to enhance the repair of third-degree burn injury. Materials & methods: Mouse model of third-degree burn was used. Adipose tissue in the form of nano-fat (NF) and MenSC-sEVs was injected subcutaneously at the site of injuries. Results: NF and sEVs were capable of enhancing wound closure and increasing neoangiogenesis. NF was also effective in accelerating the formation of granulation tissue and boosting the thickness of the new epithelial layer. Conclusion: This study demonstrates the effectiveness of NF and MenSC-sEVs as promising therapeutic approaches to facilitate the repair of skin burns.
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Affiliation(s)
- Jalil Rohani Ivari
- Department of Medical Biotechnology & Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 1696700, Iran
| | - Elahe Mahdipour
- Department of Medical Biotechnology & Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 1696700, Iran
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Suzuki T, Sato Y, Kushida Y, Tsuji M, Wakao S, Ueda K, Imai K, Iitani Y, Shimizu S, Hida H, Temma T, Saito S, Iida H, Mizuno M, Takahashi Y, Dezawa M, Borlongan CV, Hayakawa M. Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy. J Cereb Blood Flow Metab 2021; 41:1707-1720. [PMID: 33222596 PMCID: PMC8217885 DOI: 10.1177/0271678x20972656] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 104 of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and -, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.
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Affiliation(s)
- Toshihiko Suzuki
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan.,Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiaki Sato
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masahiro Tsuji
- Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuto Ueda
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan.,Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Imai
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukako Iitani
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinobu Shimizu
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hideki Hida
- Department of Neurophysiology and Brain Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Temma
- Department of Bio-Medical Imaging, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Shigeyoshi Saito
- Department of Bio-Medical Imaging, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Hidehiro Iida
- Department of Bio-Medical Imaging, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Masaaki Mizuno
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Cesar V Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Masahiro Hayakawa
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
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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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Ong WK, Chakraborty S, Sugii S. Adipose Tissue: Understanding the Heterogeneity of Stem Cells for Regenerative Medicine. Biomolecules 2021; 11:biom11070918. [PMID: 34206204 PMCID: PMC8301750 DOI: 10.3390/biom11070918] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived stem cells (ASCs) have been increasingly used as a versatile source of mesenchymal stem cells (MSCs) for diverse clinical investigations. However, their applications often become complicated due to heterogeneity arising from various factors. Cellular heterogeneity can occur due to: (i) nomenclature and criteria for definition; (ii) adipose tissue depots (e.g., subcutaneous fat, visceral fat) from which ASCs are isolated; (iii) donor and inter-subject variation (age, body mass index, gender, and disease state); (iv) species difference; and (v) study design (in vivo versus in vitro) and tools used (e.g., antibody isolation and culture conditions). There are also actual differences in resident cell types that exhibit ASC/MSC characteristics. Multilineage-differentiating stress-enduring (Muse) cells and dedifferentiated fat (DFAT) cells have been reported as an alternative or derivative source of ASCs for application in regenerative medicine. In this review, we discuss these factors that contribute to the heterogeneity of human ASCs in detail, and what should be taken into consideration for overcoming challenges associated with such heterogeneity in the clinical use of ASCs. Attempts to understand, define, and standardize cellular heterogeneity are important in supporting therapeutic strategies and regulatory considerations for the use of ASCs.
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Affiliation(s)
- Wee Kiat Ong
- School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
- Correspondence: (W.K.O.); (S.S.)
| | - Smarajit Chakraborty
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
| | - Shigeki Sugii
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
- Correspondence: (W.K.O.); (S.S.)
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Yamashita T, Kushida Y, Abe K, Dezawa M. Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases. Cells 2021; 10:cells10040961. [PMID: 33924240 PMCID: PMC8074773 DOI: 10.3390/cells10040961] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023] Open
Abstract
Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
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Affiliation(s)
- Toru Yamashita
- Department of Neurology, School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (T.Y.); (K.A.)
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, School of Medicine, Tohoku University, Sendai 980-8575, Japan;
| | - Koji Abe
- Department of Neurology, School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (T.Y.); (K.A.)
