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Goyal A, Afzal M, Goyal K, Ganesan S, Kumari M, Sunitha S, Dash A, Saini S, Rana M, Gupta G, Ali H, Wong LS, Kumarasamy V, Subramaniyan V. MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance. Regen Ther 2025; 29:303-318. [PMID: 40237010 PMCID: PMC11999318 DOI: 10.1016/j.reth.2025.03.006] [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: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Cancer remains a prominent worldwide health concern, presenting existing therapies with frequent difficulties, including major toxicity, limited effectiveness, and treatment resistance emergence. These issues highlight the necessity for novel and enhanced remedies. Exosomes, tiny extracellular vesicles that facilitate intercellular communication, have attracted interest for their potential medicinal applications. Carrying a variety of molecules, including microRNAs, small interfering RNAs, long non-coding RNAs, proteins, lipids, and DNA, these vesicles are positioned as promising cancer treatment options. Current studies have increasingly investigated the capacity of microRNAs as a strategic approach for combating malignancy. Mesenchymal stem cells (MSC) are recognized for their aptitude to augment blood vessel formation, safeguard against cellular death, and modulate immune responses. Consequently, researchers examine exosomes derived from MSCs as a safer, non-cellular choice over therapies employing MSCs, which risk undesirable differentiation. The focus is shifting towards employing miRNA-encapsulated exosomes sourced from MSCs to target and heal cancerous cells selectively. However, the exact functions of miRNAs within MSC-derived exosomes in the context of cancer are still not fully understood. Additional exploration is necessary to clarify the role of these miRNAs in malignancy progression and to pinpoint viable therapeutic targets. This review offers a comprehensive examination of exosomes derived from mesenchymal stem cells, focusing on the encapsulation of miRNAs, methods for enhancing cellular uptake and stability, and their potential applications in cancer treatment. It also addresses the difficulties linked to this methodology and considers future avenues, including insights from current clinical oncology research.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - S. Sunitha
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aniruddh Dash
- Department of Orthopaedics IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751030, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
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Balaraman AK, Arockia Babu M, Afzal M, Sanghvi G, M M R, Gupta S, Rana M, Ali H, Goyal K, Subramaniyan V, Wong LS, Kumarasamy V. Exosome-based miRNA delivery: Transforming cancer treatment with mesenchymal stem cells. Regen Ther 2025; 28:558-572. [PMID: 40034540 PMCID: PMC11872554 DOI: 10.1016/j.reth.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/14/2025] [Accepted: 01/25/2025] [Indexed: 03/05/2025] Open
Abstract
Recently, increasing interest has been in utilizing mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially exosomes, as nanocarriers for miRNA delivery in cancer treatment. Due to such characteristics, nanocarriers are specific: biocompatible, low immunogenicity, and capable of spontaneous tumor accumulation. MSC-EVs were loaded with therapeutic miRNAs and minimized their susceptibility to degradation by protecting the miRNA from accessibility to degrading enzymes and providing targeted delivery of the miRNAs to the tumor cells to modulate oncogenic pathways. In vitro and in vivo experiments suggest that MSC-EVs loaded with miRNAs may inhibit tumor growth, prevent metastasis, and increase the effectiveness of chemotherapy and radiotherapy. However, these improvements present difficulties such as isolation, scalability, and stability of delivered miRNA during storage. Furthermore, the issues related to off-target effects, as well as immunogenicity, can be a focus. The mechanisms of miRNA loading into MSC-EVs, as well as their targeting efficiency and therapeutic potential, can be outlined in this manuscript. For the final part of the manuscript, the current advances in MSC-EV engineering and potential strategies for clinical application have been described. The findings of MSC-EVs imply that they present MSC-EVs as a second-generation tool for precise oncology.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya, Selangor, 63000, Malaysia
| | - M. Arockia Babu
- Institute of Pharmaceutical Research, GLA UNIVERSITY, Mathura, UP, 281406, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Sofia Gupta
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Vetriselvan Subramaniyan
- Division of Pharmacology, School of Medical and Life Sciences, Sunway University Jalan Universiti, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology, Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
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Aljagthmi AA, Abdel-Aziz AK. Hematopoietic stem cells: Understanding the mechanisms to unleash the therapeutic potential of hematopoietic stem cell transplantation. Stem Cell Res Ther 2025; 16:60. [PMID: 39924510 PMCID: PMC11809095 DOI: 10.1186/s13287-024-04126-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/21/2024] [Indexed: 02/11/2025] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a promising approach in regenerative medicine and serves as a standard treatment for different malignant and non-malignant conditions. Despite its widespread applications, HSCT is associated with various complications that compromise patients' lives and pose considerable risks of morbidity and mortality. Understanding the molecular physiology of HSCs is fundamental to ultimately enhance the mobilization, engraftment and differentiation of HSCs, thus unleashing the full therapeutic potential of HSCT in the treated patients. This review outlines the current understanding of HSC biology and its relevance to the clinical challenges associated with HSCT. Furthermore, we critically discuss the pros and cons of the preclinical murine models exploited in the HSCT field. Understanding the molecular physiology of HSCs will ultimately unleash the full therapeutic potential of HSCT. HSCs derived from induced pluripotent stem cells (iPSCs) might present an attractive tool which could be exploited preclinically and clinically. Nonetheless, further studies are warranted to systematically evaluate their potential in terms of improving the therapeutic outcome and minimizing the adverse effects of HSCT.
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Affiliation(s)
- Amjad Ahmed Aljagthmi
- Research center, King Faisal Specialist Hospital and Research Centre, Jeddah, 21499, Kingdom of Saudi Arabia.
| | - Amal Kamal Abdel-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt
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Samundeshwari EL, Kattaru S, Kodavala S, Chandrasekhar C, Sarma PVGK. Differentiation ability of hematopoietic stem cells and mesenchymal stem cells isolated from human peripheral blood. Front Cell Dev Biol 2024; 12:1450543. [PMID: 39744010 PMCID: PMC11688275 DOI: 10.3389/fcell.2024.1450543] [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: 06/17/2024] [Accepted: 10/21/2024] [Indexed: 01/04/2025] Open
Abstract
Human hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the major stem cells of the bone marrow and are usually isolated from the peripheral blood. In the present study, we isolated these stem cells by an apheresis method from a donor who was administered granulocyte colony-stimulating factor (G-CSF). In vitro propagation of these stem cells showed a plastic-adherence property expressing CD73 and CD105 surface markers, which is a characteristic feature of MSCs. HSCs are non-adherent cells growing as a suspension culture, expressing CD150, CD133, CD34, and CD45 on their surface, which regulate the quiescence nature, and they derive energy from anaerobic glycolysis. The HSCs grow slowly compared to MSCs, are more viable, and survive for long periods under in vitro conditions, which are due to the expression of telomerase, BCL2, and Notch1 genes. The poor viability of MSCs in the culture due to the prominent expression of apoptotic genes BAX, caspase-3, and caspase-9 leads to rapid apoptosis. This was evident even in cells (astrocytes, osteocytes, and beta cells of the islets of Langerhans) differentiated from HSCs and MSCs, thus highlighting the importance of HSCs, the naive stem cells, in regeneration of tissues.
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Affiliation(s)
| | - Surekha Kattaru
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Sireesha Kodavala
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Chodimella Chandrasekhar
- Department of Hematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
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Khattab S, El Sorady M, El-Ghandour A, Visani G, Piccaluga PP. Hematopoietic and leukemic stem cells homeostasis: the role of bone marrow niche. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:1027-1055. [PMID: 39351440 PMCID: PMC11438561 DOI: 10.37349/etat.2024.00262] [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: 03/23/2024] [Accepted: 07/01/2024] [Indexed: 10/04/2024] Open
Abstract
The bone marrow microenvironment (BMM) has highly specialized anatomical characteristics that provide a sanctuary place for hematopoietic stem cells (HSCs) that allow appropriate proliferation, maintenance, and self-renewal capacity. Several cell types contribute to the constitution and function of the bone marrow niche. Interestingly, uncovering the secrets of BMM and its interaction with HSCs in health paved the road for research aiming at better understanding the concept of leukemic stem cells (LSCs) and their altered niche. In fact, they share many signals that are responsible for interactions between LSCs and the bone marrow niche, due to several biological similarities between LSCs and HSCs. On the other hand, LSCs differ from HSCs in their abnormal activation of important signaling pathways that regulate survival, proliferation, drug resistance, invasion, and spread. Targeting these altered niches can help in better treatment choices for hematological malignancies and bone marrow disorders in general and acute myeloid leukemia (AML) in particular. Moreover, targeting those niches may help in decreasing the emergence of drug resistance and lower the relapse rate. In this article, the authors reviewed the most recent literature on bone marrow niches and their relations with either normal HSCs and AML cells/LSC, by focusing on pathogenetic and therapeutic implications.
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Affiliation(s)
- Shaimaa Khattab
- Biobank of Research, IRCCS Azienda Ospedaliera-Universitaria di Bologna Policlinico di S. Orsola, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, Bologna University School of Medicine, 40138 Bologna, Italy
- Medical Research Institute, Hematology department, Alexandria University, Alexandria 21561, Egypt
| | - Manal El Sorady
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria 5310002, Egypt
| | - Ashraf El-Ghandour
- Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria 5310002, Egypt
| | - Giuseppe Visani
- Hematology and Stem Cell Transplant Center, Azienda Ospedaliera Marche Nord, 61121 Pesaro, Italy
| | - Pier Paolo Piccaluga
- Biobank of Research, IRCCS Azienda Ospedaliera-Universitaria di Bologna Policlinico di S. Orsola, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, Bologna University School of Medicine, 40138 Bologna, Italy
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Takahashi K, Aritomi S, Honkawa F, Asari S, Hirose K, Konishi A. Efficient and cost-effective differentiation of induced neural crest cells from induced pluripotent stem cells using laminin 211. Regen Ther 2024; 26:749-759. [PMID: 39290629 PMCID: PMC11406167 DOI: 10.1016/j.reth.2024.08.024] [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: 05/28/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024] Open
Abstract
Introduction Neural crest cells (NCCs) are cell populations that originate during the formation of neural crest in developmental stages. They are characterized by their multipotency, self-renewal and migration potential. Given their ability to differentiate into various types of cells such as neurons and Schwann cells, NCCs hold promise for cell therapy applications. The conventional method for obtaining NCCs involves inducing them from stem cells like induced pluripotent stem cells (iPSCs), followed by a long-term passage or purification using fluorescence-activated cell sorting (FACS). Although FACS allows high purity induced neural crest cells (iNCCs) to be obtained quickly, it is complex and costly. Therefore, there is a need for a simpler, cost-effective and less time-consuming method for cell therapy application. Methods To select differentiated iNCCs from heterogeneous cell populations quickly without using FACS, we adopted the use of scaffold material full-length laminin 211 (LN211), a recombinant, xeno-free protein suitable for cell therapy. After fist passage on LN211, iNCCs characterization was performed using polymerase chain reaction and flow cytometry. Additionally, proliferation and multipotency to various cells were evaluated. Result The iNCCs obtained using our new method expressed cranial NCC- related genes and exhibited stable proliferation ability for at least 57 days, while maintaining high expression level of the NCCs marker CD271. They demonstrated differentiation ability into several cell types: neurons, astrocytes, melanocytes, smooth muscle cells, osteoblasts, adipocytes and chondrocytes. Furthermore, they could be induced to differentiate into induced mesenchymal stem cells (iMSCs) which retain the essential functions of somatic MSCs. Conclusion In this study, we have developed novel method for obtaining high purity iNCCs differentiated from iPSCs in a short time using LN211 under xeno-free condition. Compared with traditional methods, like FACS or long-term passage, this approach enables the acquisition of a large amount of cells at a lower cost and labor, and it is expected to contribute to stable supply of large scale iNCCs for future cell therapy applications.
