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Saadh MJ, Hussein A, Bayani A, Dastafkan S, Amiri M, Akbari A, Shahsavan S, Soleimani Samarkhazan H, Shirani Asl V. Mesenchymal stem cell-derived exosomes: a novel therapeutic frontier in hematological disorders. Med Oncol 2025; 42:199. [PMID: 40327167 DOI: 10.1007/s12032-025-02742-0] [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: 02/11/2025] [Accepted: 04/23/2025] [Indexed: 05/07/2025]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells valued for their immunomodulatory and regenerative properties, positioning them as a cornerstone of regenerative medicine. Their derived exosomes small extracellular vesicles laden with bioactive molecules such as proteins, lipids, and nucleic acids have emerged as critical mediators of MSC therapeutic effects. This review systematically explores the biology of MSC-derived exosomes, detailing their biogenesis, molecular composition, and pivotal roles in hematopoiesis, inflammation, and immune regulation. In hematological disorders, including leukemia, lymphoma, and myelodysplastic syndromes, these exosomes exhibit significant therapeutic potential by modulating the tumor microenvironment, enhancing hematopoietic recovery, and suppressing malignant cell proliferation. Notable findings include their ability to induce cell cycle arrest in leukemia cells via the p53 pathway and to reduce chemoresistance through targeted signaling mechanisms, such as the IRF2/INPP4B axis. However, clinical translation is hindered by several challenges, including the standardization of isolation techniques such as ultracentrifugation which are costly and susceptible to contamination as well as difficulties in optimizing large-scale production and ensuring long-term safety and efficacy. Despite these obstacles, MSC-derived exosomes offer a promising, cell-free therapeutic alternative that minimizes risks such as immune rejection and tumorigenicity associated with whole-cell therapies. Future research must prioritize the refinement of isolation and production protocols, the development of precise delivery strategies, and the execution of comprehensive safety evaluations to unlock their full clinical potential in treating hematological disorders and beyond. This review integrates recent advancements to provide a clearer understanding of their multifaceted contributions and highlights the critical gaps that remain.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Ahmed Hussein
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | - Alireza Bayani
- Division of Hematology and Blood Bank, Department of Laboratory Science, School of Paramedical Science, Shiraz University of Med1ical Sciences, Shiraz, Iran
| | - Shayan Dastafkan
- Student Research Committee, Guilan University of Medical Sciences, Rasht, Iran
| | - Mahdie Amiri
- Department of Laboratory Sciences, Lahijan Branch, Islamic Azad University, Lahijan, Iran
| | - Atie Akbari
- Department of Family Medicine, School of Medicine, Ziaeian Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Shaghayegh Shahsavan
- HSCT Research Center, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Vida Shirani Asl
- Division of Hematology and Blood Bank, Department of Laboratory Science, School of Paramedical Science, Shiraz University of Med1ical Sciences, Shiraz, Iran.
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Kemna K, van der Burg M, Lankester A, Giera M. Hematopoietic stem cell metabolism within the bone marrow niche - insights and opportunities. Bioessays 2025; 47:e2400154. [PMID: 39506498 PMCID: PMC11755706 DOI: 10.1002/bies.202400154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/25/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024]
Abstract
Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo-SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies.
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Affiliation(s)
- Koen Kemna
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Mirjam van der Burg
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Arjan Lankester
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Martin Giera
- Center for Proteomics and MetabolomicsLeiden University Medical CenterLeidenThe Netherlands
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Romão CM, de Lara Janz F, Ruiz JLM, Lopes MAB, Cristante AF, de Barros Filho TEP, Levy D, Bydlowski SP. Expression of ABCB1, ABCC1, and LRP in Mesenchymal Stem Cells from Human Amniotic Fluid and Bone Marrow in Culture-Effects of In Vitro Osteogenic and Adipogenic Differentiation. Int J Mol Sci 2025; 26:510. [PMID: 39859227 PMCID: PMC11765172 DOI: 10.3390/ijms26020510] [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: 11/28/2024] [Revised: 12/27/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into various lineages. They have also the potential to protect themselves against harmful stimuli to maintain their functional integrity. Drug resistance-related transporters such as ABCB1 (P-glycoprotein; P-gp), ABCC1 (MRP1; multidrug resistance-related Protein 1), and LRP (lung resistance protein) may protect MSCs against toxic substances such as chemotherapeutic agents. This study evaluated ABCB1, ABCC1, and LRP before and after the differentiation of MSCs derived from human amniotic fluid (AF) and bone marrow (BM). P-gp expression in both AFMSCs and BMMSCs was analyzed by immunocytochemistry, and pump function was analyzed by cell viability assay with doxorubicin (DOX) and Rhodamine 123 (Rh 123) dye exclusion. ABCB1, ABCC1, and LRP gene expression was determined by RT-PCR both before and after osteogenic and adipogenic differentiation. The MES-SA/DX5 cell line was used as a model of resistance to DOX and the overexpression of P-gp. Both AFMSCs and BMMSCs displayed a high P-gp expression, although lower than MES-SA/DX5 control cells. It was shown that both, undifferentiated AFMSCs and BMMSCs, have high cell viability in response to DOX, similar to the MES-SA/DX5 lineage. ABCB1 was less expressed in BM than in AFMSCs in undifferentiated samples, while no differences were observed in the expression of ABCC1 and LRP. AFMSCs showed an increase in ABCB1 after osteogenic differentiation, whereas BMMSCs exhibited lower ABCB1 and ABCC1 expression after osteogenic and adipogenic differentiation. The findings suggest that ABCB1, ABCC1, and LRP gene expression in AFMSCs and BMMSCs is influenced by differentiation processes and further support the concept that these transporters modulate MSC differentiation in a cell source-dependent way.
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Affiliation(s)
- Carolina Martinez Romão
- Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo 05403-900, Brazil; (C.M.R.); (D.L.)
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil
| | - Felipe de Lara Janz
- General Biology Department, State University of Ponta Grossa (UEPG), Ponta Grossa 84010-330, Brazil;
| | - Jorge Luis Maria Ruiz
- Latin American Institute of Life and Natural Sciences, Federal University for Latin American Integration (UNILA), Foz do Iguaçu 85870-650, Brazil;
| | - Marco Antônio Borges Lopes
- Laboratory of Obstetric Physiology, Department of Obstetrics and Gynecology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil;
| | - Alexandre Fogaça Cristante
- Department of Orthopedics and Traumatology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05402-000, Brazil; (A.F.C.); (T.E.P.d.B.F.)
| | - Tarcísio Eloy Pessoa de Barros Filho
- Department of Orthopedics and Traumatology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05402-000, Brazil; (A.F.C.); (T.E.P.d.B.F.)
| | - Débora Levy
- Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo 05403-900, Brazil; (C.M.R.); (D.L.)
| | - Sérgio Paulo Bydlowski
- Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo 05403-900, Brazil; (C.M.R.); (D.L.)
- National Institute of Science and Technology in Regenerative Medicine (INCT-Regenera), CNPq, Rio de Janeiro 21941-902, Brazil
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Mohseni A, Salehi F, Rostami S, Hadiloo K, Hashemi M, Baridjavadi Z, Ahangari F, Karami N, Samani F, Tahmasebi S, Farahani N, Taheriazam A. Harnessing the power of exosomes for diagnosis, prognosis, and treatment of hematological malignancies. Stem Cell Res Ther 2025; 16:6. [PMID: 39773361 PMCID: PMC11708188 DOI: 10.1186/s13287-024-04125-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Exosomes are small extracellular vesicles of endocytic origin released by various cell types. They consist of lipid bilayers containing macromolecules such as lipids, proteins, microRNAs, growth factors, cytokines, and carbohydrates. Exosomes play a critical role in the diagnosis and treatment of various diseases. For instance, exosome contents have been utilized as biomarkers in body fluids (urine, saliva, serum) to identify cancers, autoimmune diseases, and inflammatory conditions such as sepsis. Due to their small size and ability to reach tumor microenvironments, exosomes are also used as carriers for chemotherapeutic drugs in drug delivery systems. Furthermore, evidence indicates that malignant cells release exosomes into the tumor microenvironment, influencing immune cells in a paracrine manner. Additionally, immune cell-derived exosomes, such as those from Natural Killer (NK) cells or cytotoxic T lymphocytes (CTLs), show potential as therapeutic agents in treating malignancies like leukemia. This review discusses the diagnostic role of exosomes in various hematological malignancies and explores the therapeutic potential of immune cell-derived exosomes in these diseases.