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, School of Medicine, Tohoku University, Sendai 980-8575, Japan;
- Correspondence: ; Tel.: +81-22-717-8025; Fax: +81-22-717-8030
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Iseki M, Mizuma M, Wakao S, Kushida Y, Kudo K, Fukase M, Ishida M, Ono T, Shimura M, Ise I, Suzuki Y, Sueta T, Asada R, Shimizu S, Ueno Y, Dezawa M, Unno M. The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model. Surg Today 2021; 51:634-650. [PMID: 32915286 DOI: 10.1007/s00595-020-02117-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 08/10/2020] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic endogenous pluripotent-like cells residing in the bone marrow that exert a tissue reparative effect by replacing damaged/apoptotic cells through spontaneous differentiation into tissue-constituent cells. Post-hepatectomy liver failure (PHLF) is a potentially fatal complication. The main purpose of this study was to evaluate the safety and efficiency of allogeneic Muse cell administration via the portal vein in a swine model of PHLF. METHODS Swine Muse cells, collected from swine bone marrow-mesenchymal stem cells (MSCs) as SSEA-3(+) cells, were examined for their characteristics. Then, 1 × 107 allogeneic-Muse cells and allogeneic-MSCs and vehicle were injected via the portal vein in a 70% hepatectomy swine model. RESULTS Swine Muse cells exhibited characteristics comparable to previously reported human Muse cells. Compared to the MSC and vehicle groups, the Muse group showed specific homing of the administered cells into the liver, resulting in improvements in the control of hyperbilirubinemia (P = 0.04), prothrombin international normalized ratio (P = 0.05), and suppression of focal necrosis (P = 0.04). Integrated Muse cells differentiated spontaneously into hepatocyte marker-positive cells. CONCLUSIONS Allogeneic Muse cell administration may provide a reparative effect and functional recovery in a 70% hepatectomy swine model and thus may contribute to the treatment of PHLF.
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Affiliation(s)
- Masahiro Iseki
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Sendai, Japan
| | | | - Katsuyoshi Kudo
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Masahiko Fukase
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Masaharu Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Tomoyuki Ono
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Mitsuhiro Shimura
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Ichiro Ise
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Yukie Suzuki
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
| | - Teruko Sueta
- Comprehensive Education Center for Community Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryuta Asada
- Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan
| | - Shinobu Shimizu
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan
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Aprile D, Alessio N, Demirsoy IH, Squillaro T, Peluso G, Di Bernardo G, Galderisi U. MUSE Stem Cells Can Be Isolated from Stromal Compartment of Mouse Bone Marrow, Adipose Tissue, and Ear Connective Tissue: A Comparative Study of Their In Vitro Properties. Cells 2021; 10:761. [PMID: 33808472 PMCID: PMC8065981 DOI: 10.3390/cells10040761] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 01/10/2023] Open
Abstract
The cells present in the stromal compartment of many tissues are a heterogeneous population containing stem cells, progenitor cells, fibroblasts, and other stromal cells. A SSEA3(+) cell subpopulation isolated from human stromal compartments showed stem cell properties. These cells, known as multilineage-differentiating stress-enduring (MUSE) cells, are capable of resisting stress and possess an excellent ability to repair DNA damage. We isolated MUSE cells from different mouse stromal compartments, such as those present in bone marrow, subcutaneous white adipose tissue, and ear connective tissue. These cells showed overlapping in vitro biological properties. The mouse MUSE cells were positive for stemness markers such as SOX2, OCT3/4, and NANOG. They also expressed TERT, the catalytic telomerase subunit. The mouse MUSE cells showed spontaneous commitment to differentiation in meso/ecto/endodermal derivatives. The demonstration that multilineage stem cells can be isolated from an animal model, such as the mouse, could offer a valid alternative to the use of other stem cells for disease studies and envisage of cellular therapies.