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Affiliation(s)
- Kazuma Takahashi
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
| | - Shizuka Aritomi
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
| | - Fumie Honkawa
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
| | - Sayaka Asari
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
| | - Ken Hirose
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
| | - Atsushi Konishi
- Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kanagawa, Kawasaki, 210-8681, Japan
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Ramezani A, Tafazoli A, Salimi F, Ghavami M, Arjmandi H, Khalesi B, Hashemi ZS, Khalili S. Current knowledge on therapeutic, diagnostic, and prognostics applications of exosomes in multiple myeloma: Opportunities and challenges. Arch Biochem Biophys 2024; 756:109994. [PMID: 38626818 DOI: 10.1016/j.abb.2024.109994] [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: 11/13/2023] [Revised: 03/04/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024]
Abstract
Interactions between the plasma cells and the BM microenvironment of Multiple myeloma (MM) take place through factors such as exosomes. Many studies have confirmed the role of exosomes in these interactions. By carrying proteins, cytokines, lipids, microRNAs, etc. as their cargo, exosomes can regulate the interactions between MM plasma cells and neighboring cells and participate in the signaling between cancer cells and the environment. It has been shown that MM-derived exosomes can induce angiogenesis, enhance osteoblast activity, confer drug resistance, and have immunosuppressive properties. Abnormal cargos in endosomes originating from MM patients, can be used as a cancer biomarker to detect or screen early prognosis in MM patients. The native nanostructure of exosomes, in addition to their biocompatibility, stability, and safety, make them excellent candidates for therapeutic, drug delivery, and immunomodulatory applications against MM. On the other hand, exosomes derived from dendritic cells (DC) may be used as vaccines against MM. Thanks to the development of new 'omics' approaches, we anticipate to hear more about exosomes in fight against MM. In the present review, we described the most current knowledge on the role of exosomes in MM pathogenesis and their potential role as novel biomarkers and therapeutic tools in MM.
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Affiliation(s)
- Aghdas Ramezani
- Department of Molecular Imaging, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Aida Tafazoli
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Fatemeh Salimi
- Production Department, Carayakhteh Co (Ltd), Tehran, Iran.
| | - Mahlegha Ghavami
- Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
| | - Hanie Arjmandi
- Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran.
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj 3197619751, Iran.
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
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Zare Moghaddam M, Mousavi MJ, Ghotloo S. Stem cell-based therapy for systemic lupus erythematous. J Transl Autoimmun 2024; 8:100241. [PMID: 38737817 PMCID: PMC11087996 DOI: 10.1016/j.jtauto.2024.100241] [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: 01/11/2024] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Systemic lupus erythematosus (SLE), an autoimmune disease, is among the most prevalent rheumatic autoimmune disorders. It affects autologous connective tissues caused by the breakdown of self-tolerance mechanisms. During the last two decades, stem cell therapy has been increasingly considered as a therapeutic option in various diseases, including parkinson's disease, alzheimer, stroke, spinal cord injury, multiple sclerosis, inflammatory bowel disease, liver disease, diabete, heart disease, bone disease, renal disease, respiratory diseases, and hematological abnormalities such as anemia. This is due to the unique properties of stem cells that divide and differentiate to the specialized cells in the damaged tissues. Moreover, they impose immunomodulatory properties affecting the diseases caused by immunological abnormalities such as rheumatic autoimmune disorders. In the present manuscript, efficacy of stem cell therapy with two main types of stem cells, including mesenchymal stem cell (MSC), and hematopoietic stem cells (HSC) in animal models or human patients of SLE, has been reviewed. Taken together, MSC and HSC therapies improved the disease activity, and severity in kidney, lung, liver, and bone (improvement in the clinical manifestation). In addition, a change in the immunological parameters occurred (improvement in immunological parameters). The level of autoantibodies, including antinuclear antibody (ANA), and anti-double-stranded deoxyribonucleic acid antibodies (dsDNA Abs) reduced. A conversion of Th1/Th2 ratio (in favor of Th2), and Th17/Treg (in favor of Treg) was also detected. In spite of many advantages of MSC and HSC transplantations, including efficacy, safety, and increased survival rate of SLE patients, some complications, including recurrence of the disease, occurrence of infections, and secondary autoimmune diseases (SAD) were observed after transplantation that should be addressed in the next studies.
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Affiliation(s)
- Maryam Zare Moghaddam
- Department of Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Javad Mousavi
- Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Somayeh Ghotloo
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Clinical Laboratory Sciences, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Tsai ET, Tseng HC, Liu YH, Wu YR, Peng SY, Lai WY, Lin YY, Chen SP, Chiou SH, Yang YP, Chien Y. Comparison of the mesodermal differentiation potential between embryonic stem cells and scalable induced pluripotent stem cells. J Chin Med Assoc 2024; 87:488-497. [PMID: 38451105 DOI: 10.1097/jcma.0000000000001082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have promising potential in clinical application, whereas their limited amount and sources hinder their bioavailability. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have become prominent options in regenerative medicine as both possess the ability to differentiate into MSCs. METHODS Recently, our research team has successfully developed human leukocyte antigen (HLA)-homozygous iPSC cell lines with high immune compatibility, covering 13.5% of the Taiwanese population. As we deepen our understanding of the differences between these ESCs and HLA-homozygous iPSCs, our study focused on morphological observations and flow cytometry analysis of specific surface marker proteins during the differentiation of ESCs and iPSCs into MSCs. RESULTS The results showed no significant differences between the two pluripotent stem cells, and both of them demonstrated the equivalent ability to further differentiate into adipose, cartilage, and bone cells. CONCLUSION Our research revealed that these iPSCs with high immune compatibility exhibit the same differentiation potential as ESCs, enhancing the future applicability of highly immune-compatible iPSCs.
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Affiliation(s)
- En-Tung Tsai
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Huan-Chin Tseng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yu-Hao Liu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - You-Ren Wu
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Yuan Peng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Wei-Yi Lai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Ying Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Pin Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Frid K, Usmann A, Markovits-Pachter T, Binyamin O, Petrou P, Kassis I, Karussis D, Gabizon R. Granagard administration prolongs the survival of human mesenchymal stem cells transplanted into a mouse model of multiple sclerosis. J Neuroimmunol 2024; 389:578313. [PMID: 38401393 DOI: 10.1016/j.jneuroim.2024.578313] [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: 09/06/2023] [Revised: 01/29/2024] [Accepted: 02/08/2024] [Indexed: 02/26/2024]
Abstract
The clinical effect of human Mesenchymal stem cells (hMSCs) transplanted into EAE mice/MS patients is short lived due to poor survival of the transplanted cells. Since Granagard, a nanoformulation of pomegranate seed oil, extended the presence of Neuronal Stem cells transplanted into CJD mice brains, we tested whether this safe food supplement can also elongate the survival of hMSCs transplanted into EAE mice. Indeed, pathological studies 60 days post transplantation identified human cells only in brains of Granagard treated mice, concomitant with increased clinical activity. We conclude that Granagard may prolong the activity of stem cell transplantation in neurological diseases.
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Affiliation(s)
- Kati Frid
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Areen Usmann
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Tsipora Markovits-Pachter
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Orli Binyamin
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Panayota Petrou
- Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Ibrahim Kassis
- Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Dimitri Karussis
- Medical School, The Hebrew University, Jerusalem, Israel; Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Ruth Gabizon
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel.
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11
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Zheng L, Zhang L, Guo Y, Xu X, Liu Z, Yan Z, Fu R. The immunological role of mesenchymal stromal cells in patients with myelodysplastic syndrome. Front Immunol 2022; 13:1078421. [PMID: 36569863 PMCID: PMC9767949 DOI: 10.3389/fimmu.2022.1078421] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a common hematological malignant disease, characterized by malignant hematopoietic stem cell proliferation in the bone marrow (BM); clinically, it mainly manifests clinically mainly by as pathological hematopoiesis, hemocytopenia, and high-risk transformation to acute leukemia. Several studies have shown that the BM microenvironment plays a critical role in the progression of MDS. In this study, we specifically evaluated mesenchymal stromal cells (MSCs) that exert immunomodulatory effects in the BM microenvironment. This immunomodulatory effect occurs through direct cell-cell contact and the secretion of soluble cytokines or micro vesicles. Several researchers have compared MSCs derived from healthy donors to low-risk MDS-associated bone mesenchymal stem cells (BM-MSCs) and have found no significant abnormalities in the MDS-MSC phenotype; however, these cells have been observed to exhibit altered function, including a decline in osteoblastic function. This altered function may promote MDS progression. In patients with MDS, especially high-risk patients, MSCs in the BM microenvironment regulate immune cell function, such as that of T cells, B cells, natural killer cells, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSCs), macrophages, and Treg cells, thereby enabling MDS-associated malignant cells to evade immune cell surveillance. Alterations in MDS-MSC function include genomic instability, microRNA production, histone modification, DNA methylation, and abnormal signal transduction and cytokine secretion.