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Affiliation(s)
- Amirata Mohseni
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Fatemeh Salehi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Samaneh Rostami
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Kaveh Hadiloo
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Baridjavadi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Ahangari
- Department of Immunology, Pasteur Institue of Iran, Tehran, Iran
| | - Najibeh Karami
- Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Samani
- Blood Transfusion Research Center, High Institute for Research and Education in transfusion medicine, Iranian Blood Transfusion Organization (IBTO), Tehran, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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5
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Kasherwal V, Kale V, Vaidya A. Extracellular vesicles secreted by leukemic cells as mediators of dysregulated hematopoiesis: acute myeloid leukemia as a case in point. Expert Rev Hematol 2025; 18:225-237. [PMID: 40008450 DOI: 10.1080/17474086.2025.2471860] [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: 10/26/2024] [Revised: 01/23/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
INTRODUCTION Acute myeloid leukemia (AML) cells exhibit a profound capacity for resistance to conventional chemotherapeutic agents, posing a substantial challenge to existing therapeutic paradigms. Interestingly, this happens in the face of a luxuriant proliferation of leukemic blasts in the peripheral blood. This paradox of concurrent proliferative activity and cellular quiescence underscores a complex biological phenomenon that is intricately mediated by AML-derived Extracellular vesicles (EVs). AREAS COVERED An extensive literature review search was done on PubMed/Scopus/Web of Sciences databases to identify studies published between 2013 and 2024 elucidating and demonstrating the effect of AML-derived EVs, Microvesicles (MVs) and Exosomes (Exos) in regulating the normal and dysregulated bone marrow (BM) niche. EXPERT OPINION The review delves into understanding the molecular mechanisms underlying the dual behavior of AML cells - proliferation and quiescence, with a special focus on the role of the EVs and their subtypes viz. Exos and MVs in establishing a discrete BM microenvironment that is subversive to chemotherapy. It offers a novel perspective on the intricate interplay between the leukemic cells and their microenvironment, with implications for therapeutic interventions targeting AML persistence and drug resistance.
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Affiliation(s)
- Vishakha Kasherwal
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
| | - Anuradha Vaidya
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, India
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6
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Patel MZ, Jiang Y, Kakumani PK. Somatic piRNA and PIWI-mediated post-transcriptional gene regulation in stem cells and disease. Front Cell Dev Biol 2024; 12:1495035. [PMID: 39717847 PMCID: PMC11663942 DOI: 10.3389/fcell.2024.1495035] [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: 09/11/2024] [Accepted: 11/25/2024] [Indexed: 12/25/2024] Open
Abstract
PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that bind to the PIWI subclass of the Argonaute protein family and are essential for maintaining germline integrity. Initially discovered in Drosophila, PIWI proteins safeguard piRNAs, forming ribonucleoprotein (RNP) complexes, crucial for regulating gene expression and genome stability, by suppressing transposable elements (TEs). Recent insights revealed that piRNAs and PIWI proteins, known for their roles in germline maintenance, significantly influence mRNA stability, translation and retrotransposon silencing in both stem cells and bodily tissues. In the current review, we explore the multifaceted roles of piRNAs and PIWI proteins in numerous biological contexts, emphasizing their involvement in stem cell maintenance, differentiation, and the development of human diseases. Additionally, we discussed the up-and-coming animal models, beyond the classical fruit fly and earthworm systems, for studying piRNA-PIWIs in self-renewal and cell differentiation. Further, our review offers new insights and discusses the emerging roles of piRNA-dependent and independent functions of PIWI proteins in the soma, especially the mRNA regulation at the post-transcriptional level, governing stem cell characteristics, tumor development, and cardiovascular and neurodegenerative diseases.
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Affiliation(s)
| | | | - Pavan Kumar Kakumani
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL, Canada
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Garbayo E, El Moukhtari SH, Rodríguez-Nogales C, Agirre X, Rodriguez-Madoz JR, Rodriguez-Marquez P, Prósper F, Couvreur P, Blanco-Prieto MJ. RNA-loaded nanoparticles for the treatment of hematological cancers. Adv Drug Deliv Rev 2024; 214:115448. [PMID: 39303823 DOI: 10.1016/j.addr.2024.115448] [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: 02/19/2024] [Revised: 06/07/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
Hematological cancers encompass a diverse group of malignancies affecting the blood, bone marrow, lymph nodes, and spleen. These disorders present unique challenges due to their complex etiology and varied clinical manifestations. Despite significant advancements in understanding and treating hematological malignancies, innovative therapeutic approaches are continually sought to enhance patient outcomes. This review highlights the application of RNA nanoparticles (RNA-NPs) in the treatment of hematological cancers. We delve into detailed discussions on in vitro and preclinical studies involving RNA-NPs for adult patients, as well as the application of RNA-NPs in pediatric hematological cancer. The review also addresses ongoing clinical trials involving RNA-NPs and explores the emerging field of CAR-T therapy engineered by RNA-NPs. Finally, we discuss the challenges still faced in translating RNA-NP research to clinics.
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Affiliation(s)
- Elisa Garbayo
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain
| | - Souhaila H El Moukhtari
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain
| | - Carlos Rodríguez-Nogales
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain
| | - Xabier Agirre
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Juan R Rodriguez-Madoz
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Paula Rodriguez-Marquez
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Felipe Prósper
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain; Hemato-Oncology Program, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pío XII 55, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain; Departmento de Hematología and CCUN, Clínica Universidad de Navarra, University of Navarra, Avenida Pío XII 36, 31008 Pamplona, Spain
| | - Patrick Couvreur
- Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Saclay, Orsay Cedex, France.
| | - María J Blanco-Prieto
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN). Avenida Pio XII 36, 31008 Pamplona, Spain.
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Shil RK, Mohammed NBB, Dimitroff CJ. Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma. Front Immunol 2024; 15:1469794. [PMID: 39386209 PMCID: PMC11461229 DOI: 10.3389/fimmu.2024.1469794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its involvement in immune homeostasis and cancer biology with an emphasis on multiple myeloma (MM) pathophysiology, highlighting its complex and context-dependent dual functions as a pro- and anti-tumorigenic molecule and its potential implications for therapy in MM patients.
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Affiliation(s)
- Rajib K. Shil
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Norhan B. B. Mohammed
- The Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, United States
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Charles J. Dimitroff
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
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Srivastava J, Kundal K, Rai B, Saxena P, Katiyar S, Tripathy N, Yadav S, Gupta R, Kumar R, Nityanand S, Chaturvedi CP. Global microRNA profiling of bone marrow-MSC derived extracellular vesicles identifies miRNAs associated with hematopoietic dysfunction in aplastic anemia. Sci Rep 2024; 14:19654. [PMID: 39179703 PMCID: PMC11343855 DOI: 10.1038/s41598-024-70369-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 08/16/2024] [Indexed: 08/26/2024] Open
Abstract
Recently, we have reported that extracellular vesicles (EVs) from the bone marrow mesenchymal stromal cells (BM-MSC) of aplastic anemia (AA) patients inhibit hematopoietic stem and progenitor cell (HSPC) proliferative and colony-forming ability and promote apoptosis. One mechanism by which AA BM-MSC EVs might contribute to these altered HSPC functions is through microRNAs (miRNAs) encapsulated in EVs. However, little is known about the role of BM-MSC EVs derived miRNAs in regulating HSPC functions in AA. Therefore, we performed miRNA profiling of EVs from BM-MSC of AA (n = 6) and normal controls (NC) (n = 6) to identify differentially expressed miRNAs. The Integrated DEseq2 analysis revealed 34 significantly altered mature miRNAs, targeting 235 differentially expressed HSPC genes in AA. Hub gene analysis revealed 10 HSPC genes such as IGF-1R, IGF2R, PAK1, PTPN1, etc., which are targeted by EV miRNAs and had an enrichment of chemokine, MAPK, NK cell-mediated cytotoxicity, Rap1, PI3k-Akt, mTOR signalling pathways which are associated with hematopoietic homeostasis. We further showed that miR-139-5p and its target, IGF-1R (hub-gene), might regulate HSPC proliferation and apoptosis, which may serve as potential therapeutic targets in AA. Overall, the study highlights that AA BM-MSC EV miRNAs could contribute to impaired HSPC functions in AA.
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Affiliation(s)
- Jyotika Srivastava
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Kavita Kundal
- Computational Genomics and Transcriptomics Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Kandi, Hyderabad, 502285, Telangana, India
| | - Bhuvnesh Rai
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Pragati Saxena
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Shobhita Katiyar
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Naresh Tripathy
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Sanjeev Yadav
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Ruchi Gupta
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India
| | - Rahul Kumar
- Computational Genomics and Transcriptomics Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, Kandi, Hyderabad, 502285, Telangana, India
| | - Soniya Nityanand
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India.