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Affiliation(s)
- Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Nicola Alessio
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Ibrahim H. Demirsoy
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Tiziana Squillaro
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | | | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
- Genome and Stem Cell Center (GENKOK), Erciyes University, 38280 Kayseri, Turkey
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Mitani K, Ito Y, Takene Y, Hatoya S, Sugiura K, Inaba T. Long-Term Trypsin Treatment Promotes Stem Cell Potency of Canine Adipose-Derived Mesenchymal Stem Cells. Stem Cells Dev 2021; 30:337-349. [PMID: 33528297 DOI: 10.1089/scd.2020.0175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) isolated from adipose tissue (adipose-derived stem cells [ADSCs]) are considered one of the most promising cell types for applications in regenerative medicine. However, the regenerative potency of ADSCs may vary because of heterogeneity. Long-term trypsin treatment (LTT) is known to significantly concentrate multilineage-differentiating stress-enduring (Muse) cells from human MSCs. In this study, we aimed to generate cells with high stem cell potency from canine ADSCs using LTT. After 16 h of treatment with trypsin, surviving ADSCs (LTT-tolerant cells) had significantly enhanced expression of stage-specific embryonic antigen (SSEA)-1, a mouse embryonic stem cell marker, and fucosyltransferase 9, one of several fucosyltransferases for SSEA-1 biosynthesis. However, LTT-tolerant cells did not enhance the expression of SSEA-3, a known human Muse cell marker. LTT-tolerant cells, however, showed significantly higher self-renewal capacity in the colony-forming unit fibroblast assay than ADSCs. In addition, the LTT-tolerant cells formed cell clusters similar to embryoid bodies and expressed undifferentiated markers. Moreover, these cells differentiated into cells of all three germ layers and showed significantly higher levels of α 2-6 sialic acid (Sia)-specific lectins, known as differentiation potential markers of human MSCs, than ADSCs. LTT-tolerant cells had a normal karyotype and had low telomerase activity, showing little carcinogenetic potency. LTT-tolerant cells also showed significantly increased activity of transmigration in the presence of chemoattractants and had increased expression of migration-related genes compared with ADSCs. In addition, LTT-tolerant cells had stronger suppressive activity against mitogen-stimulated lymphocyte proliferation than ADSCs. Overall, these results indicated that the LTT-tolerant cells in canine ADSCs have similar properties as human Muse cells (although one of the undifferentiated markers is different) and are expected to be a promising tool for regenerative therapy in dogs.
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Affiliation(s)
- Kosuke Mitani
- Research and Development Department, J-ARM Co., Ltd., Osaka, Japan.,Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Yuki Ito
- Research and Development Department, J-ARM Co., Ltd., Osaka, Japan
| | - Yukio Takene
- Research and Development Department, J-ARM Co., Ltd., Osaka, Japan
| | - Shingo Hatoya
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Kikuya Sugiura
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Toshio Inaba
- Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
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Therapeutic Potential of Mesenchymal Stromal Cells and Extracellular Vesicles in the Treatment of Radiation Lesions-A Review. Cells 2021; 10:cells10020427. [PMID: 33670501 PMCID: PMC7922519 DOI: 10.3390/cells10020427] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/08/2021] [Accepted: 02/13/2021] [Indexed: 12/14/2022] Open
Abstract
Ionising radiation-induced normal tissue damage is a major concern in clinic and public health. It is the most limiting factor in radiotherapy treatment of malignant diseases. It can also cause a serious harm to populations exposed to accidental radiation exposure or nuclear warfare. With regard to the clinical use of radiation, there has been a number of modalities used in the field of radiotherapy. These includes physical modalities such modified collimators or fractionation schedules in radiotherapy. In addition, there are a number of pharmacological agents such as essential fatty acids, vasoactive drugs, enzyme inhibitors, antioxidants, and growth factors for the prevention or treatment of radiation lesions in general. However, at present, there is no standard procedure for the treatment of radiation-induced normal tissue lesions. Stem cells and their role in tissue regeneration have been known to biologists, in particular to radiobiologists, for many years. It was only recently that the potential of stem cells was studied in the treatment of radiation lesions. Stem cells, immediately after their successful isolation from a variety of animal and human tissues, demonstrated their likely application in the treatment of various diseases. This paper describes the types and origin of stem cells, their characteristics, current research, and reviews their potential in the treatment and regeneration of radiation induced normal tissue lesions. Adult stem cells, among those mesenchymal stem cells (MSCs), are the most extensively studied of stem cells. This review focuses on the effects of MSCs in the treatment of radiation lesions.