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Affiliation(s)
- Likun Zheng
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Lei Zhang
- Department of Orthopedics, Kailuan General Hospital, Tangshan, Hebei, China
| | - Yixuan Guo
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhenyu Yan
- Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,*Correspondence: Rong Fu,
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12
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Lu Y, Han Y, Zhou L, Shi G, Bai L, Wang K, Qin C. A comparative study of mouse bone marrow mesenchymal stem cells isolated using three easy-to-perform approaches. FEBS Open Bio 2022; 12:2154-2165. [PMID: 36153697 PMCID: PMC9714364 DOI: 10.1002/2211-5463.13493] [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: 03/31/2022] [Revised: 09/07/2022] [Accepted: 09/23/2022] [Indexed: 01/25/2023] Open
Abstract
Mouse bone marrow mesenchymal stem cells (mBM-MSCs) are important for preclinical tissue regeneration and repair studies. In the present study, we isolated mBM-MSCs using three easy-to-perform methods (whole bone marrow-adherent culture, density-gradient centrifugation, and bone digestion), and then compared the morphology, proliferation, differentiation, and paracrine factor profiles of the isolated mBM-MSCs. Of these three isolation methods, the bone digestion method resulted in the highest quantity of mBM-MSCs with high growth potential and moderate differentiation. Conversely, the mBM-MSCs isolated through the whole bone marrow-adherent method exhibited the lowest potency for proliferation and differentiation. The differentially expressed factors between mBM-MSCs were primarily those involved in immune responses. The highly expressed secreted factors included cytokines/members of the chemokine family, growth factors, and protein binding/proteinase activity. These findings provide a fundamental reference for development of MSC isolation methods.
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Affiliation(s)
- Yalan Lu
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Yunlin Han
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Li Zhou
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Guiying Shi
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Lin Bai
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Kewei Wang
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
| | - Chuan Qin
- Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China, Institute of Laboratory Animal Science, Peking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina
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13
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Kamiya D, Takenaka-Ninagawa N, Motoike S, Kajiya M, Akaboshi T, Zhao C, Shibata M, Senda S, Toyooka Y, Sakurai H, Kurihara H, Ikeya M. Induction of functional xeno-free MSCs from human iPSCs via a neural crest cell lineage. NPJ Regen Med 2022; 7:47. [PMID: 36109564 PMCID: PMC9477888 DOI: 10.1038/s41536-022-00241-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/08/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractMesenchymal stem/stromal cells (MSCs) are adult multipotent stem cells. Here, we induced MSCs from human induced pluripotent stem cells (iPSCs) via a neural crest cell (NCC) lineage under xeno-free conditions and evaluated their in vivo functions. We modified a previous MSC induction method to work under xeno-free conditions. Bovine serum albumin-containing NCC induction medium and fetal bovine serum-containing MSC induction medium were replaced with xeno-free medium. Through our optimized method, iPSCs differentiated into MSCs with high efficiency. To evaluate their in vivo activities, we transplanted the xeno-free-induced MSCs (XF-iMSCs) into mouse models for bone and skeletal muscle regeneration and confirmed their regenerative potency. These XF-iMSCs mainly promoted the regeneration of surrounding host cells, suggesting that they secrete soluble factors into affected regions. We also found that the peroxidasin and IGF2 secreted by the XF-iMSCs partially contributed to myotube differentiation. These results suggest that XF-iMSCs are important for future applications in regenerative medicine.
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14
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Garrigós MM, de Oliveira FA, Nucci MP, Nucci LP, Alves ADH, Dias OFM, Gamarra LF. How mesenchymal stem cell cotransplantation with hematopoietic stem cells can improve engraftment in animal models. World J Stem Cells 2022; 14:658-679. [PMID: 36157912 PMCID: PMC9453272 DOI: 10.4252/wjsc.v14.i8.658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/27/2022] [Accepted: 07/26/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Bone marrow transplantation (BMT) can be applied to both hematopoietic and nonhematopoietic diseases; nonetheless, it still comes with a number of challenges and limitations that contribute to treatment failure. Bearing this in mind, a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.
AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.
METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment. We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English. In PubMed, we initially identified 555 articles and after selection, only 12 were chosen. In Scopus, 2010 were identified, and six were left after the screening and eligibility process.
RESULTS Of the 2565 articles found in the databases, only 18 original studies met the eligibility criteria. HSC distribution by source showed similar ratios, with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1 × 107 cells by intravenous or intrabone routes. However, MSCs had a high prevalence of human donors with a variety of sources (umbilical cord blood, bone marrow, tonsil, adipose tissue or fetal lung), using a lower dose, mainly 106 cells and ranging 104 to 1.5 × 107 cells, utilizing the same routes. MSCs were characterized prior to administration in almost every experiment. The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy. The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism, followed by hematopoietic reconstitution and survival analysis. Besides the engraftment, homing and cellularity were also evaluated in some studies.
CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models, in the absence of toxicity.
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Affiliation(s)
- Murilo Montenegro Garrigós
- Hospital Israelita Albert Einstein, São Paulo 05652-900, São Paulo, Brazil
- Instituto de Química, Universidade de São Paulo, São Paulo 05508-900, São Paulo, Brazil
| | | | - Mariana Penteado Nucci
- Hospital Israelita Albert Einstein, São Paulo 05652-900, São Paulo, Brazil
- LIM44-Hospital das Clínicas, Faculdade Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil
| | - Leopoldo Penteado Nucci
- Centro Universitário do Planalto Central, Área Especial para Industria nº 02 Setor Leste - Gama-DF, Brasília 72445-020, Distrito Federal, Brazil
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15
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Nauman G, Danzl NM, Lee J, Borsotti C, Madley R, Fu J, Hölzl MA, Dahmani A, Dorronsoro Gonzalez A, Chavez É, Campbell SR, Yang S, Satwani P, Liu K, Sykes M. Defects in Long-Term APC Repopulation Ability of Adult Human Bone Marrow Hematopoietic Stem Cells (HSCs) Compared with Fetal Liver HSCs. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1652-1663. [PMID: 35315788 PMCID: PMC8976823 DOI: 10.4049/jimmunol.2100966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/25/2022] [Indexed: 04/28/2023]
Abstract
Immunodeficient mice reconstituted with immune systems from patients, or personalized immune (PI) mice, are powerful tools for understanding human disease. Compared with immunodeficient mice transplanted with human fetal thymus tissue and fetal liver-derived CD34+ cells administered i.v. (Hu/Hu mice), PI mice, which are transplanted with human fetal thymus and adult bone marrow (aBM) CD34+ cells, demonstrate reduced levels of human reconstitution. We characterized APC and APC progenitor repopulation in human immune system mice and detected significant reductions in blood, bone marrow (BM), and splenic APC populations in PI compared with Hu/Hu mice. APC progenitors and hematopoietic stem cells (HSCs) were less abundant in aBM CD34+ cells compared with fetal liver-derived CD34+ cell preparations, and this reduction in APC progenitors was reflected in the BM of PI compared with Hu/Hu mice 14-20 wk posttransplant. The number of HSCs increased in PI mice compared with the originally infused BM cells and maintained functional repopulation potential, because BM from some PI mice 28 wk posttransplant generated human myeloid and lymphoid cells in secondary recipients. Moreover, long-term PI mouse BM contained functional T cell progenitors, evidenced by thymopoiesis in thymic organ cultures. Injection of aBM cells directly into the BM cavity, transgenic expression of hematopoietic cytokines, and coinfusion of human BM-derived mesenchymal stem cells synergized to enhance long-term B cell and monocyte levels in PI mice. These improvements allow a sustained time frame of 18-22 wk where APCs and T cells are present and greater flexibility for modeling immune disease pathogenesis and immunotherapies in PI mice.
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Affiliation(s)
- Grace Nauman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Nichole M Danzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jaeyop Lee
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Chiara Borsotti
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Rachel Madley
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jianing Fu
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Markus A Hölzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Alexander Dahmani
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Akaitz Dorronsoro Gonzalez
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Éstefania Chavez
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Sean R Campbell
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Suxiao Yang
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Prakash Satwani
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Pediatrics, Columbia University Medical Center, Columbia University, New York, NY
| | - Kang Liu
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; and
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY;
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY
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16
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Gilchrist AE, Harley BA. Engineered Tissue Models to Replicate Dynamic Interactions within the Hematopoietic Stem Cell Niche. Adv Healthc Mater 2022; 11:e2102130. [PMID: 34936239 PMCID: PMC8986554 DOI: 10.1002/adhm.202102130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/19/2021] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem cells are the progenitors of the blood and immune system and represent the most widely used regenerative therapy. However, their rarity and limited donor base necessitate the design of ex vivo systems that support HSC expansion without the loss of long-term stem cell activity. This review describes recent advances in biomaterials systems to replicate features of the hematopoietic niche. Inspired by the native bone marrow, these instructive biomaterials provide stimuli and cues from cocultured niche-associated cells to support HSC encapsulation and expansion. Engineered systems increasingly enable study of the dynamic nature of the matrix and biomolecular environment as well as the role of cell-cell signaling (e.g., autocrine feedback vs paracrine signaling between dissimilar cells). The inherent coupling of material properties, biotransport of cell-secreted factors, and cell-mediated remodeling motivate dynamic biomaterial systems as well as characterization and modeling tools capable of evaluating a temporally evolving tissue microenvironment. Recent advances in HSC identification and tracking, model-based experimental design, and single-cell culture platforms facilitate the study of the effect of constellations of matrix, cell, and soluble factor signals on HSC fate. While inspired by the HSC niche, these tools are amenable to the broader stem cell engineering community.
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Affiliation(s)
- Aidan E. Gilchrist
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Brendan A.C. Harley
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801
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17
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The RIG-I-NRF2 axis regulates the mesenchymal stromal niche for bone marrow transplantation. Blood 2022; 139:3204-3221. [PMID: 35259210 DOI: 10.1182/blood.2021013048] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 02/18/2022] [Indexed: 11/20/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) support bone formation and constitute the stromal niche in regulating hematopoietic stem cells (HSCs). Stromal niche dysfunction affects HSC engraftment during transplantation; however, the underlying mechanisms remain elusive. In the present study, we found that all-trans retinoic acid (ATRA) and inflammation stress upregulated retinoic acid-inducible gene I (RIG-I) in BMSCs. Excess RIG-I expression damaged the clonogenicity, bone-forming ability of BMSCs and, particularly, their stromal niche function that supports HSC expansion in vitro and engraftment in vivo. Mechanistically, RIG-I elevation promoted the degradation of NRF2, a checkpoint for antioxidant cellular response, by altering the RIG-I-Trim25-Keap1-NRF2 complex, leading to reactive oxygen species (ROS) accumulation and BMSC damage. Genetic inhibition of RIG-I sustained NRF2 protein levels and reduced ROS levels in ATRA-treated BMSCs, thus preserving their clonogenicity, bone-forming ability, and stromal niche function in supporting HSC engraftment in mice. More importantly, RIG-I inhibition recovered the ATRA-treated stromal niche function, to enhance HSC engraftment and emergency myelopoiesis for innate immunity against the bacterium Listeria monocytogenes during transplantation. Overall, we identified a non-canonical role of RIG-I in the regulation of the stromal niche for HSC transplantation.