- King George's Medical University, Lucknow, India.
| | - Chandra Prakash Chaturvedi
- Department of Hematology, Stem Cell Research Center, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Barely Road, Lucknow, 226014, Uttar Pradesh, India.
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Fathi E, Valipour B, Jafari S, Kazemi A, Montazersaheb S, Farahzadi R. The role of the hematopoietic stem/progenitor cells-derived extracellular vesicles in hematopoiesis. Heliyon 2024; 10:e35051. [PMID: 39157371 PMCID: PMC11327835 DOI: 10.1016/j.heliyon.2024.e35051] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/20/2024] Open
Abstract
Hematopoietic stem cells (HSCs) are tightly regulated by specific microenvironments called niches to produce an appropriate number of mature blood cell types. Self-renewal and differentiation are two hallmarks of hematopoietic stem and progenitor cells, and their balance is critical for proper functioning of blood and immune cells throughout life. In addition to cell-intrinsic regulation, extrinsic cues within the bone marrow niche and systemic factors also affect the fate of HSCs. Despite this, many paracrine and endocrine factors that influence the function of hematopoietic cells remain unknown. In hematological malignancies, malignant cells remodel their niche into a permissive environment to enhance the survival of leukemic cells. These events are accompanied by loss of normal hematopoiesis. It is well known that extracellular vehicles (EVs) mediate intracellular interactions under physiological and pathological conditions. In other words, EVs transfer biological information to surrounding cells and contribute not only to physiological functions but also to the pathogenesis of some diseases, such as cancers. Therefore, a better understanding of cell-to-cell interactions may lead to identification of potential therapeutic targets. Recent reports have suggested that EVs are evolutionarily conserved constitutive mediators that regulate hematopoiesis. Here, we focus on the emerging roles of EVs in normal and pathological conditions, particularly in hematological malignancies. Owing to the high abundance of EVs in biological fluids, their potential use as biomarkers and therapeutic tools is discussed.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behnaz Valipour
- Department of Basic Sciences and Health, Sarab Faculty of Medical Sciences, Sarab, Iran
| | - Sevda Jafari
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abdolhassan Kazemi
- Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Parasitology and Mycology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Aytekin A, Yazir Y, Duruksu G, Öztürk A. Comparison of aquaporin profile of advanced passage mesenchymal stem cells with early passage mesenchymal stem cells and determination of its effect on adipogenic differentiation efficiency. Tissue Cell 2024; 89:102448. [PMID: 38917601 DOI: 10.1016/j.tice.2024.102448] [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: 05/02/2024] [Revised: 06/11/2024] [Accepted: 06/14/2024] [Indexed: 06/27/2024]
Abstract
OBJECTIVE Our study aimed to compare aquaporin profiles in advanced and early passage bone marrow-derived mesenchymal stem cells (BM-MSCs) and assess the impact of aquaporin changes after adipogenic differentiation. Aquaporins are crucial for stem cell survival and differentiation during their life cycle. We focused on the role of aquaporins in the cell structures of advanced and early passage stem cells. METHODS In our study, BM-MSCs were used for our objectives. Characterization of the cells was evaluated via flow cytometry using stem cell surface markers. The characterized BM-MSCs were divided into control and differentiation groups at passages 3 (P3) and 8 (P8). AQP1, AQP3, AQP7, AQP9, and AQP10 expression levels on days 0, 1, 3, 7, 14, and 21 were evaluated using Real Time-PCR, ELISA, and immunofluorescence studies. RESULTS The cells were characterized by flow cytometry and confirmed to exhibit BM-MSC characteristics. At P3 and P8, differentiation was initiated, and AQP protein expression was observed to initially increase and then decrease on subsequent days. The increase in AQP protein expression at P3 occurred earlier than that at P8. Gene expression analysis demonstrated a statistically significant increase in AQP gene expression on days when AQP protein expression decreased. Moreover, statistical differences were observed between late and early passage AQP profiles. CONCLUSION Our study examined the composition of AQPs in BM-MSCs in association with cell passage, and found that AQPs play a role in the differentiation process. The connection between the AQP profile and aging might be related to differentiation capacity, which could have implications for slowing down cellular aging and developing new therapeutic approaches.
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Affiliation(s)
- Ayşegül Aytekin
- Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Yusufhan Yazir
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey; Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University, Kocaeli, Turkey; Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey.
| | - Gökhan Duruksu
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey; Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University, Kocaeli, Turkey
| | - Ahmet Öztürk
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey; Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University, Kocaeli, Turkey; Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
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12
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Eroz I, Kakkar PK, Lazar RA, El-Jawhari J. Mesenchymal Stem Cells in Myelodysplastic Syndromes and Leukaemia. Biomedicines 2024; 12:1677. [PMID: 39200142 PMCID: PMC11351218 DOI: 10.3390/biomedicines12081677] [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: 06/26/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 09/01/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM) and have an essential role in the regulation of haematopoietic stem cell (HSC) differentiation and proliferation. Myelodysplastic syndromes (MDSs) are a group of myeloid disorders impacting haematopoietic stem and progenitor cells (HSCPs) that are characterised by BM failure, ineffective haematopoiesis, cytopenia, and a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as in cell cycle arrest and pro-tumorigenic roles including the induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, and immunomodulation function and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators abnormally secreted by MSCs, including increased expression of inflammatory factors and decreased expression of haematopoietic factors, contributing to the development and progression of MDSs. Therefore, MSCs can be targeted for the treatment of MDSs and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.
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Affiliation(s)
- Ilayda Eroz
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Prabneet Kaur Kakkar
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Renal Antoinette Lazar
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Jehan El-Jawhari
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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13
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Wang L, Wang L, Wang R, Xu T, Wang J, Cui Z, Cheng F, Wang W, Yang X. Endometrial stem cell-derived exosomes repair cisplatin-induced premature ovarian failure via Hippo signaling pathway. Heliyon 2024; 10:e31639. [PMID: 38831834 PMCID: PMC11145543 DOI: 10.1016/j.heliyon.2024.e31639] [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: 12/16/2023] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/05/2024] Open
Abstract
Stem cells have been documented as a new therapeutic method for ovarian injuries such as premature ovarian failure (POF). However, effects of exosomes (Exos) derived from human endometrial stem cells (EnSCs) on diminished ovarian failure remain to be carefully elucidated. Our study aims to investigate the mechanisms of EnSC-Exos in the recovery of the cisplatin-induced granulosa cell injury model in vitro or POF mouses model in vivo and whether the Hippo signaling pathway is involved in the regulation. In this study, we established successful construction of the cisplatin-induced granulosa cell injury model and evaluated Hippo signaling pathway activation in cisplatin-damaged granulosa cells (GCs). Furthermore, laser scanning confocal microscope and immunofluorescence demonstrated that EnSC-Exos can be transferred to cisplatin-damaged GCs to decrease apoptosis. In addition, the enhanced expression of YAP at the protein level as well as YAP/TEAD target genes, such as CTGF, ANKRD1, and the increase of YAP into the nucleus in immunofluorescence staining after the addition of EnSC-Exos to cisplatin-damaged GCs confirmed the suppression of Hippo signaling pathway. While in vivo, EnSC-Exos successfully remedied POF in a mouse model. Collectively, our findings suggest that chemotherapy-induced POF was associated with the activating of Hippo signaling pathway. Human EnSC-Exos significantly elevated the proliferation of ovarian GCs and the ovarian function by regulating Hippo signaling pathway. These findings provide new insights for further understanding of EnSC-Exos in the recovery of ovary function.
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Affiliation(s)
- Lijun Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Lihui Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Rongli Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Ting Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Jingyuan Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Zhiwei Cui
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Feiyan Cheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Wei Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Xinyuan Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, China
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14
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Wang X, Li A, Fan H, Li Y, Yang N, Tang Y. Astrocyte-Derived Extracellular Vesicles for Ischemic Stroke: Therapeutic Potential and Prospective. Aging Dis 2024; 15:1227-1254. [PMID: 37728588 PMCID: PMC11081164 DOI: 10.14336/ad.2023.0823-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/23/2023] [Indexed: 09/21/2023] Open
Abstract
Stroke is a leading cause of death and disability in the world. Astrocytes are special glial cells within the central nervous system and play important roles in mediating neuroprotection and repair processes during stroke. Extracellular vesicles (EVs) are lipid bilayer particles released from cells that facilitate intercellular communication in stroke by delivering proteins, lipids, and RNA to target cells. Recently, accumulating evidence suggested that astrocyte-derived EVs (ADEVs) are actively involved in mediating numerous biological processes including neuroprotection and neurorepair in stroke and they are realized as an excellent therapeutic approach for treating stroke. In this review we systematically summarize the up-to-date research on ADEVs in stroke, and prospects for its potential as a novel therapeutic target for stroke. We also provide an overview of the effects and functions of ADEVs on stroke recovery, which may lead to developing clinically relevant therapies for stroke.