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Abstract
Stem cell-based regenerative therapies may rescue the central nervous system following ischemic stroke. Mesenchymal stem cells exhibit promising regenerative capacity in in vitro studies but display little to no incorporation in host tissue after transplantation in in vivo models of stroke. Despite these limitations, clinical trials using mesenchymal stem cells have produced some functional benefits ascribed to their ability to modulate the host's inflammatory response coupled with their robust safety profile. Regeneration of ischemic brain tissue using stem cells, however, remains elusive in humans. Multilineage-differentiating stress-enduring (Muse) cells are a distinct subset of mesenchymal stem cells found sporadically in connective tissue of nearly every organ. Since their discovery in 2010, these endogenous reparative stem cells have been investigated for their therapeutic potential against a variety of diseases, including acute myocardial infarction, stroke, chronic kidney disease, and liver disease. Preclinical studies have exemplified Muse cells' unique ability mobilize, differentiate, and engraft into damaged host tissue. Intravenously transplanted Muse cells in mouse lacunar stroke models afforded functional recovery and long-term engraftment into the host neural network. This mini-review article highlights these biological properties that make Muse cells an exceptional candidate donor source for cell therapy in ischemic stroke. Elucidating the mechanism behind the therapeutic potential of Muse cells will undoubtedly help optimize stem cell therapy for stroke and advance the field of regenerative medicine.
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Affiliation(s)
- You Jeong Park
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida (Y.J.P., M.M., C.V.B.)
| | - Kuniyasu Niizuma
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, Miyagi, Sendai, Japan (K.N.)
| | - Maxim Mokin
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida (Y.J.P., M.M., C.V.B.)
| | - Mari Dezawa
- Department of Histology, Tohoku University, Japan (M.D.)
| | - Cesar V Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida (Y.J.P., M.M., C.V.B.)
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Cao J, Yang Z, Xiao R, Pan B. Regenerative potential of pluripotent nontumorgenetic stem cells: Multilineage differentiating stress enduring cells (Muse cells). Regen Ther 2020; 15:92-96. [PMID: 33426206 PMCID: PMC7770368 DOI: 10.1016/j.reth.2020.04.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/17/2020] [Accepted: 04/25/2020] [Indexed: 12/15/2022] Open
Abstract
Multilineage differentiating stress enduring cells (Muse cells), double positive for SSEA-3 and CD105, can be isolated by fluorescence-activated cell sorting (FACS) or sever cellular conditions from dermal fibroblasts, bone marrow stem cells (BMSCs), adipose tissue derived stem cells (ADSCs), fresh bone marrow and liposuction fat. When cultured in a single-cell suspension, Muse cells can grow into characteristic cell clusters. Muse cells maintain pluripotency as evidenced by pluripotent markers in vitro. Besides, Muse cells have no tumorigenesis up to 6 months in SCID mice. Muse cells differentiate into cells representative of all three germ layers both spontaneously and under specific induction. In comparison to mesenchymal stem cells (MSCs), Muse cells show higher homing and migration capabilities to damaged sites which is predominantly attributed to S1P–S1PR2 axis. The regenerative effects of Muse cells have been demonstrated by many models in vivo or in vitro, including stroke, intracerebral hemorrhage, myocardial infarction, aortic aneurysm, lung injuries, liver fibrosis, focal segmental glomerulosclerosis, osteochondral defects and skin ulcer. In general, migration, differentiation and paracrine play a pivotal role in the regeneration capability. Here we review the isolation, core properties, preclinical studies as well as the underling molecular and cellular details to highlight their regenerative potential.