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18
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Muthu S, Jeyaraman M, Kotner MB, Jeyaraman N, Rajendran RL, Sharma S, Khanna M, Rajendran SNS, Oh JM, Gangadaran P, Ahn BC. Evolution of Mesenchymal Stem Cell Therapy as an Advanced Therapeutic Medicinal Product (ATMP)-An Indian Perspective. Bioengineering (Basel) 2022; 9:111. [PMID: 35324800 PMCID: PMC8945480 DOI: 10.3390/bioengineering9030111] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 02/05/2023] Open
Abstract
Stem cells can be defined as the cells that have the capacity to both self-renew and give rise to differentiated cells. Under the right conditions and signals, depending on their origin and bio-plasticity, stem cells can differentiate into multiple cell lineages and develop into various mature cells. Stem cell therapy is a fast-developing branch of medicine that includes the most innovative regenerative therapies for the restoration of cell and tissue function in individuals with severe diseases. Stem cell research has resulted in the emergence of cell-based therapies for disorders that are resistant to conventional drugs and therapies, and they are considered under the category of an Advanced Therapeutic Medicinal Product (ATMP). The FDA and the European Medicines Agency (EMA) devised a new strategy in 2017 with the aim of unifying the standards for development of ATMPs such that it is easy to exchange information at the international level. In this review, we discuss the evolution of mesenchymal stem cell-based therapy as an ATMP in the global and Indian scenarios, along with the guidelines governing their usage and clinical application of these therapeutics.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, India;
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India
- Department of Orthopaedics, Faculty of Medicine-Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute University, Chennai 600095, India
| | - Moinuddin Basha Kotner
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. Ram Manohar Lohiya National Law University, Lucknow 226012, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. Ram Manohar Lohiya National Law University, Lucknow 226012, India
- Fellow in Joint Replacement, Atlas Hospitals, The Tamil Nadu Dr. MGR Medical University, Tiruchirappalli 620002, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
| | - Shilpa Sharma
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Manish Khanna
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
| | - Sree Naga Sowndary Rajendran
- Department of Medicine, Sri Venkateshwaraa Medical College Hospital and Research Centre, Puducherry 605107, India;
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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Mirfakhraie R, Ardakani MT, Hajifathali A, Karami S, Moshari MR, Hassani M, Firouz SM, Roshandel E. Highlighting the interaction between immunomodulatory properties of mesenchymal stem cells and signaling pathways contribute to Graft Versus Host Disease management. Transpl Immunol 2022; 71:101524. [PMID: 34990789 DOI: 10.1016/j.trim.2021.101524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/29/2021] [Accepted: 12/29/2021] [Indexed: 12/11/2022]
Abstract
Background Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been increasingly used as a therapeutic approach for hematological malignancies. Several potential strategies have been developed for treating or preventing allo-HSCT complications, specifically graft-versus-host disease (GVHD). GVHD could significantly affect the morbidity and mortality of patients after allo-HSCT. Curative treatment and prophylaxis regimens for GVHD could reduce GVHD incidence and improve survival rate. Among these therapeutic strategies, mesenchymal stem cell (MSCs) mediated immunomodulation has been explored widely in clinical trials. MSCs immunomodulation ability in GVHD correlates with the interactions of MSCs with innate and adaptive immune cells. However, signaling pathways responsible for MSCs' impact on GVHD regulation, like JAK/STAT, NOTCH, MAPK/ERK, and NFκβ signaling pathways, have not been clearly described yet. This review aims to illuminate the effect of MSCs-mediated immunomodulation in GVHD management after allo-HSCT representing the role of MSCs therapy on signaling pathways in GVHD. Conclusion MSCs could potentially modulate immune responses, prevent GVHD, and improve survival after allo-HSCT. Previous studies have investigated different signaling pathways' contributions to MSCs immunoregulatory ability. Accordingly, targeting signaling pathways components involved in MSCs related GVHD regulation is proven to be beneficial.
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Affiliation(s)
- Reza Mirfakhraie
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maria Tavakoli Ardakani
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Karami
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Moshari
- Department of Anesthesiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of General Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Mashayekhi Firouz
- Department of Immunology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Allegra A, Di Gioacchino M, Tonacci A, Petrarca C, Musolino C, Gangemi S. Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies. Cells 2021; 10:2865. [PMID: 34831088 PMCID: PMC8616233 DOI: 10.3390/cells10112865] [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: 10/05/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/16/2022] Open
Abstract
Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Mario Di Gioacchino
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
| | - Alessandro Tonacci
- National Research Council of Italy (IFC-CNR), Clinical Physiology Institute, 56124 Pisa, Italy;
| | - Claudia Petrarca
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
- National Research Council of Italy (IFC-CNR), Clinical Physiology Institute, 56124 Pisa, Italy;
- Department of Medicine and Science of Ageing, G. D’Annunzio University, 66100 Chieti, Italy
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
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21
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Tayler IM, Stowers RS. Engineering hydrogels for personalized disease modeling and regenerative medicine. Acta Biomater 2021; 132:4-22. [PMID: 33882354 DOI: 10.1016/j.actbio.2021.04.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/26/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
Technological innovations and advances in scientific understanding have created an environment where data can be collected, analyzed, and interpreted at scale, ushering in the era of personalized medicine. The ability to isolate cells from individual patients offers tremendous promise if those cells can be used to generate functional tissue replacements or used in disease modeling to determine optimal treatment strategies. Here, we review recent progress in the use of hydrogels to create artificial cellular microenvironments for personalized tissue engineering and regenerative medicine applications, as well as to develop personalized disease models. We highlight engineering strategies to control stem cell fate through hydrogel design, and the use of hydrogels in combination with organoids, advanced imaging methods, and novel bioprinting techniques to generate functional tissues. We also discuss the use of hydrogels to study molecular mechanisms underlying diseases and to create personalized in vitro disease models to complement existing pre-clinical models. Continued progress in the development of engineered hydrogels, in combination with other emerging technologies, will be essential to realize the immense potential of personalized medicine. STATEMENT OF SIGNIFICANCE: In this review, we cover recent advances in hydrogel engineering strategies with applications in personalized medicine. Specifically, we focus on material systems to expand or control differentiation of patient-derived stem cells, and hydrogels to reprogram somatic cells to pluripotent states. We then review applications of hydrogels in developing personalized engineered tissues. We also highlight the use of hydrogel systems as personalized disease models, focusing on specific examples in fibrosis and cancer, and more broadly on drug screening strategies using patient-derived cells and hydrogels. We believe this review will be a valuable contribution to the Special Issue and the readership of Acta Biomaterialia will appreciate the comprehensive overview of the utility of hydrogels in the developing field of personalized medicine.
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22
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Putra I, Shen X, Anwar KN, Rabiee B, Samaeekia R, Almazyad E, Giri P, Jabbehdari S, Hayat MR, Elhusseiny AM, Ghassemi M, Mahmud N, Edward DP, Joslin CE, Rosenblatt MI, Dana R, Eslani M, Hematti P, Djalilian AR. Preclinical Evaluation of the Safety and Efficacy of Cryopreserved Bone Marrow Mesenchymal Stromal Cells for Corneal Repair. Transl Vis Sci Technol 2021; 10:3. [PMID: 34383879 PMCID: PMC8362636 DOI: 10.1167/tvst.10.10.3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose Mesenchymal stromal cells (MSCs) have been shown to enhance tissue repair as a cell-based therapy. In preparation for a phase I clinical study, we evaluated the safety, dosing, and efficacy of bone marrow–derived MSCs after subconjunctival injection in preclinical animal models of mice, rats, and rabbits. Methods Human bone marrow–derived MSCs were expanded to passage 4 and cryopreserved. Viability of MSCs after thawing and injection through small-gauge needles was evaluated by vital dye staining. The in vivo safety of human and rabbit MSCs was studied by subconjunctivally injecting MSCs in rabbits with follow-up to 90 days. The potency of MSCs on accelerating wound healing was evaluated in vitro using a scratch assay and in vivo using 2-mm corneal epithelial debridement wounds in mice. Human MSCs were tracked after subconjunctival injection in rat and rabbit eyes. Results The viability of MSCs after thawing and immediate injection through 27- and 30-gauge needles was 93.1% ± 2.1% and 94.9% ± 1.3%, respectively. Rabbit eyes demonstrated mild self-limiting conjunctival inflammation at the site of injection with human but not rabbit MSCs. In scratch assay, the mean wound healing area was 93.5% ± 12.1% in epithelial cells co-cultured with MSCs compared with 40.8% ± 23.1% in controls. At 24 hours after wounding, all MSC-injected murine eyes had 100% corneal wound closure compared with 79.9% ± 5.5% in controls. Human MSCs were detectable in the subconjunctival area and peripheral cornea at 14 days after injection. Conclusions Subconjunctival administration of MSCs is safe and effective in promoting corneal epithelial wound healing in animal models. Translational Relevance These results provide preclinical data to support a phase I clinical study.