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Affiliation(s)
- Xianghui Wang
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Aihua Li
- Department of rehabilitation medicine, Jinan Hospital, Jinan, China
| | - Huaju Fan
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
| | - Yanyan Li
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
| | - Nana Yang
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Yaohui Tang
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
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15
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Wang L, Wang W, Hu D, Liang Y, Liu Z, Zhong T, Wang X. Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives. Front Immunol 2024; 15:1346587. [PMID: 38690261 PMCID: PMC11058222 DOI: 10.3389/fimmu.2024.1346587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/03/2024] [Indexed: 05/02/2024] Open
Abstract
Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.
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Affiliation(s)
- Lijuan Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weihua Wang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yan Liang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhanyu Liu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoling Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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16
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Wu CH, Weng TF, Li JP, Wu KH. Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia. Int J Mol Sci 2024; 25:2527. [PMID: 38473775 DOI: 10.3390/ijms25052527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs' role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs' biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies.
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Affiliation(s)
- Cheng-Hsien Wu
- School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Te-Fu Weng
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ju-Pi Li
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Kang-Hsi Wu
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
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17
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Fuest S, Salviano-Silva A, Maire CL, Xu Y, Apel C, Grust ALC, Delle Coste A, Gosau M, Ricklefs FL, Smeets R. Doping of casted silk fibroin membranes with extracellular vesicles for regenerative therapy: a proof of concept. Sci Rep 2024; 14:3553. [PMID: 38347108 PMCID: PMC10861453 DOI: 10.1038/s41598-024-54014-y] [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: 12/15/2023] [Accepted: 02/07/2024] [Indexed: 02/15/2024] Open
Abstract
Bioactive material concepts for targeted therapy have been an important research focus in regenerative medicine for years. The aim of this study was to investigate a proof-of-concept composite structure in the form of a membrane made of natural silk fibroin (SF) and extracellular vesicles (EVs) from gingival fibroblasts. EVs have multiple abilities to act on their target cell and can thus play crucial roles in both physiology and regeneration. This study used pH neutral, degradable SF-based membranes, which have excellent cell- and tissue-specific properties, as the carrier material. The characterization of the vesicles showed a size range between 120 and 180 nm and a high expression of the usual EV markers (e.g. CD9, CD63 and CD81), measured by nanoparticle tracking analysis (NTA) and single-EV flow analysis (IFCM). An initial integration of the EVs into the membrane was analyzed using scanning and transmission electron microscopy (SEM and TEM) and vesicles were successfully detected, even if they were not homogeneously distributed in the membrane. Using direct and indirect tests, the cytocompatibility of the membranes with and without EVs could be proven and showed significant differences compared to the toxic control (p < 0.05). Additionally, proliferation of L929 cells was increased on membranes functionalized with EVs (p > 0.05).
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Affiliation(s)
- Sandra Fuest
- Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
| | - Amanda Salviano-Silva
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Cecile L Maire
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Yong Xu
- Department of Biohybrid and Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute of RWTH Aachen University and Hospital, 52074, Aachen, Germany
| | - Christian Apel
- Department of Biohybrid and Medical Textiles (BioTex), AME - Institute of Applied Medical Engineering, Helmholtz Institute of RWTH Aachen University and Hospital, 52074, Aachen, Germany
| | - Audrey Laure Céline Grust
- Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Arianna Delle Coste
- Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Martin Gosau
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Franz L Ricklefs
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ralf Smeets
- Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
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18
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Somadder R, Faraj L, Datta S, Kanapathipillai M, Ghosh G. Effect of extracellular matrices on production and potency of mesenchymal stem cell-derived exosomes. Biotechnol J 2024; 19:e2300474. [PMID: 38403471 DOI: 10.1002/biot.202300474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/17/2023] [Accepted: 12/23/2023] [Indexed: 02/27/2024]
Abstract
Mesenchymal stem cell (MSC) derived exosomes have emerged as potential acellular therapeutics for various tissue regenerative applications. However, successful clinical translation of exosome-based therapy is limited by lack of a structured production platform. Thus, in this study, the effect of decellularized extracellular matrix (dECM) was assessed on the production and potency of exosomes secreted by bone marrow-derived human MSCs. The results indicate that there was a ∼2-fold increase in MSC-exosome production when MSCs were cultured on dECM compared to TCP. Further, our study revealed that dECM generation induced by ascorbic acid (AA) up to 100 µg mL-1 highly increased exosome yield thereby indicating a potential scale up method for MSC exosome production. The bioactivity of exosomes was investigated by their ability to improve the healing of wounded human skin explants. Wound closure was enhanced in the presence of exosomes isolated from MSCs cultured on ascorbic acid-induced dECM compared to TCP generated MSC-exosomes. In summary, this study suggests a promising solution to a major bottleneck in large-scale production of MSC exosomes for cell-free therapy.
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Affiliation(s)
- Rittika Somadder
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan-Dearborn, Dearborn, Michigan, USA
| | - Lina Faraj
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan-Dearborn, Dearborn, Michigan, USA
| | - Saurav Datta
- Amgen Bioprocessing Center, Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, California, USA
| | - Mathumai Kanapathipillai
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan-Dearborn, Dearborn, Michigan, USA
| | - Gargi Ghosh
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan-Dearborn, Dearborn, Michigan, USA
- Amgen Bioprocessing Center, Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, California, USA
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19
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Chaudhary JK, Ahamad N, Rath PC. Mesenchymal stem cells (MSCs) from the mouse bone marrow show differential expression of interferon regulatory factors IRF-1 and IRF-2. Mol Biol Rep 2024; 51:97. [PMID: 38194130 DOI: 10.1007/s11033-023-09025-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Interferon regulatory factors (IRF-1 and IRF-2) are transcription factors widely implicated in various cellular processes, including regulation of inflammatory responses to pathogens, cell proliferation, oncogenesis, differentiation, autophagy, and apoptosis. METHODS We have studied the expression of IRF-1, IRF-2 mRNAs by RT-PCR, cellular localization of the proteins by immunofluorescence, and expression of mRNAs of genes regulated by IRF-1, IRF-2 by RT-PCR in mouse bone marrow cells (BMCs) and mesenchymal stem cells (MSCs). RESULTS Higher level of IRF-1 mRNA was observed in BMCs and MSCs compared to that of IRF-2. Similarly, differential expression of IRF-1 and IRF-2 proteins was observed in BMCs and MSCs. IRF-1 was predominantly localized in the cytoplasm, whereas IRF-2 was localized in the nuclei of BMCs. MSCs showed nucleo-cytoplasmic distribution of IRF-1 and nuclear localization of IRF-2. Constitutive expression of IRF-1 and IRF-2 target genes: monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and caspase-1 was observed in both BMCs and MSCs. MSCs showed constitutive expression of the pluripotency-associated factors, Oct3/4 and Sox-2. Lipopolysaccharide (LPS)-treatment of MSCs induced prominent cellular localization of IRF-1 and IRF-2. CONCLUSIONS Our results suggest that IRF-1 and IRF-2 exhibit differential expression of their mRNAs and subcellular localization of the proteins in BMCs and MSCs. These cells also show differential levels of constitutive expression of IRF-1 and IRF-2 target genes. This may regulate immune-responsive properties of BMCs and MSCs through IRF-1, IRF-2-dependent gene expression and protein-protein interaction. Regulating IRF-1 and IRF-2 may be helpful for immunomodulatory functions of MSCs for cell therapy and regenerative medicine.