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Affiliation(s)
- Jiankun Cao
- Plastic Surgery Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhigang Yang
- Plastic Surgery Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ran Xiao
- Plastic Surgery Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Pan
- th Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Rossi M, Roda B, Zia S, Vigliotta I, Zannini C, Alviano F, Bonsi L, Zattoni A, Reschiglian P, Gennai A. Characterization of the Tissue and Stromal Cell Components of Micro-Superficial Enhanced Fluid Fat Injection (Micro-SEFFI) for Facial Aging Treatment. Aesthet Surg J 2020; 40:679-690. [PMID: 29905790 DOI: 10.1093/asj/sjy142] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND New microfat preparations provide material suitable for use as a regenerative filler for different facial areas. To support the development of new robust techniques for regenerative purposes, the cellular content of the sample should be considered. OBJECTIVES To evaluate the stromal vascular fraction (SVF) cell components of micro-superficial enhanced fluid fat injection (SEFFI) samples via a technique to harvest re-injectable tissue with minimum manipulation. The results were compared to those obtained from SEFFI samples. METHODS Microscopy analysis was performed to visualize the tissue structure. Micro-SEFFI samples were also fractionated using Celector,® an innovative non-invasive separation technique, to provide an initial evaluation of sample fluidity and composition. SVFs obtained from SEFFI and micro-SEFFI were studied. Adipose stromal cells (ASCs) were isolated and characterized by proliferation and differentiation capacity assays. RESULTS Microscopic and quality analyses of micro-SEFFI samples by Celector® confirmed the high fluidity and sample cellular composition in terms of red blood cell contamination, the presence of cell aggregates, and extracellular matrix fragments. ASCs were isolated from adipose tissue harvested using SEFFI and micro-SEFFI systems. These cells were demonstrated to have a good proliferation rate and differentiation potential towards mesenchymal lineages. CONCLUSIONS Despite the small sizes and low cellularity observed in micro-SEFFI-derived tissue, we were able to isolate stem cells. This result partially explains the regenerative potential of autologous micro-SEFFI tissue grafts. In addition, using this novel Celector® technology, tissues used for aging treatment were characterized analytically, and the adipose tissue composition was evaluated with no need for extra sample processing. LEVEL OF EVIDENCE: 5
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Affiliation(s)
- Martina Rossi
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Barbara Roda
- Department of Chemistry, University of Bologna, Bologna, Italy
| | | | | | - Chiara Zannini
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Francesco Alviano
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Laura Bonsi
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Andrea Zattoni
- Department of Chemistry, University of Bologna, Bologna, Italy
| | | | - Alessandro Gennai
- Center for Clinical Research, Telemedicine and Telepharmacy, University of Camerino, Camerino, Italy
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Balistreri CR, De Falco E, Bordin A, Maslova O, Koliada A, Vaiserman A. Stem cell therapy: old challenges and new solutions. Mol Biol Rep 2020; 47:3117-3131. [PMID: 32128709 DOI: 10.1007/s11033-020-05353-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 02/26/2020] [Indexed: 12/11/2022]
Abstract
Stem cell therapy (SCT), born as therapeutic revolution to replace pharmacological treatments, remains a hope and not yet an effective solution. Accordingly, stem cells cannot be conceivable as a "canonical" drug, because of their unique biological properties. A new reorientation in this field is emerging, based on a better understanding of stem cell biology and use of cutting-edge technologies and innovative disciplines. This will permit to solve the gaps, failures, and long-term needs, such as the retention, survival and integration of stem cells, by employing pharmacology, genetic manipulation, biological or material incorporation. Consequently, the clinical applicability of SCT for chronic human diseases will be extended, as well as its effectiveness and success, leading to long-awaited medical revolution. Here, some of these aspects are summarized, reviewing and discussing recent advances in this rapidly developing research field.
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Affiliation(s)
- Carmela Rita Balistreri
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy.
| | - Elena De Falco
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Antonella Bordin
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Olga Maslova
- National University of Life and Environmental Sciences of Ukraine, Kyiv, Ukraine
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Abstract
Autologous fat grafting has become a popular and well-established technique used by plastic surgeons in a variety of aesthetic and reconstructive procedures. An understanding of the basic science principles underlying fat grafting is crucial to explaining its extensive utility for soft tissue rejuvenation, volume augmentation, and body contouring-and the unpredictable fat resorption rates after grafting that pose a significant challenge for plastic surgeons. While the scientific principles of fat grafting can theoretically be exploited to optimize fat grafting techniques and increase fat tissue survival, a consensus has yet been established as to the best practices for this procedure. This review discusses the biology of adipose tissue and the scientific principles behind its behavior and survival in autologous fat grafting.