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Affiliation(s)
- Ilham Putra
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiang Shen
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Khandaker N Anwar
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Behnam Rabiee
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ravand Samaeekia
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Enmar Almazyad
- Department of Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Pushpanjali Giri
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Sayena Jabbehdari
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mohammed R Hayat
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Abdelrahman M Elhusseiny
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mahmood Ghassemi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Nadim Mahmud
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Deepak P Edward
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.,Department of Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Charlotte E Joslin
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Peiman Hematti
- Department of Medicine and University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
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23
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Mallis P, Michalopoulos E, Chatzistamatiou T, Giokas CS. Interplay between mesenchymal stromal cells and immune system: clinical applications in immune-related diseases. EXPLORATION OF IMMUNOLOGY 2021. [DOI: 10.37349/ei.2021.00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 11/08/2024]
Abstract
Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Theofanis Chatzistamatiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece 2Histocompatibility & Immunogenetics Lab, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
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24
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Nguyen-Truong M, Hematti P, Wang Z. Current status of myocardial restoration via the paracrine function of mesenchymal stromal cells. Am J Physiol Heart Circ Physiol 2021; 321:H112-H127. [PMID: 34085844 DOI: 10.1152/ajpheart.00217.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Mesenchymal stromal cells (MSCs) have been studied for nearly two decades as a therapy for myocardial restoration. An emerging direction to repair myocardium is through their paracrine function, which includes the utilization of MSC-derived conditioned medium or extracellular vesicles. In this review, we go over the unique characteristics of MSCs that make it suitable for "off the shelf," cell-free regenerative therapy, current MSC-derived cell-free approaches including their advantages and disadvantages, and the known mechanisms of action of the paracrine effect of MSCs. With a summary of the clinical trials and preclinical studies of MSC-derived cell-free therapy, we classify the aforementioned mechanisms into angiogenesis, immunomodulation, extracellular matrix remodeling, antiapoptosis, and antioxidation. Particularly, we discuss on ways researchers have worked toward enhancing these desired properties to improve the therapeutic outcomes and the investigation of mechanobiology involved in MSC paracrine function. Lastly, we bring up the remaining challenges in this arising field and suggestions for future directions to improve our understanding and control over the potential of MSC paracrine function for myocardial restoration.
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Affiliation(s)
| | - Peiman Hematti
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - Zhijie Wang
- School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado.,Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
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25
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Mansourabadi AH, Mohamed Khosroshahi L, Noorbakhsh F, Amirzargar A. Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with the focus on Tregs, CAR Tregs, and Mesenchymal stem cells. Int Immunopharmacol 2021; 97:107669. [PMID: 33965760 DOI: 10.1016/j.intimp.2021.107669] [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] [Received: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Organ transplantation is a practical treatment for patients with end-stage organ failure. Despite the advances in short-term graft survival, long-term graft survival remains the main challenge considering the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressive drugs. Since a novel therapeutic strategy to induce allograft tolerance seems urgent, focusing on developing novel and safe approaches to prolong graft survival is one of the main goals of transplant investigators. Researchers in the field of organ transplantation are interested in suppressing or optimizing the immune responses by focusing on immune cells including mesenchymal stem cells (MSCs), polyclonal regulatory Tcells (Tregs), and antigen-specific Tregs engineered with chimeric antigen receptors (CAR Tregs). We review the mechanistic pathways, phenotypic and functional characteristics of these cells, and their promising application in organ transplantation.
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Affiliation(s)
- Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran; Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran
| | - Leila Mohamed Khosroshahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
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26
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Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
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Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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27
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The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery. J Pers Med 2021; 11:jpm11030161. [PMID: 33668854 PMCID: PMC7996318 DOI: 10.3390/jpm11030161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by means of supporting hematopoietic stem cell transplantation. Based on pre-clinical and clinical advances in neuroblastoma and other malignancies, we assess both the strong potential and the associated risks of using mesenchymal stromal cells in the therapy for neuroblastoma. Furthermore, we examine feasibility and safety aspects and discuss future directions for harnessing the advantageous properties of mesenchymal stromal cells for the advancement of therapy success.
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28
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Xu M, Su X, Xiao X, Yu H, Li X, Keating A, Wang S, Zhao RC. Hydrogen Peroxide-Induced Senescence Reduces the Wound Healing-Promoting Effects of Mesenchymal Stem Cell-Derived Exosomes Partially via miR-146a. Aging Dis 2021; 12:102-115. [PMID: 33532131 PMCID: PMC7801275 DOI: 10.14336/ad.2020.0624] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/24/2020] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have beneficial effects on wound healing. MSCs function through direct cell-cell communication or indirectly through paracrine secretion of exosomes. Here, we found that MSC-derived exosomes had pro-wound healing effects via promotion of angiogenesis; however, this promoting effect was significantly reduced when senescence was induced in parental MSCs by hydrogen peroxide (H2O2). Further experiments showed that decreased miR-146a expression in exosomes derived from senescent MSCs (s-exo) contributed to these findings. In vitro, the pro-angiogenic effect of s-exo on tube formation in human umbilical vein endothelial cells was significantly reduced compared with that of exosomes derived from control MSCs (c-exo). In vivo, higher tube numbers and longer tube lengths were observed in the c-exo group compared with the s-exo group. Using microarray analysis, we found that miR-146a level in s-exo was lower than that in c-exo. Knockdown of miR-146a in c-exo decreased its capacity to promote angiogenesis, and overexpression of miR-146a in s-exo partially rescued its impaired pro-angiogenic capacity, thereby confirming that downregulation of miR-146a contributed to the reduced pro-wound healing capacity of s-exo. Our study is the first to demonstrate that cell senescence induced by H2O2 alters the pro-angiogenic ability of exosomes by modulating the expression of exosomal miRNAs, especially miR-146a, thus providing new insights into the correlation between parental cell state and exosome content and function.
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Affiliation(s)
- Meiqian Xu
- 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xiaodong Su
- 2Brain Tumor Research Center, Beijing Neurosurgical Institute, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing 100070, China
| | - Xian Xiao
- 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Hongliang Yu
- 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xiaoxia Li
- 3Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao 266071, China
| | - Armand Keating
- 4Cell Therapy Translational Research Laboratory, Princess Margaret, Cancer Centre, Toronto, Ontario M5G 2M9, Canada.,5Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G2M9, Canada.,6Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada
| | - Shihua Wang
- 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Robert Chunhua Zhao
- 1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing 100005, China
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29
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Hochheuser C, Windt LJ, Kunze NY, de Vos DL, Tytgat GA, Voermans C, Timmerman I. Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications. Stem Cells Dev 2021; 30:59-78. [PMID: 33287630 PMCID: PMC7826431 DOI: 10.1089/scd.2020.0142] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma (NB) is the second most common solid cancer in childhood, accounting for 15% of cancer-related deaths in children. In high-risk NB patients, the majority suffers from metastasis. Despite intensive multimodal treatment, long-term survival remains <40%. The bone marrow (BM) is among the most common sites of distant metastasis in patients with high-risk NB. In this environment, small populations of tumor cells can persist after treatment (minimal residual disease) and induce relapse. Therapy resistance of these residual tumor cells in BM remains a major obstacle for the cure of NB. A detailed understanding of the microenvironment and its role in tumor progression is of utmost importance for improving the treatment efficiency of NB. In BM, mesenchymal stromal cells (MSCs) constitute an important part of the microenvironment, where they support hematopoiesis and modulate immune responses. Their role in tumor progression is not completely understood, especially for NB. Although MSCs have been found to promote epithelial-mesenchymal transition, tumor growth, and metastasis and to induce chemoresistance, some reports point toward a tumor-suppressive effect of MSCs. In this review, we aim to compile current knowledge about the role of MSCs in NB development and progression. We evaluate arguments that depict tumor-supportive versus -suppressive properties of MSCs in the context of NB and give an overview of factors involved in MSC-NB crosstalk. A focus lies on the BM as a metastatic niche, since that is the predominant site for NB metastasis and relapse. Finally, we will present opportunities and challenges for therapeutic targeting of MSCs in the BM microenvironment.
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Affiliation(s)
- Caroline Hochheuser
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Laurens J. Windt
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nina Y. Kunze
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Dieuwke L. de Vos
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Carlijn Voermans
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ilse Timmerman
- Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
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30
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Rostami T, Monzavi SM, Poustchi H, Khoshdel AR, Behfar M, Hamidieh AA. Analysis of determinant factors of liver fibrosis progression in ex-thalassemic patients. Int J Hematol 2021; 113:145-157. [PMID: 33033952 DOI: 10.1007/s12185-020-02998-4] [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: 02/25/2020] [Revised: 08/20/2020] [Accepted: 09/07/2020] [Indexed: 02/08/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) potentially renders thalassemia patients disease-free with presumably cessation of associated complications. This study analyzes the liver fibrosis status and the determinants of its progression in ex-thalassemic patients. The liver fibrosis status of 108 pediatric transfusion-dependent β-thalassemia major patients was evaluated before and one year after allo-HSCT using transient elastography (TE). All patients achieved normal hematopoiesis. In univariate analyses, not in all, but in patients developing significant post-HSCT iron overload or hepatic graft-versus-host disease (GvHD), as well as recipients of bone marrow stem cells (BMSC), significant TE increment occurred. In multivariable analyses, through a model with large effect size (Adj.R2 = 26%, F(3,104) = 13.53, P < 0.001), post-HSCT serum ferritin and hepatic GvHD were ascertained as independent determinants of significant TE increase, and the effect of stem cell graft source approached the level of significance. Excluding the patients with intermediate/high Lucarelli risk classes, the TE increase was significantly greater only in BMSC recipients (P = 0.033). Although the risk impact of allograft source on liver fibrosis progression requires further evaluation; hepatic status of ex-thalassemic patients can be preserved after HSCT, if hepatic GvHD is controlled and adequate post-transplantation iron depletion is ensured.
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Affiliation(s)
- Tahereh Rostami
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mostafa Monzavi
- Department of Pediatric Stem Cell Transplantation, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Reza Khoshdel
- Modern Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Maryam Behfar
- Department of Pediatric Stem Cell Transplantation, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Pediatric Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Department of Pediatric Stem Cell Transplantation, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Pediatric Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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31
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de la Torre P, Flores AI. Current Status and Future Prospects of Perinatal Stem Cells. Genes (Basel) 2020; 12:6. [PMID: 33374593 PMCID: PMC7822425 DOI: 10.3390/genes12010006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023] Open
Abstract
The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.
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Affiliation(s)
| | - Ana I. Flores
- Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Avda. Cordoba s/n, 28041 Madrid, Spain;
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Adib Sereshki MM, Bahar B, Ghavamzadeh A, Mousavi SA, Alimoghaddam K. Long--Term Free Survival of Two Class III β-Thalassemic Patients after Non-Myeloablative Stem Cell Transplantation. Int J Hematol Oncol Stem Cell Res 2020; 14:118-122. [PMID: 32461795 PMCID: PMC7231797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
At present, hematopoietic stem cell transplantation is the only curative treatment for β thalassemia patients. Conventional myeloablative stem cell transplantation is associated with significant morbidity and mortality, and non-myeloablative stem cell transplantation is associated with high graft failure rate. Some modification in this treatment approach can result in successful transplantation in thalassemia patients. Two successful Fludarabine-based non-myeloablative stem cell transplantation in two Class III β thalassemia patients are reported here. The first patient was a 14-year old girl that developed rapid engraftment and full chimerism after rapid tapering of cyclosporine as graft-versus-host disease (GVHD) prophylaxis drug according to our protocol. Another patient was a 24-year old female patient that developed cyclosporine toxicity, and early tapering of cyclosporine helped for rapid engraftment and successful transplantation. After these two successful experiments in non-myeloablative peripheral blood stem cell transplantation for our class III β thalassemia patients, we concluded that Fludarabine-based non-myeloablative stem cell transplantation with adequate number of stem cells at the time of transplantation and rapid tapering of GVHD prophylaxis drugs after transplantation can potentially help for rapid engraftment and successful stem cell transplantation in high risk β-thalassemia patients.