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Affiliation(s)
- Jitendra Kumar Chaudhary
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Naseem Ahamad
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Pramod C Rath
- Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
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20
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Zhao F, Fan Z, Jia R, Liu Q, Wang M, Sui J, Liu H. Mesenchymal Stem Cells Accelerate Recovery of Acetic Acid-Induced Chronic Gastric Ulcer by Regulating Ekt/Akt/TRIM29 Axis. Stem Cells Int 2024; 2024:6202123. [PMID: 38213743 PMCID: PMC10781525 DOI: 10.1155/2024/6202123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 11/08/2023] [Accepted: 12/07/2023] [Indexed: 01/13/2024] Open
Abstract
Chronic gastric ulcer (CGU), a prevalent digestive disease, has a high incidence and is seriously harmful to human health. Mesenchymal stem cells (MSCs) have been proven to have beneficial therapeutic effects in many human diseases. Here, a CGU model induced by acetic acid in mice was used to evaluate the repair effects and potential mechanism of human umbilical cord-derived MSCs (hUC-MSCs) and hUC-MSCs derived conditioned medium (hUC-MSC-CM). We found that hUC-MSCs and hUC-MSC-CM treatment significantly repaired morphological characteristics of CGU, improved proliferation and decreased apoptosis of gastric cells, and promoted the generation of new blood vessels in granulation tissues. In addition, we could detect the homing of MSCs in gastric tissue, and MSCs may differentiate into Lgr5-positive cells. As well as this, in vitro experiments showed that hUC-MSC-CM could promote cell proliferation, stimulate cell cycle progression, and reduce the incidence of apoptosis. The transcriptome of cells and the iTRAQ proteome of gastric tissues suggest that MSCs may play a therapeutic role by increasing the expression of TRIM29. Additionally, it was found that knocking down TRIM29 significantly decreased the ameliorative effects of hUC-MSC-CM on cell apoptosis. As a result of further molecular experiments, it was found that TRIM29 is capable of phosphorylating Erk/Akt in specific cell type. As a whole, it appears that hUC-MSCs can be an effective therapeutic approach for promoting gastric ulcer healing and may exert therapeutic effects in the form of paracrine and differentiation into gastric cells.
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Affiliation(s)
- Feiyue Zhao
- Handan Pharmaceutical Co. Ltd., Handan, Hebei Province, China
- Key Laboratory of Chinese Medicine for Gastric Medicine, Handan, Hebei Province, China
| | - Zhibin Fan
- Handan Pharmaceutical Co. Ltd., Handan, Hebei Province, China
| | - Ruikang Jia
- Handan Pharmaceutical Co. Ltd., Handan, Hebei Province, China
| | - Qichao Liu
- Handan Pharmaceutical Co. Ltd., Handan, Hebei Province, China
| | - Menglei Wang
- Key Laboratory of Chinese Medicine for Gastric Medicine, Handan, Hebei Province, China
| | - Jianliang Sui
- School of Life Science and Food Engineering, Hebei University of Engineering, Handan, Hebei Province, China
| | - Huiyun Liu
- Handan Pharmaceutical Co. Ltd., Handan, Hebei Province, China
- Key Laboratory of Chinese Medicine for Gastric Medicine, Handan, Hebei Province, China
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Zhang C, Jiang C, Jin J, Lei P, Cai Y, Wang Y. Cartilage fragments combined with BMSCs-Derived exosomes can promote tendon-bone healing after ACL reconstruction. Mater Today Bio 2023; 23:100819. [PMID: 37810754 PMCID: PMC10550801 DOI: 10.1016/j.mtbio.2023.100819] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 09/11/2023] [Accepted: 09/23/2023] [Indexed: 10/10/2023] Open
Abstract
Anterior cruciate ligament reconstruction (ACLR) often fails due to the inability of tendon-bone integration to regenerate normal tissues and formation of fibrous scar tissues in the tendon-bone interface. Cartilage fragments and exosomes derived from bone mesenchymal stromal cells (BMSCs-Exos) can enhance enthesis healing. Nevertheless, the effects on the tendon-bone healing of ACLR remain unknown. This study found that BMSCs-Exos can promote the proliferation of chondrocytes in cartilage fragments, and activated the expression of chondro-related genes SOX9 and Aggrecan. The optimal effect concentration was 1012 events/uL. Besides, BMSCs-Exos could significantly upregulated the expression of BMP7 and Smad5 in cartilage fragments, and further enhanced the expression of chondrogenic genes. Moreover, this study established a rat model of ACLR and implanted the BMSCs-Exos/cartilage fragment complex into the femoral bone tunnel. Results demonstrated that the mean diameters of the femoral bone tunnels were significantly smaller in the BE-CF group than those in the CF group (p = 0.038) and control group (p = 0.007) at 8 weeks after surgery. Besides, more new bone formation was observed in the femoral tunnels in the BE-CF group, as demonstrated by a larger BV/TV ratio based on the reconstructed CT scans. Histological results also revealed the regeneration of tendon-bone structures, especially fibrocartilage. Thus, these findings provide a promising result that BMSCs-Exos/cartilage fragment complex can prevent the enlargement of bone tunnel and promote tendon-bone healing after ACLR, which may have resulted from the regulation of the BMP7/Smad5 signaling axis.
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Affiliation(s)
- Chi Zhang
- Center for Sports Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310008, China
- Institute of Sports Medicine of Zhejiang University, 388 Yuhangtang Road, Hangzhou, 310030, China
| | - Chao Jiang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiale Jin
- Center for Sports Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310008, China
| | - Pengfei Lei
- Center for Sports Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310008, China
| | - Youzhi Cai
- Center for Sports Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310008, China
- Institute of Sports Medicine of Zhejiang University, 388 Yuhangtang Road, Hangzhou, 310030, China
| | - Yue Wang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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22
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Wang H, Bi X, Zhang R, Yuan H, Xu J, Zhang K, Qi S, Zhang X, Jiang M. Adipose-Derived Mesenchymal Stem Cell Facilitate Hematopoietic Stem Cell Proliferation via the Jagged-1/Notch-1/Hes Signaling Pathway. Stem Cells Int 2023; 2023:1068405. [PMID: 38020206 PMCID: PMC10653966 DOI: 10.1155/2023/1068405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 08/29/2023] [Accepted: 09/25/2023] [Indexed: 12/01/2023] Open
Abstract
Background Poor graft function (PGF) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Current therapies, such as CD34+ cell infusion, have shown limited effectiveness. Conversely, mesenchymal stem cells (MSCs) show potential in addressing PGF. Adipose-derived mesenchymal stem cells (ADSCs) effectively support long-term hematopoietic stem cell proliferation. Therefore, this study aimed to investigate the mechanisms underlying the long-term hematopoietic support provided by ADSCs. Methods ADSCs were isolated from mice and subsequently identified. In vitro experiments involved coculturing ADSCs as feeders with Lin-Sca-1+c-kit+ (LSK) cells from mice for 2 and 5 weeks. The number of LSK cells was quantified after coculture. Scanning electron microscopy was utilized to observe the interaction between ADSCs and LSK cells. Hes-1 expression was assessed using western blot and real-time quantitative PCR. An γ-secretase inhibitor (GSI) was used to confirm the involvement of the Jagged-1/Notch-1/Hes-1 pathway in LSK cell expansion. Additionally, Jagged-1 was knocked down in ADSCs to demonstrate its significance in ADSC-mediated hematopoietic support. In vivo experiments were conducted to study the hematopoietic support provided by ADSCs through the infusion of LSK, LSK + fibroblasts, and LSK + ADSCs, respectively. Mouse survival, platelet count, leukocyte count, and hemoglobin levels were monitored. Results ADSCs showed high-Jagged-1 expression and promoted LSK cell proliferation. There was a direct interaction between ADSCs and LSK cells. After coculture, Hes-1 expression increased in LSK cells. Moreover, GSI-reduced LSK cell proliferation and Hes-1 expression. Knockdown of Jagged-1 attenuated ADSCs-mediated promotion of LSK cell proliferation. Furthermore, ADSCs facilitated hematopoietic recovery and promoted the survival of NOD/SCID mice. Conclusion The hematopoietic support provided by ADSCs both in vivo and in vitro may be mediated, at least in part, through the Jagged-1/Notch-1 signaling pathway. These findings provide valuable insights into the mechanisms underlying ADSCs-mediated hematopoietic support and may have implications for improving the treatment of PGF following HSCT.