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Affiliation(s)
- Linden Shih
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Matthew J Davis
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Sebastian J Winocour
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
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Baptista LS. Adipose stromal/stem cells in regenerative medicine: Potentials and limitations. World J Stem Cells 2020; 12:1-7. [PMID: 32110271 PMCID: PMC7031762 DOI: 10.4252/wjsc.v12.i1.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 10/11/2019] [Accepted: 11/14/2019] [Indexed: 02/07/2023] Open
Abstract
This article presents the stem and progenitor cells from subcutaneous adipose tissue, briefly comparing them with their bone marrow counterparts, and discussing their potential for use in regenerative medicine. Subcutaneous adipose tissue differs from other mesenchymal stromal/stem cells (MSCs) sources in that it contains a pre-adipocyte population that dwells in the adventitia of robust blood vessels. Pre-adipocytes are present both in the stromal-vascular fraction (SVF; freshly isolated cells) and in the adherent fraction of adipose stromal/stem cells (ASCs; in vitro expanded cells), and have an active role on the chronic inflammation environment established in obesity, likely due their monocytic-macrophage lineage identity. The SVF and ASCs have been explored in cell therapy protocols with relative success, given their paracrine and immunomodulatory effects. Importantly, the widely explored multipotentiality of ASCs has direct application in bone, cartilage and adipose tissue engineering. The aim of this editorial is to reinforce the peculiarities of the stem and progenitor cells from subcutaneous adipose tissue, revealing the spheroids as a recently described biotechnological tool for cell therapy and tissue engineering. Innovative cell culture techniques, in particular 3D scaffold-free cultures such as spheroids, are now available to increase the potential for regeneration and differentiation of mesenchymal lineages. Spheroids are being explored not only as a model for cell differentiation, but also as powerful 3D cell culture tools to maintain the stemness and expand the regenerative and differentiation capacities of mesenchymal cell lineages.
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Affiliation(s)
- Leandra Santos Baptista
- Multidisciplinary Center for Biological Research (Numpex-Bio), Federal University of Rio de Janeiro (UFRJ) Campus Duque de Caxias, Duque de Caxias, RJ 25245-390, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Translational Biomedicine (Biotrans), Unigranrio, Campus I, Duque de Caxias, Duque de Caxias, RJ 25250-020, Brazil
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
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The Role of Adipose-Derived Stem Cells, Dermal Regenerative Templates, and Platelet-Rich Plasma in Tissue Engineering-Based Treatments of Chronic Skin Wounds. Stem Cells Int 2020; 2020:7056261. [PMID: 32399048 PMCID: PMC7199611 DOI: 10.1155/2020/7056261] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 11/29/2019] [Indexed: 12/12/2022] Open
Abstract
The continuous improvements in the field of both regenerative medicine and tissue engineering have allowed the design of new and more efficacious strategies for the treatment of chronic or hard-to-heal skin wounds, which represent heavy burden, from a medical and economic point of view. These novel approaches are based on the usage of three key methodologies: stem cells, growth factors, and biomimetic scaffolds. These days, the adipose tissue can be considered the main source of multipotent mesenchymal stem cells, especially adipose-derived stem cells (ASCs). ASCs are easily accessible from various fat depots and show an intrinsic plasticity in giving rise to cell types involved in wound healing and angiogenesis. ASCs can be found in fat grafts, historically used in the treatment of chronic wounds, and have been evaluated as such in both animal models and human trials, to exploit their capability of accelerating wound closure and inducing a correct remodeling of the newly formed fibrovascular tissue. Since survival and fitness of ASCs need to be improved, they are now employed in conjunction with advanced wound dressings, together with dermal regenerative templates and platelet-rich plasma (as a source of growth and healing factors). In this work, we provide an overview of the current knowledge on the topic, based on existing studies and on our own experience.