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Affiliation(s)
| | - Babak Bahar
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Alimoghaddam
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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33
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Fumagalli G, Monfrini M, Donzelli E, Rodriguez-Menendez V, Bonandrini B, Figliuzzi M, Remuzzi A, D’Amico G, Cavaletti G, Scuteri A. Protective Effect of Human Mesenchymal Stem Cells on the Survival of Pancreatic Islets. Int J Stem Cells 2020; 13:116-126. [PMID: 31887847 PMCID: PMC7119207 DOI: 10.15283/ijsc19094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/09/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Transplantation of pancreatic islets is an intriguing new therapeutic option to face the worldwide spread problem of Type-I diabetes. Currently, its clinical use is limited by several problems, mainly based on the high number of islets required to restore normoglycaemia and by the low survival of the transplanted tissue. A promising attempt to overcome the limits to such an approach was represented by the use of Mesenchymal Stem Cells (MSC). Despite the encouraging results obtained with murine-derived MSC, little is still known about their protective mechanisms. The aim of the present study was to verify the effectiveness, (besides murine MSC), of clinically relevant human-derived MSC (hMSC) on protecting pancreatic islets, thus also shedding light on the putative differences between MSC of different origin. METHODS AND RESULTS Threefold kinds of co-cultures were therefore in vitro set up (direct, indirect and mixed), to analyze the hMSC effect on pancreatic islet survival and function and to study the putative mechanisms involved. Although in a different way with respect to murine MSC, also human derived cells demonstrated to be effective on protecting pancreatic islet survival. This effect could be due to the release of some trophic factors, such as VEGF and Il-6, and by the reduction of inflammatory cytokine TNF-α. CONCLUSIONS Therefore, hMSC confirmed their great clinical potential to improve the feasibility of pancreatic islet transplantation therapy against diabetes.
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Affiliation(s)
- Giulia Fumagalli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- PhD Program in Neuroscience, University of Milano-Bicocca, Monza (MB), Italy
| | - Marianna Monfrini
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
| | - Elisabetta Donzelli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Virginia Rodriguez-Menendez
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Barbara Bonandrini
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marina Figliuzzi
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Andrea Remuzzi
- Department of Management, Information and Production Engineering, University of Bergamo, Dalmine (BG), Italy
| | - Giovanna D’Amico
- Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Monza (MB), Italy
| | - Guido Cavaletti
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Arianna Scuteri
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
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Naderi N, Griffin MF, Mosahebi A, Butler PE, Seifalian AM. Adipose derived stem cells and platelet rich plasma improve the tissue integration and angiogenesis of biodegradable scaffolds for soft tissue regeneration. Mol Biol Rep 2020; 47:2005-2013. [PMID: 32072400 PMCID: PMC7688190 DOI: 10.1007/s11033-020-05297-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 01/31/2020] [Indexed: 11/30/2022]
Abstract
Current surgical reconstruction for soft tissue replacement involves lipotransfer to restore soft tissue replacements but is limited by survival and longevity of the fat tissue. Alternative approaches to overcome these limitations include using biodegradable scaffolds with stem cells with growth factors to generate soft tissue. Adipose derived stem cells (ADSCs) offer great potential to differentiate into adipose, and can be delivered using biodegradable scaffolds. However, the optimal scaffold to maximise this approach is unknown. This study investigates the biocompatibility of nanocomposite scaffolds (POSS-PCL) to deliver ADSCs with and without the addition of growth factors using platelet rich plasma (PRP) in vivo. Rat ADSCs were isolated and then seeded on biodegradable scaffolds (POSS-PCL). In addition, donor rats were used to isolate PRP to modify the scaffolds. The implants were then subcutaneously implanted for 3-months to assess the effect of PRP and ADSC on POSS-PCL scaffolds biocompatibility. Histology after explanation was examined to assess tissue integration (H&E) and collagen production (Massons Trichome). Immunohistochemistry was used to assess angiogenesis (CD3, α-SMA), immune response (CD45, CD68) and adipose formation (PPAR-γ). At 3-months PRP-ADSC-POSS-PCL scaffolds demonstrated significantly increased tissue integration and angiogenesis compared to PRP, ADSC and unmodified scaffolds (p < 0.05). In addition, PRP-ADSC-POSS-PCL scaffolds showed similar levels of CD45 and CD68 staining compared to unmodified scaffolds. Furthermore, there was increased PPAR-γ staining demonstrated at 3-months with PRP-ADSC-POSS-PCL scaffolds (p < 0.05). POSS-PCL nanocomposite scaffolds provide an effective delivery system for ADSCs. PRP and ADSC work synergistically to enhance the biocompatibility of POSS-PCL scaffolds and provide a platform technology for soft tissue regeneration.
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Affiliation(s)
- N Naderi
- UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, UK.,Royal Free London NHS Foundation Trust Hospital, London, UK.,Plastic and Reconstructive Surgery Department, Royal Free Hospital, University College London, Pond Street, London, UK
| | - M F Griffin
- UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, UK. .,Royal Free London NHS Foundation Trust Hospital, London, UK. .,Plastic and Reconstructive Surgery Department, Royal Free Hospital, University College London, Pond Street, London, UK.
| | - A Mosahebi
- UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, UK.,Royal Free London NHS Foundation Trust Hospital, London, UK.,Plastic and Reconstructive Surgery Department, Royal Free Hospital, University College London, Pond Street, London, UK
| | - P E Butler
- UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, UK.,Royal Free London NHS Foundation Trust Hospital, London, UK.,Plastic and Reconstructive Surgery Department, Royal Free Hospital, University College London, Pond Street, London, UK
| | - A M Seifalian
- UCL Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College London, London, UK.,Director/Professor Nanotechnology & Regenerative Medicine, NanoRegMed Ltd, London, UK
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35
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Stem cells out of the bag: characterization of ex vivo expanded mesenchymal stromal cells for possible clinical use. Future Sci OA 2020; 6:FSO449. [PMID: 32140248 PMCID: PMC7050601 DOI: 10.2144/fsoa-2019-0129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in establishing a MSC expansion protocol is the large volume of bone marrow (BM) required. We studied whether cells trapped within a collection bag and filter system could be considered as a source of MSC. Results: From the 20 BM collection bag and filter systems, we recovered an average of 1.68 × 108 mononuclear cells, which is the equivalent to 60 ml of filtered BM. Mononuclear cells were expanded ex vivo to 17 × 106 MSC, with purity shown by a CD44+, CD105+, CD90+ and CD73+ immunophenotype, a reduction of 20% proliferating cells in a mixed lymphocyte reaction and also the ability of adipocyte differentiation. Conclusion: Long-term MSC cultures were established from the usually discarded BM collection bag and filter, maintaining an appropriate phenotype and function, being suitable for both investigation and clinical settings. Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in obtaining MSC is the large volume of bone marrow (BM) required from a healthy donor. From usually discarded collection bags of BM collected for transplant, we recovered a number of cells equivalent to 60 ml of BM and expanded functional MSC with high purity. We believe that those recovered cells are an alternative to BM for obtaining MSC. The routinely recovery of such cells in reference centers, in a way similar to a public cord-blood bank, could benefit the scientific community, once further research is conducted to confirm results.
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36
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Muraya K, Kawasaki T, Yamamoto T, Akutsu H. Enhancement of Cellular Adhesion and Proliferation in Human Mesenchymal Stromal Cells by the Direct Addition of Recombinant Collagen I Peptide to the Culture Medium. Biores Open Access 2019; 8:210-218. [PMID: 31763065 PMCID: PMC6873350 DOI: 10.1089/biores.2019.0012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have considerable potential for a wide range of clinical applications and regenerative medicine and cell therapy. As a consequence, there is considerable interest in developing robust culture methods for producing large number of MSCs for use in repair of injured tissues or treatment of diseases. In general, tissue culture plates or flasks that have been precoated with substrates derived from animal tissues are used in the production of MSCs. However, these substrates can potentially cause serious problems due to contamination of the MSCs with animal-derived components. In this study, we evaluated the use of a type I collagen-based recombinant peptide (RCP) for MSC culture in an attempt to avoid the problems associated with animal cell-derived substances. This RCP is xeno free, has an increased RGD (Arg–Gly–Asp) sequence, and has high molecular weight uniformity. The effect of RCP on promotion of cellular adhesion and proliferation of MSCs was investigated in cultures in which RCP was included in the culture medium. The effects of RCP on promotion of cellular adhesion and proliferation of MSCs were investigated by comparing cultures in which the additive was present in the culture medium and those where the culture plates were coated with RCP. In addition, changes in gene expression profiles during cell culture were monitored by real time-polymerase chain reaction. Our analyses showed that RCP enhanced cellular adhesion and proliferation in cultures in which the additive was included in the culture medium. Our findings indicate that adding RCP to the culture medium could save time and cost in MSC culture. Our gene expression analysis indicated that RCP enhanced expression of genes encoding proteins associated with the extracellular matrix and cell adhesion.