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Affiliation(s)
- Hongbo Wang
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Xiaojuan Bi
- The State Key Laboratory of Pathogenesis and Prevention of Central Asian High Incidence Diseases, Institute of Clinical Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Rongyao Zhang
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Hailong Yuan
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Jianli Xu
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Kaile Zhang
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Songqing Qi
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Xue Zhang
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
| | - Ming Jiang
- Hematology Center, The First Affiliated Hospital of Xinjiang Medical University (Xinjiang Uygur Autonomous Region Institute of Hematology), Urumqi 830054, China
- Stem Cell Research Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
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Chen H, Yao H, Chi J, Li C, Liu Y, Yang J, Yu J, Wang J, Ruan Y, Pi J, Xu JF. Engineered exosomes as drug and RNA co-delivery system: new hope for enhanced therapeutics? Front Bioeng Biotechnol 2023; 11:1254356. [PMID: 37823027 PMCID: PMC10562639 DOI: 10.3389/fbioe.2023.1254356] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/05/2023] [Indexed: 10/13/2023] Open
Abstract
Chemotherapy often faces some obstacles such as low targeting effects and drug resistance, which introduce the low therapeutic efficiency and strong side effects. Recent advances in nanotechnology allows the use of novel nanosystems for targeted drug delivery, although the chemically synthesized nanomaterials always show unexpected low biocompability. The emergence of exosome research has offered a better understanding of disease treatment and created novel opportunities for developing effective drug delivery systems with high biocompability. Moreover, RNA interference has emerged as a promising strategy for disease treatments by selectively knocking down or over-expressing specific genes, which allows new possibilities to directly control cell signaling events or drug resistance. Recently, more and more interests have been paid to develop optimal delivery nanosystems with high efficiency and high biocompability for drug and functional RNA co-delivery to achieve enhanced chemotherapy. In light of the challenges for developing drug and RNA co-delivery system, exosomes have been found to show very attractive prospects. This review aims to explore current technologies and challenges in the use of exosomes as drug and RNA co-delivery system with a focus on the emerging trends and issues associated with their further applications, which may contribute to the accelerated developments of exosome-based theraputics.
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Affiliation(s)
- Haorong Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Hanbo Yao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiaxin Chi
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Chaowei Li
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yilin Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiayi Yang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiaqi Yu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiajun Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yongdui Ruan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Jun-Fa Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-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: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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Li H, Ren X, Pang X, Yang P, Lu Y, Guan F, Wang Y, Li X. LacNAc modification in bone marrow stromal cells enhances resistance of myelodysplastic syndrome cells to chemotherapeutic drugs. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119492. [PMID: 37207914 DOI: 10.1016/j.bbamcr.2023.119492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/03/2023] [Accepted: 05/10/2023] [Indexed: 05/21/2023]
Abstract
Chemotherapeutic drugs are used routinely for treatment for myelodysplastic syndrome (MDS) patients but are ineffective in a substantial proportion of patients. Abnormal hematopoietic microenvironments, in addition to spontaneous characteristics of malignant clones, contribute to ineffective hematopoiesis. In our study, we found expression of enzyme β1,4-galactosyltransferase 1 (β4GalT1), which regulates N-acetyllactosamine (LacNAc) modification of proteins, is elevated in bone marrow stromal cells (BMSCs) of MDS patients, and also contributes to drug ineffectiveness through a protective effect on malignant cells. Our investigation of the underlying molecular mechanism revealed that β4GalT1-overexpressing BMSCs promoted MDS clone cells resistant to chemotherapeutic drugs and also showed enhanced secretion of cytokine CXCL1 through degradation of tumor protein p53. Chemotherapeutic drug tolerance of myeloid cells was inhibited by application of exogenous LacNAc disaccharide and blocking of CXCL1. Our findings clarify the functional role of β4GalT1-catalyzed LacNAc modification in BMSCs of MDS. Clinical alteration of this process is a potential new strategy that may substantially enhance effectiveness of therapies for MDS and other malignancies, by targeting a niche interaction.
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Affiliation(s)
- Hongjiao Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Xiaoyue Ren
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Xingchen Pang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Pengyu Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Yurong Lu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, Shaanxi, China.
| | - Xiang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China; Institute of Hematology, School of Medicine, Northwest University, Xi'an, Shaanxi, China.
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Xie Z, Tang J, Chen Z, Wei L, Chen J, Liu Q. Human bone marrow mesenchymal stem cell-derived extracellular vesicles reduce inflammation and pyroptosis in acute kidney injury via miR-223-3p/HDAC2/SNRK. Inflamm Res 2023; 72:553-576. [PMID: 36640195 PMCID: PMC9840168 DOI: 10.1007/s00011-022-01653-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/23/2022] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) have been demonstrated as a potential therapeutic agent in acute kidney injury (AKI). However, little is known about the mechanisms of action of BMSC-derived EVs in AKI. Based on this, our research was designed to investigate the mechanism behind BMSC-derived EVs controlling inflammation and pyroptosis during AKI. METHODS Peripheral blood from AKI patients was used for detection of microRNA (miR)-223-3p, HDAC2, and SNRK expression. An AKI rat model was established, and HK-2 cell injury was induced by lipopolysaccharide (LPS) to establish a cellular model. Co-culture with BMSC-derived EVs and/or gain- and loss-of-function assays were conducted in LPS-treated HK-2 to evaluate the functions of BMSCs-EVs, miR-223-3p, HDAC2, and SNRK. AKI rats were simultaneously injected with EVs and short hairpin RNAs targeting SNRK. The interactions among miR-223-3p, HDAC2, and SNRK were evaluated by RIP, ChIP, and dual-luciferase gene reporter assays. RESULTS Patients with AKI had low miR-223-3p and SNRK expression and high HDAC2 expression in peripheral blood. Mechanistically, miR-223-3p targeted HDAC2 to accelerate SNRK transcription. In LPS-treated HK-2 cells, BMSCs-EVs overexpressing miR-223-3p increased cell viability and diminished cell apoptosis, KIM-1, LDH, IL-1β, IL-6, TNF-α, NLRP3, ASC, cleaved caspase-1, and IL-18 expression, and GSDMD cleavage, which was nullified by HDAC2 overexpression or SNRK silencing. In AKI rats, BMSCs-EV-shuttled miR-223-3p reduced CRE and BUN levels, apoptosis, inflammation, and pyroptosis, which was abrogated by SNRK silencing. CONCLUSION Conclusively, BMSC-derived EV-encapsulated miR-223-3p mitigated AKI-induced inflammation and pyroptosis by targeting HDAC2 and promoting SNRK transcription.
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Affiliation(s)
- Zhijuan Xie
- Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Jun Tang
- Department of Emergency, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Zhong Chen
- Department of Nuclear Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Lanji Wei
- Health Management Center, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Jianying Chen
- Department of Rheumatology and Immunology, Hunan Province Mawangdui Hospital, Changsha, 410016, Hunan, People's Republic of China
| | - Qin Liu
- Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China.
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Draguet F, Bouland C, Dubois N, Bron D, Meuleman N, Stamatopoulos B, Lagneaux L. Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review. Pharmaceutics 2023; 15:pharmaceutics15020558. [PMID: 36839879 PMCID: PMC9964668 DOI: 10.3390/pharmaceutics15020558] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/29/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompatible, non-immunogenic, and stable in circulation, and they are able to cross biological barriers. Furthermore, EVs have a great potential for drug delivery. Different EV isolation protocols and loading methods have been tested and compared. Published and ongoing clinical trials, and numerous preclinical studies indicate that EVs are safe and well tolerated. Moreover, the latest studies suggest their applications as nanocarriers. The current review will describe the potential for MSC-derived EVs as drug delivery systems (DDS) in disease treatment, and their advantages. Thereafter, we will outline the different EV isolation methods and loading techniques, and analyze relevant preclinical studies. Finally, we will describe ongoing and published clinical studies. These elements will outline the benefits of MSC-derived EV DDS over several aspects.