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Li X, Wu A, Han C, Chen C, Zhou T, Zhang K, Yang X, Chen Z, Qin A, Tian H, Zhao J. Bone marrow-derived mesenchymal stem cells in three-dimensional co-culture attenuate degeneration of nucleus pulposus cells. Aging (Albany NY) 2019; 11:9167-9187. [PMID: 31666429 PMCID: PMC6834418 DOI: 10.18632/aging.102390] [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] [Received: 04/14/2019] [Accepted: 10/21/2019] [Indexed: 12/11/2022]
Abstract
Intervertebral disc degeneration (IDD) is an irreversible aging-associated clinical condition of unclear etiology. Mesenchymal stem cells (MSCs) have the potential to delay IDD, but the mechanisms by which MSCs attenuate senescence-related degeneration of nucleus pulposus cells (NPCs) remain uncertain. The present study employed a three-dimensional (3D) co-culture system to explore the influence of MSCs on NPC degeneration induced by TNF-α in rat cells. We found that co-culture with bone marrow-derived MSCs (BMSCs) reduced senescence-associated β-galactosidase expression, increased cell proliferation, decreased matrix metalloproteinase 9, increased Coll-IIa production, and reduced TGFβ/NF-κB signaling in senescent NPCs. In addition, expression of zinc metallopeptidase STE24 (ZMPSTE24), whose dysfunction is related to premature cell senescence and aging, was decreased in senescent NPCs but restored upon BMSC co-culture. Accordingly, ZMPSTE24 overexpression in NPCs inhibited the pro-senescence effects of TGFβ/NF-κB activation upon TNF-α stimulation, while both CRISPR/Cas9-mediated silencing and pharmacological ZMPSTE24 inhibition prevented those effects. Ex-vivo experiments on NP explants provided supporting evidence for the protective effect of MSCs against NPC senescence and IDD. Although further molecular studies are necessary, our results suggest that MSCs may attenuate or prevent NP fibrosis and restore the viability and functional status of NPCs through upregulation of ZMPSTE24.
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Affiliation(s)
- Xunlin Li
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Aimin Wu
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China.,Department of Spine Surgery, Zhejiang Spine Surgery Centre, Orthopaedic Hospital, The Second Affiliated Hospital and Yuying Children's Hospital of the Wenzhou Medical University, The Second School of Medicine Wenzhou Medical University, The Key Orthopaedic Laboratory of Zhejiang Province, Wenzhou, P. R. China
| | - Chen Han
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Chen Chen
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Tangjun Zhou
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Kai Zhang
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Xiao Yang
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Zhiqian Chen
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - An Qin
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Haijun Tian
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
| | - Jie Zhao
- Department of Orthopaedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, P. R. China
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O'Connor KC. Molecular Profiles of Cell-to-Cell Variation in the Regenerative Potential of Mesenchymal Stromal Cells. Stem Cells Int 2019; 2019:5924878. [PMID: 31636675 PMCID: PMC6766122 DOI: 10.1155/2019/5924878] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 08/20/2019] [Indexed: 12/22/2022] Open
Abstract
Cell-to-cell variation in the regenerative potential of mesenchymal stromal cells (MSCs) impedes the translation of MSC therapies into clinical practice. Cellular heterogeneity is ubiquitous across MSC cultures from different species and tissues. This review highlights advances to elucidate molecular profiles that identify cell subsets with specific regenerative properties in heterogeneous MSC cultures. Cell surface markers and global signatures are presented for proliferation and differentiation potential, as well as immunomodulation and trophic properties. Key knowledge gaps are discussed as potential areas of future research. Molecular profiles of MSC heterogeneity have the potential to enable unprecedented control over the regenerative potential of MSC therapies through the discovery of new molecular targets and as quality attributes to develop robust and reproducible biomanufacturing processes. These advances would have a positive impact on the nascent field of MSC therapeutics by accelerating the development of therapies with more consistent and effective treatment outcomes.
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Affiliation(s)
- Kim C. O'Connor
- Department of Chemical and Biomolecular Engineering, Tulane University, New Orleans, Louisiana, USA
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
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Musorina AS, Zenin VV, Turilova VI, Yakovleva TK, Poljanskaya GG. Characterization of a Nonimmortalized Mesenchymal Stem Cell Line Isolated from Human Epicardial Adipose Tissue. ACTA ACUST UNITED AC 2019. [DOI: 10.1134/s1990519x19040060] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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