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Affiliation(s)
- Koji Muraya
- Bioscience and Technology Development Center, FUJIFILM Corporation, Kanagawa, Japan
| | - Tomoyuki Kawasaki
- Department of Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Takeshi Yamamoto
- Bioscience and Technology Development Center, FUJIFILM Corporation, Kanagawa, Japan
| | - Hidenori Akutsu
- Department of Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan
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Kale VP. Application of "Primed" Mesenchymal Stromal Cells in Hematopoietic Stem Cell Transplantation: Current Status and Future Prospects. Stem Cells Dev 2019; 28:1473-1479. [PMID: 31559908 DOI: 10.1089/scd.2019.0149] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Regenerative potential of mesenchymal stem/stromal cells (MSCs) has led to their application in various cellular therapies. Since in vivo these cells are present in very low numbers, they need expansion in culture to get clinically relevant numbers; however, such long-term ex vivo manipulation leads to loss of their regenerative capacity. Although use of naïve MSCs is still the most common approach used in various therapies, several strategies, both genetic and pharmacological, are being tried out to boost the regenerative capacity of in vitro expanded MSCs. Such manipulations are very commonly reported for regeneration of various tissues like bone, cartilage, kidney, pancreas, and others. Likewise, several efforts have been made to investigate priming of MSCs to enhance their immunoregulatory activity, but such efforts have not been made to the same extent for enhancing the efficacy of hematopoietic stem cell transplantation (HSCT). Development of such approaches for HSCT would not only be useful for enhancing the transplantation efficacy of cord blood cells, which are fewer in numbers, and aged HSCs, which could be functionally compromised, but also for genetically modified HSCs, which are likely to be both, fewer in number and functionally compromised. This review specifically deals with application of "primed" MSCs in the scenario of HSCT.
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Affiliation(s)
- Vaijayanti P Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis School of Biological Sciences, Symbiosis International University, Pune, India
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38
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Cho KA, Lee HJ, Jeong H, Kim M, Jung SY, Park HS, Ryu KH, Lee SJ, Jeong B, Lee H, Kim HS. Tonsil-derived stem cells as a new source of adult stem cells. World J Stem Cells 2019; 11:506-518. [PMID: 31523370 PMCID: PMC6716082 DOI: 10.4252/wjsc.v11.i8.506] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 07/25/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Located near the oropharynx, the tonsils are the primary mucosal immune organ. Tonsil tissue is a promising alternative source for the high-yield isolation of adult stem cells, and recent studies have reported the identification and isolation of tonsil-derived stem cells (T-SCs) from waste surgical tissue following tonsillectomies in relatively young donors (i.e., under 10 years old). As such, T-SCs offer several advantages, including superior proliferation and a shorter doubling time compared to bone marrow-derived mesenchymal stem cells (MSCs). T-SCs also exhibit multi-lineage differentiation, including mesodermal, endodermal (e.g., hepatocytes and parathyroid-like cells), and even ectodermal cells (e.g., Schwann cells). To this end, numbers of researchers have evaluated the practical use of T-SCs as an alternative source of autologous or allogenic MSCs. In this review, we summarize the details of T-SC isolation and identification and provide an overview of their application in cell therapy and regenerative medicine.
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Affiliation(s)
- Kyung-Ah Cho
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07985, South Korea
| | - Hyun Jung Lee
- Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, South Korea
| | - Hansaem Jeong
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Miri Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Soo Yeon Jung
- Department of Otorhinolaryngology, College of Medicine, Ewha Womans University, Seoul 07985, South Korea
| | - Hae Sang Park
- Department of Otorhinolaryngology, College of Medicine, Hallym University, Chuncheon 24252, South Korea
| | - Kyung-Ha Ryu
- Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul 07985, South Korea
| | - Seung Jin Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Byeongmoon Jeong
- Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, South Korea
| | - Hyukjin Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Han Su Kim
- Department of Otorhinolaryngology, College of Medicine, Ewha Womans University, Seoul 07985, South Korea
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Vaidya A, Singh S, Limaye L, Kale V. Chimeric feeders of mesenchymal stromal cells and stromal cells modified with constitutively active AKT expand hematopoietic stem cells. Regen Med 2019; 14:535-553. [PMID: 31115264 DOI: 10.2217/rme-2018-0157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: To examine whether AKT-modified stromal cells expand human CD34+ hematopoietic stem cells (HSCs). Methods: Coculture, in vitro functional assays, immuno-fluorescence microscopy, flow cytometry. Results: M2-10B4 stromal cells (M2) modified with AKT1 (M2-AKT) expanded primitive CD34+38- HSCs, but affected their functionality. A chimeric feeder layer comprising naive human bone marrow-derived mesenchymal stromal cells and M2-AKT not only overcame the negative effects of M2-AKT, but, unexpectedly, also gave a synergistic effect on the growth and functionality of the HSCs. Conditioned medium of bone marrow stromal cells worked as effectively, but cell-cell contact between HSCs and M2-AKT cells was necessary for the synergistic effect of M2-AKT and bone marrow-derived mesenchymal stromal cells or their CM. Conclusion: Chimeric feeders expand HSCs.
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Affiliation(s)
- Anuradha Vaidya
- Stem Cell Lab, National Centre for Cell Science, Pune 411007, India.,Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune 412115, India.,Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune 412115, India
| | - Shweta Singh
- Stem Cell Lab, National Centre for Cell Science, Pune 411007, India
| | - Lalita Limaye
- Stem Cell Lab, National Centre for Cell Science, Pune 411007, India
| | - Vaijayanti Kale
- Stem Cell Lab, National Centre for Cell Science, Pune 411007, India.,Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune 412115, India
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40
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Chamberlain CS, Clements AEB, Kink JA, Choi U, Baer GS, Halanski MA, Hematti P, Vanderby R. Extracellular Vesicle-Educated Macrophages Promote Early Achilles Tendon Healing. Stem Cells 2019; 37:652-662. [PMID: 30720911 PMCID: PMC6850358 DOI: 10.1002/stem.2988] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 12/14/2018] [Accepted: 01/21/2019] [Indexed: 12/20/2022]
Abstract
Tendon healing follows a complex series of coordinated events, which ultimately produces a mechanically inferior tissue more scar‐like than native tendon. More regenerative healing occurs when anti‐inflammatory M2 macrophages play a more dominant role. Mesenchymal stromal/stem cells (MSCs) are able to polarize macrophages to an M2 immunophenotype via paracrine mechanisms. We previously reported that coculture of CD14+ macrophages (MQs) with MSCs resulted in a unique M2‐like macrophage. More recently, we generated M2‐like macrophages using only extracellular vesicles (EVs) isolated from MSCs creating “EV‐educated macrophages” (also called exosome‐educated macrophages [EEMs]), thereby foregoing direct use of MSCs. For the current study, we hypothesized that cell therapy with EEMs would improve in vivo tendon healing by modulating tissue inflammation and endogenous macrophage immunophenotypes. We evaluated effects of EEMs using a mouse Achilles tendon rupture model and compared results to normal tendon healing (without any biologic intervention), MSCs, MQs, or EVs. We found that exogenous administration of EEMs directly into the wound promoted a healing response that was significantly more functional and more regenerative. Injured tendons treated with exogenous EEMs exhibited (a) improved mechanical properties, (b) reduced inflammation, and (c) earlier angiogenesis. Treatment with MSC‐derived EVs alone were less effective functionally but stimulated a biological response as evidenced by an increased number of endothelial cells and decreased M1/M2 ratio. Because of their regenerative and immunomodulatory effects, EEM treament could provide a novel strategy to promote wound healing in this and various other musculoskeletal injuries or pathologies where inflammation and inadequate healing is problematic. Stem Cells2019;37:652–662
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Affiliation(s)
- Connie S Chamberlain
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Anna E B Clements
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - John A Kink
- Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA
| | - Ugeun Choi
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA
| | - Geoffrey S Baer
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Matthew A Halanski
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA
| | - Ray Vanderby
- Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA
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41
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Sharma A, Mawrie D, Magdalene D, Jaganathan BG. Isolation of Multipotent Mesenchymal Stem Cells from Human Extraocular Muscle Tissue. Bio Protoc 2019; 9:e3167. [PMID: 33654973 DOI: 10.21769/bioprotoc.3167] [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: 12/12/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 11/02/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have attracted significant attention as potential therapeutic cells to treat various diseases ranging from tissue injuries, graft versus host disease, degenerative diseases and cancer. Since the initial discovery of MSCs in the bone marrow cells, MSCs have been successfully isolated from various adult and neo-natal tissues, albeit the procedures are often coupled with difficulties in harvesting tissue and produce low yield of cells, requiring extensive expansion in vitro. Here, we explored extra-ocular muscle tissues obtained from patients as a novel source of MSCs which express characteristic cell surface markers of MSCs and show multilineage differentiation potential with high proliferation capacity.
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Affiliation(s)
- Amit Sharma
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
| | - Darilang Mawrie
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
| | - Damaris Magdalene
- Department of Pediatric Ophthalmology, Sri Sankaradeva Nethralaya, Guwahati, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Group, Department of Biosciences and Bioengineering, Guwahati, India
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42
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Unveiling Mesenchymal Stromal Cells' Organizing Function in Regeneration. Int J Mol Sci 2019; 20:ijms20040823. [PMID: 30769851 PMCID: PMC6413004 DOI: 10.3390/ijms20040823] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/03/2019] [Accepted: 02/11/2019] [Indexed: 12/16/2022] Open
Abstract
Regeneration is a fundamental process attributed to the functions of adult stem cells. In the last decades, delivery of suspended adult stem cells is widely adopted in regenerative medicine as a leading means of cell therapy. However, adult stem cells cannot complete the task of human body regeneration effectively by themselves as far as they need a receptive microenvironment (the niche) to engraft and perform properly. Understanding the mechanisms underlying mammalian regeneration leads us to an assumption that improved outcomes of cell therapy require a specific microenvironment that is generated in damaged areas prior to stem cell delivery. To a certain extent, it may be achieved by the delivery of mesenchymal stromal cells (MSCs), not in dispersed form, but rather in self-organized cell sheets (CS) ⁻ tissue-like structures comprised of viable cells and microenvironment components: extracellular matrix and soluble factors deposited in the matrix. In this review, we highlight the potential role of MSCs as regeneration organizers and speculate that this function emerges in CS. This concept shifts our understanding of the therapeutic mechanism underlying a widely known CS-based delivery method for regenerative medicine.