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Affiliation(s)
- Florian Draguet
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
- Correspondence:
| | - Cyril Bouland
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
- Department of Stomatology and Maxillofacial Surgery, Saint-Pierre Hospital, 322 Rue Haute, 1000 Brussels, Belgium
- Department of Maxillofacial and Reconstructive Surgery, Grand Hôpital de Charleroi, 3 Grand’Rue, 6000 Charleroi, Belgium
| | - Nathan Dubois
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
| | - Dominique Bron
- Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
- Department of Haematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
- Medicine Faculty, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Basile Stamatopoulos
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
- Medicine Faculty, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy (LCCT), Jules Bordet Institute, Université Libre de Bruxelles (ULB), 90 Rue Meylemeersch, 1070 Brussels, Belgium
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Li H, Gu J, Sun X, Zuo Q, Li B, Gu X. Isolation of Swine Bone Marrow Lin-/CD45-/CD133 + Cells and Cardio-protective Effects of its Exosomes. Stem Cell Rev Rep 2023; 19:213-229. [PMID: 35925437 PMCID: PMC9822881 DOI: 10.1007/s12015-022-10432-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND The identification in murine bone marrow (BM) of CD133 + /Lin-/CD45- cells, possessing several features of pluripotent stem cells, encouraged us to investigate if similar population of cells could be also isolated from the swine BM. Heart failure is the terminal stage of many cardiovascular diseases, and its key pathological basis is cardiac fibrosis (CF). Research showed that stem cell derived exosomes may play a critical role in cardiac fibrosis. The effect of exosomes (Exos) on CF has remained unclear. OBJECTIVE To establish an isolation and amplification method of CD133 + /Lin-/CD45- cells from newbron swine BM in vitro, explore an highly efficient method to enrich swine bone marrow derived CD133 + /Lin-/CD45- cells and probe into their biological characteristics further. Furher more, to extract exosomes from it and explore its effect on CF. METHODS The mononuclear cells isolated from swine bone marrow by red blood cell (RBC) lysing buffer were coated by adding FcR blocking solution and coupled with CD133 antibody immunomagnetic beads, obtaining CD133 + cell group via Magnetic Activated Cell Sorting (MACS). In steps, the CD133 + /Lin-/CD45- cells were collected by fluorescence-activated cell sorting (FACS) labeled with CD133, Lin and CD45 antibodies, which were cultured and amplified in vitro. The biological features of CD133 + /Lin-/CD45- cells were studied in different aspects, including morphological trait observed with inverted microscope, ultrastructural characteristics observed under transmission electron microscope, expression of pluripotent markersidentified by immunofluorescent staining and Alkaline phosphatase staining. The Exos were extracted using a sequential centrifugation approach and its effects on CF were analyzed in Angiotensin II (Ang-II) induced-cardiac fibrosis in vivo. Rats in each group were treated for 4 weeks, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE) and Masson's trichrome staining. RESULTS The CD133 + /Lin-/CD45- cells accounted for about 0.2%-0.5% of the total mononuclear cells isolated from swine bone marrow. The combination of MACS and FACS to extract CD133 + /Lin-/CD45- cells could improved efficiency and reduced cell apoptosis. The CD133 + /Lin-/CD45- cells featured typical traits of pluripotent stem cells, the nucleus is large, mainly composed of euchromatin, with less cytoplasm and larger nucleoplasmic ratio, which expressed pluripotent markers (SSEA-1, Oct-4, Nanog and Sox-2) and alkaline phosphatase staining was positive.Animal experiment indicated that the cardiac injury related indexes (BNP、cTnI、CK-MB and TNF-α), the expression of key gene Smad3 and the degree of cardiac fibrosis in Exo treatment group were significantly reduced compared with the control group. 4 weeks after the treatment, cardiac ejection fraction (EF) value in the model group showed a remarkable decrease, indicating the induction of HF model. While Exo elevated the EF values, demonstrating cardio-protective effects. CONCLUSION The CD133 + /Lin-/CD45- cells derived from swine bone marrow were successfully isolated and amplified, laying a good foundation for further research on this promising therapeutic cell. The Exos may be a promising potential treatment strategy for CF.
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Affiliation(s)
- Hongxiao Li
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Jianjun Gu
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Xiaolin Sun
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Qisheng Zuo
- College of Animal Science and Technology, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Bichun Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Xiang Gu
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China.
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China.
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Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia 2022; 36:2784-2792. [PMID: 36307485 PMCID: PMC9712109 DOI: 10.1038/s41375-022-01715-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/26/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022]
Abstract
Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow "hematopoietic" stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
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Affiliation(s)
- Peter J Quesenberry
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA.
| | - Sicheng Wen
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
| | - Laura R Goldberg
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
- Division of Hematology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mark S Dooner
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
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30
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Luo F, Guo W, Liu W. Exosomes derived from bone marrow mesenchymal stem cells inhibit human aortic vascular smooth muscle cells calcification via the miR-15a/15b/16/NFATc3/OCN axis. Biochem Biophys Res Commun 2022; 635:65-76. [DOI: 10.1016/j.bbrc.2022.09.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 09/15/2022] [Accepted: 09/19/2022] [Indexed: 12/15/2022]
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MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway. Int J Pharm 2022; 627:122214. [PMID: 36152993 DOI: 10.1016/j.ijpharm.2022.122214] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/05/2022] [Accepted: 09/16/2022] [Indexed: 11/21/2022]
Abstract
Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.
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Zhao Y, Chen Y, Wang Z, Xu C, Qiao S, Liu T, Qi K, Tong D, Li C. Bone Marrow Mesenchymal Stem Cell Exosome Attenuates Inflammasome-Related Pyroptosis via Delivering circ_003564 to Improve the Recovery of Spinal Cord Injury. Mol Neurobiol 2022; 59:6771-6789. [PMID: 36038697 DOI: 10.1007/s12035-022-03006-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/16/2022] [Indexed: 10/15/2022]
Abstract
Bone marrow mesenchymal stem cell (BMSC) is previously reported to present a certain effect on treating spinal cord injury (SCI), while the underlying mechanism is largely uncovered. Therefore, the current study aimed to investigate the involvement of exosome-delivered circRNA profile in the BMSC's effect on pyroptosis for SCI treatment. H2O2 treated rat primary neurons were cultured with normal medium, BMSC, BMSC plus GW4869, and BMSC-derived exosome, respectively, then inflammasome-related pyroptosis markers, and circRNA profiles were detected. Subsequently, circ_003564-knockdown BMSC exosome was transfected into H2O2 treated rat primary neurons and NGF-stimulated PC-12 cells. Furthermore, in vivo validation was conducted. BMSC and BMSC-derived exosome both decreased inflammasome-related pyroptosis markers including cleaved caspase-1, GSDMD, NLRP3, IL-1β, and IL-18 in H2O2-treated neurons, while exosome-free BMSC (BMSC plus GW4869) did not obviously reduce these factors. Microarray assay revealed that BMSC (vs. exosome-free BMSC) and BMSC-derived exosome (vs. normal medium) greatly regulated circRNA profiles, which were enriched in neuroinflammation pathways (such as neurotrophin, apoptosis, and TNF). Among three functional candidate circRNAs (circ_015525, circ_008876, and circ_003564), circ_003564 was most effective to regulate inflammasome-related pyroptosis. Interestingly, circ_003564-knockdown BMSC exosome showed higher expression of inflammasome-related pyroptosis markers compared to negative-control-knockdown BMSC exosome in H2O2 treated primary neurons/NGF-stimulated PC-12 cells. In vivo, BMSC exosome improved the function recovery and decreased tissue injury and inflammasome-related pyroptosis in SCI rats, whose effect was attenuated by circ_003564 knockdown transfection. BMSC exosome attenuates inflammasome-related pyroptosis via delivering circ_003564, contributing to its treatment efficacy for SCI.
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Affiliation(s)
- Yanyin Zhao
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yu Chen
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhiwei Wang
- Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
| | - Changli Xu
- Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
| | - Suchi Qiao
- Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Tianze Liu
- Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
| | - Ke Qi
- Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China
| | - Dake Tong
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Cheng Li
- Department of Orthopedics, Changhai Hospital, Naval Medical University, No. 168 Changhai Road, Shanghai, 200433, China.
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Zhang L, Lin Y, Zhang X, Shan C. Research progress of exosomes in orthopedics. Front Genet 2022; 13:915141. [PMID: 36081990 PMCID: PMC9445804 DOI: 10.3389/fgene.2022.915141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022] Open
Abstract
Exosomes are nano-extracellular vesicles secreted by a variety of cells. They are composed of a double-layer membrane that can transport a variety of proteins, coding and non-coding genes, and bioactive substances. Exosomes participate in information transmission between cells and regulate processes such as cell proliferation, migration, angiogenesis, and phenotypic transformation. They have broad prospects in the occurrence, development, and treatment of many diseases including orthopedics. Exosomes derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, osteoclasts, and their precursors are recognized to play pivotal roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. This articlesummarizes the characteristics of exosomes and their research progress in bone remodeling, bone tumors, vascular skeletal muscle injury, spinal cord injury, degenerative disc diseases, cartilage degeneration, osteoarthritis, necrosis of the femoral head, and osteoporosis.
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Srivastava J, Katiyar S, Chaturvedi CP, Nityanand S. Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34 + hematopoietic stem and progenitor cells. Cell Biol Int 2022; 46:1970-1976. [PMID: 35998254 DOI: 10.1002/cbin.11885] [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: 10/05/2021] [Revised: 05/30/2022] [Accepted: 07/25/2022] [Indexed: 11/07/2022]
Abstract
Mesenchymal stromal cells (MSC) regulate hematopoiesis in the bone marrow (BM) niche and extracellular vesicles (EVs) released by BM-MSC are important mediators of the cross-talk between BM-MSC and hematopoietic stem and progenitor cells (HSPC). We have previously demonstrated that BM-MSC of severe aplastic anemia (SAA) patients have an altered expression of hematopoiesis regulatory molecules. In the present study, we observed that CD34+ HSPC when cocultured with BM-MSC EVs from aplastic anemia patients exhibited a significant reduction in colony-forming units (p = .001), cell proliferation (p = .002), and increased apoptosis (p > .001) when compared to coculture with BM-MSC EVs from controls. Collectively, our results highlight that EVs derived from the BM-MSC of SAA patients impair the hematopoiesis supporting function of HSPC.