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Yadak R, Breur M, Bugiani M. Gastrointestinal Dysmotility in MNGIE: from thymidine phosphorylase enzyme deficiency to altered interstitial cells of Cajal. Orphanet J Rare Dis 2019; 14:33. [PMID: 30736844 PMCID: PMC6368792 DOI: 10.1186/s13023-019-1016-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 01/31/2019] [Indexed: 12/24/2022] Open
Abstract
Background MNGIE is a rare and fatal disease in which absence of the enzyme thymidine phosphorylase induces systemic accumulation of thymidine and deoxyuridine and secondary mitochondrial DNA alterations. Gastrointestinal (GI) symptoms are frequently reported in MNGIE patients, however, they are not resolved with the current treatment interventions. Recently, our understanding of the GI pathology has increased, which rationalizes the pursuit of more targeted therapeutic strategies. In particular, interstitial cells of Cajal (ICC) play key roles in GI physiology and are involved in the pathogenesis of the GI dysmotility. However, understanding of the triggers of ICC deficits in MNGIE is lacking. Herein, we review the current knowledge about the pathology of GI dysmotility in MNGIE, discuss potential mechanisms in relation to ICC loss/dysfunction, remark on the limited contribution of the current treatments, and propose intervention strategies to overcome ICC deficits. Finally, we address the advances and new research avenues offered by organoids and tissue engineering technologies, and propose schemes to implement to further our understanding of the GI pathology and utility in regenerative and personalized medicine in MNGIE. Conclusion Interstitial cells of Cajal play key roles in the physiology of the gastrointestinal motility. Evaluation of their status in the GI dysmotility related to MNGIE would be valuable for diagnosis of MNGIE. Understanding the underlying pathological and molecular mechanisms affecting ICC is an asset for the development of targeted prevention and treatment strategies for the GI dysmotility related to MNGIE.
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Affiliation(s)
- Rana Yadak
- Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Marjolein Breur
- Department of Child Neurology, VU University Medical center, Amsterdam, The Netherlands
| | - Marianna Bugiani
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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Abu-Khader A, Law KW, Jahan S, Manesia JK, Pasha R, Hovey O, Pineault N. Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties. Stem Cells 2018; 37:345-356. [PMID: 30520180 DOI: 10.1002/stem.2956] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 11/05/2018] [Accepted: 11/14/2018] [Indexed: 12/27/2022]
Abstract
Ex vivo expansion of hematopoietic stem cell (HSCs) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood transplantation. Serum-free medium conditioned with osteoblasts (i.e., osteoblast-conditioned medium [OCM]) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets in mice transplanted with OCM-expanded progenitors. Herein, we characterized the cellular and molecular mechanisms responsible for these osteoblast-derived properties. Limiting dilution transplantation assays revealed that osteoblasts secrete soluble factors that synergize with exogenously added cytokines to promote the production of progenitors with short-term platelet engraftment activities, and to a lesser extent with long-term platelet engraftment activities. OCM also modulated the expression repertoire of cell-surface receptors implicated in the trafficking of HSC and progenitors to the bone marrow. Furthermore, OCM contains growth factors with prosurvival and proliferation activities that synergized with stem cell factor. Insulin-like growth factor (IGF)-2 was found to be present at higher levels in OCM than in control medium conditioned with MSC. Inhibition of the IGF-1 receptor, which conveys IGF-2' intracellular signaling, largely abolished the growth-promoting activity of OCM on immature CD34+ subsets and progenitors in OCM cultures. Finally, IGF-1R effects appear to be mediated in part by the coactivator β-catenin. In summary, these results provide new insights into the paracrine regulatory activities of osteoblasts on HSC, and how these can be used to modulate the engraftment properties of human HSC and progenitors expanded in culture. Stem Cells 2019;37:345-356.
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Affiliation(s)
- Ahmad Abu-Khader
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada.,Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan
| | - Kyle W Law
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada
| | - Suria Jahan
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada.,Biochemistry, Microbiology, and Immunology Department, University of Ottawa, Ottawa, Canada
| | - Javed K Manesia
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada
| | - Roya Pasha
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada
| | - Owen Hovey
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada.,Biochemistry, Microbiology, and Immunology Department, University of Ottawa, Ottawa, Canada
| | - Nicolas Pineault
- Canadian Blood Services, Centre for Innovation, Ottawa, Ontario, Canada.,Biochemistry, Microbiology, and Immunology Department, University of Ottawa, Ottawa, Canada
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Bone marrow MSCs in MDS: contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia 2018; 33:1487-1500. [PMID: 30575819 PMCID: PMC6756222 DOI: 10.1038/s41375-018-0310-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/15/2018] [Accepted: 10/16/2018] [Indexed: 01/13/2023]
Abstract
The study of myelodysplastic syndromes (MDS) in murine models has now indicated the possible involvement of the bone marrow microenvironment in the generation of dysplastic hematopoietic cells. However, there is scant work on patient samples and the role of hypomethylating agents on the bone marrow stromal cells of MDS patients is unclear. We show that human MDS-MSCs exhibit phenotypic, transcriptomic and epigenetic abnormalities. Stimuli provided by MDS-MSCs impaired the growth and function of healthy HSPCs, which is further sustained autonomously in HSPCs for significant periods of time resulting in a failure for active hematopoietic engraftment across primary and secondary transplant recipients (chimerism: 0.34–91% vs 2.78%, engraftment frequencies: at 0.06 ± 0.02 vs full engraftment for MDS-MSC vs healthy groups, respectively). Hypomethylation of MDS-MSCs improved overall engraftment in most of the MDS-MSC groups tested (2/7 with p < 0.01, 3/7 with p < 0.05 and 2/7 with no significant difference). MDS-MSCs that fail to respond to hypomethylating therapy are associated with patients with rapid adverse disease transformation and this further suggests that MDS-MSCs may be an integral part of disease progression and have prognostic value as well as potential as a therapeutic target.
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Maxillary Sinus Lift Using Autologous Periosteal Micrografts: A New Regenerative Approach and a Case Report of a 3-Year Follow-Up. Case Rep Dent 2018; 2018:3023096. [PMID: 30140472 PMCID: PMC6081519 DOI: 10.1155/2018/3023096] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/14/2018] [Indexed: 12/30/2022] Open
Abstract
This case report discusses about an innovative bone regeneration method that involves the use of autologous periosteal micrografts, which were used for a maxillary sinus floor lift in a 52-year-old female patient. This method allows for harvesting of a graft that is to be seeded on a PLGA scaffold and involves collection of a very little amount of palatal periosteal tissue in the same surgical site after elevation of a flap and disaggregation of it by using a Rigenera® filter. Histological samples collected at the time of implant installation demonstrate a good degree of bone regeneration. The clinical and radiographic outcomes at the 3-year follow-up visit showed an adequate stability of hard and soft tissues around the implants. This report demonstrates the possibility to obtain a sufficient quality and quantity of bone with a progenitor cell-based micrograft and in turn make the site appropriate for an implant-supported rehabilitation procedure, with stable results over a period of two years.
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Nanobiosensing Platforms for Real-Time and Non-Invasive Monitoring of Stem Cell Pluripotency and Differentiation. SENSORS 2018; 18:s18092755. [PMID: 30134637 PMCID: PMC6163950 DOI: 10.3390/s18092755] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/17/2018] [Accepted: 08/17/2018] [Indexed: 01/05/2023]
Abstract
Breakthroughs in the biomedical and regenerative therapy fields have led to the influential ability of stem cells to differentiate into specific types of cells that enable the replacement of injured tissues/organs in the human body. Non-destructive identification of stem cell differentiation is highly necessary to avoid losses of differentiated cells, because most of the techniques generally used as confirmation tools for the successful differentiation of stem cells can result in valuable cells becoming irrecoverable. Regarding this issue, recent studies reported that both Raman spectroscopy and electrochemical sensing possess excellent characteristics for monitoring the behavior of stem cells, including differentiation. In this review, we focus on numerous studies that have investigated the detection of stem cell pluripotency and differentiation in non-invasive and non-destructive manner, mainly by using the Raman and electrochemical methods. Through this review, we present information that could provide scientific or technical motivation to employ or further develop these two techniques for stem cell research and its application.
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Comparison of Hematopoietic and Spermatogonial Stem Cell Niches from the Regenerative Medicine Aspect. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1107:15-40. [PMID: 29882209 DOI: 10.1007/5584_2018_217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Bello AB, Park H, Lee SH. Current approaches in biomaterial-based hematopoietic stem cell niches. Acta Biomater 2018; 72:1-15. [PMID: 29578087 DOI: 10.1016/j.actbio.2018.03.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 02/07/2018] [Accepted: 03/14/2018] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) are multipotent progenitor cells that can differentiate and replenish blood and immune cells. While there is a growing demand for autologous and allogeneic HSC transplantation owing to the increasing incidence of hereditary and hematologic diseases, the low population of HSCs in cord-blood and bone marrow (the main source of HSCs) hinders their medical applicability. Several cytokine and growth factor-based methods have been developed to expand the HSCs in vitro; however, the expansion rate is low, or the expanded cells fail to survive upon engraftment. This is at least in part because the overly simplistic polystyrene culture substrates fail to fully replicate the microenvironments or niches where these stem cells live. Bone marrow niches are multi-dimensional, complex systems that involve both biochemical (cells, growth factors, and cytokines) and physiochemical (stiffness, O2 concentration, and extracellular matrix presentation) factors that regulate the quiescence, proliferation, activation, and differentiation of the HSCs. Although several studies have been conducted on in vitro HSC expansion via 2D and 3D biomaterial-based platforms, additional work is required to engineer an effective biomaterial platform that mimics bone marrow niches. In this study, the factors that regulate the HSC in vivo were explained and their applications in the engineering of a bone marrow biomaterial-based platform were discussed. In addition, current approaches, challenges, and the future direction of a biomaterial-based culture and expansion of the HSC were examined. STATEMENT OF SIGNIFICANCE Hematopoietic stem cells (HSC) are multipotent cells that can differentiate and replace the blood and immune cells of the body. However, in vivo, there is a low population of these cells, and thus their use in biotherapeutic and medical applications is limited (i.e., bone marrow transplantation). In this review, the biochemical factors (growth factors, cytokines, co-existing cells, ECM, gas concentrations, and differential gene expression) that may regulate the over-all fate of HSC, in vivo, were summarized and discussed. Moreover, different conventional and recent biomaterial platforms were reviewed, and their potential in generating a biomaterial-based, BM niche-mimicking platform for the efficient growth and expansion of clinically relevant HSCs in-vitro, was discussed.
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Affiliation(s)
- Alvin Bacero Bello
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea; Department of Biomedical Science, CHA University, Seongnam-Si 13488, Republic of Korea
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea.
| | - Soo-Hong Lee
- Department of Biomedical Science, CHA University, Seongnam-Si 13488, Republic of Korea.
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Timari H, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Pashoutan Sarvar D, Aqmasheh S. The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate. Adv Pharm Bull 2017; 7:531-546. [PMID: 29399543 PMCID: PMC5788208 DOI: 10.15171/apb.2017.065] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/25/2017] [Accepted: 11/28/2017] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.
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Affiliation(s)
- Hamze Timari
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliakbar Movassaghpour
- Hematology Oncology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sara Aqmasheh
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
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