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Affiliation(s)
- Jyotika Srivastava
- Department of Hematology and Stem Cell Research Centre, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Shobhita Katiyar
- Department of Hematology and Stem Cell Research Centre, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Chandra P Chaturvedi
- Department of Hematology and Stem Cell Research Centre, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Soniya Nityanand
- Department of Hematology and Stem Cell Research Centre, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Su Y, Sun X, Liu X, Qu Q, Yang L, Chen Q, Liu F, Li Y, Wang Q, Huang B, Huang XH, Zhang XJ. hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype. J Hematol Oncol 2022; 15:99. [PMID: 35864538 PMCID: PMC9306027 DOI: 10.1186/s13045-022-01315-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/06/2022] [Indexed: 01/22/2023] Open
Abstract
Background Both extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Methods An aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4+ were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect. Results The clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4+ T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment. Conclusions hUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-022-01315-2.
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Affiliation(s)
- Yan Su
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Xueyan Sun
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Xiao Liu
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Qingyuan Qu
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Liping Yang
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Qi Chen
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Fengqi Liu
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China.,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.,Collaborative Innovation Center of Hematology, Peking University, Beijing, China.,National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Yueying Li
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Chinese Academy of Sciences, China National Center for Bioinformation, Beijing, China
| | - Qianfei Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Chinese Academy of Sciences, China National Center for Bioinformation, Beijing, China
| | - Bo Huang
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Hui Huang
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China. .,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China. .,Collaborative Innovation Center of Hematology, Peking University, Beijing, China. .,National Clinical Research Center for Hematologic Disease, Beijing, China.
| | - Xiao-Jun Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China. .,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China. .,Collaborative Innovation Center of Hematology, Peking University, Beijing, China. .,National Clinical Research Center for Hematologic Disease, Beijing, China.
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Cheng P, Cao T, Zhao X, Lu W, Miao S, Ning F, Wang D, Gao Y, Wang L, Pei G, Yang L. Nidogen1-enriched extracellular vesicles accelerate angiogenesis and bone regeneration by targeting Myosin-10 to regulate endothelial cell adhesion. Bioact Mater 2022; 12:185-197. [PMID: 35310379 PMCID: PMC8897190 DOI: 10.1016/j.bioactmat.2021.10.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022] Open
Abstract
The technique bottleneck of repairing large bone defects with tissue engineered bone is the vascularization of tissue engineered grafts. Although some studies have shown that extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) promote bone healing and repair by accelerating angiogenesis, the effector molecules and the mechanism remain unclear, which fail to provide ideas for the future research and development of cell-free interventions. Here, we found that Nidogen1-enriched EV (EV-NID1) derived from BMSCs interferes with the formation and assembly of focal adhesions (FAs) by targeting myosin-10, thereby reducing the adhesion strength of rat arterial endothelial cells (RAECs) to the extracellular matrix (ECM), and enhancing the migration and angiogenesis potential of RAECs. Moreover, by delivery with composite hydrogel, EV-NID1 is demonstrated to promote angiogenesis and bone regeneration in rat femoral defects. This study identifies the intracellular binding target of EV-NID1 and further elucidates a novel approach and mechanism, thereby providing a cell-free construction strategy with precise targets for the development of vascularized tissue engineering products.
Nidogen1 is enriched in extracellular vesicles (EV-NID1) derived from BMSCs. EV-NID1 interferes with the formation and assembly of focal adhesions (FAs). Myosin-10 was identified as the intracellular binding target of EV-NID1. The composite hydrogel loaded with EV-NID1 promotes the repair of bone defects by accelerating angiogenesis.
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Affiliation(s)
- Pengzhen Cheng
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Tianqing Cao
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xueyi Zhao
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Weiguang Lu
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Sheng Miao
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Fenru Ning
- Department of Neonatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Dong Wang
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yi Gao
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Long Wang
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Guoxian Pei
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
- Corresponding author.
| | - Liu Yang
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
- Corresponding author.
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A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2124627. [PMID: 35571252 PMCID: PMC9098338 DOI: 10.1155/2022/2124627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.
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Liu X, Hu L, Liu F. Mesenchymal stem cell-derived extracellular vesicles for cell-free therapy of ocular diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:102-117. [PMID: 39698446 PMCID: PMC11648472 DOI: 10.20517/evcna.2022.08] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/31/2022] [Accepted: 04/18/2022] [Indexed: 12/20/2024]
Abstract
Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have noticeably attracted clinicians' attention in treating ocular diseases. As the paracrine factor of MSCs and an alternative for cell-free therapies, MSC-EVs can be conveniently dropped over the ocular surface or diffused through the retina upon intravitreal injection, without increasing the risks of cellular rejection and tumor formation. For clinical translation, a standardized and scalable production, as well as reprogramming the MSC-EVs, are highly encouraged. This review aims to assess the potential approaches for EV production and functional modification, in addition to summarizing the worldwide clinical trials initiated for various physiological systems and the specific biochemical effects of MSC-EVs on the therapy of eye diseases. Recent advances in the therapy of ocular diseases based on MSC-EVs are reviewed, and the associated challenges and prospects are discussed as well.
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Affiliation(s)
- Xiaoling Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Liang Hu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Fei Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Science, Wenzhou 325000, Zhejiang, China
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Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, Wu J. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther 2022; 13:93. [PMID: 35246235 PMCID: PMC8895864 DOI: 10.1186/s13287-022-02751-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. Main body In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. Conclusion In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02751-0.
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Affiliation(s)
- Ying Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,Department of Gastroenterology, The First Hospital, Jilin University, Changchun, 130021, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,International Center of Future Science, Jilin University, Changchun, 130021, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liguang Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China. .,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
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Yuan P, Li Z, Shao B, Zeng T, Wu X, Wang Y, Zhao Y, Wu W. Extracellular vesicles derived from starving BMSCs enhance survival of chondrocyte aggregates in grafts by attenuating chondrocyte apoptosis and enabling stable cartilage regeneration for craniofacial reconstruction. Acta Biomater 2022; 140:659-673. [PMID: 34902618 DOI: 10.1016/j.actbio.2021.12.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/25/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022]
Abstract
The improvement of cell survival in cartilage tissue engineering remains a challenge, especially for large-sized, specifically shaped cartilage grafts used in reconstructing craniofacial defects. In this study, we found that bone marrow mesenchymal stem cells (BMSCs) pre-conditioned in a starving environment enhanced the anti-apoptosis potential of co-transplanted chondrocytes, which significantly enhanced their survival rates before host nutrition was resumed. Further examination revealed that extracellular vesicles (EVs) derived from starving BMSCs played essential roles in ameliorating apoptosis and regulating autophagy of chondrocytes, thereby enhancing the survival of cultured chondrocytes. In vivo studies demonstrated that EVs derived from starving BMSCs significantly improved the survival of chondrocyte bricks, which confirmed the effects of nasal augmentation. These pre-treated chondrocyte bricks showed continuous cartilage growth in vivo and acquired chondrogenesis comparable to that following the chondrocyte-BMSC co-transplantation approach. This study provided new insights on how BMSC-derived EVs improved cartilage reconstruction in the craniofacial regions and offered a new approach for regenerating cartilaginous organs based on cell macroaggregates. STATEMENT OF SIGNIFICANCE: The use of extracellular vesicles (EVs) of mesenchymal stem cells has been considered as a promising approach in cartilage tissue engineering. In the present study, for the first time, we investigated the protective effect of EVs secreted by starving bone marrow mesenchymal stem cells (BMSCs) on chondrocytes in vitro and in vivo. The results demonstrated that EVs secreted by starving BMSCs inhibited chondrocyte apoptosis and chondrocyte autophagy through many microRNAs, thereby improving the survival of grafts. Transcriptomic analysis revealed the potential mechanisms of this protective effect.
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Affiliation(s)
- Pingping Yuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China; Center of Oral Implantology, Inner Mongolia Autonomous Region People's Hospital & Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, China
| | - Zhiye Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Bo Shao
- Center of Oral Implantology, Inner Mongolia Autonomous Region People's Hospital & Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, China
| | - Tian Zeng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Xiaopeng Wu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Yinggang Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Yimin Zhao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Wei Wu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China.
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Wang BZ, Luo L, Vunjak-Novakovic G. RNA and Protein Delivery by Cell-Secreted and Bioengineered Extracellular Vesicles. Adv Healthc Mater 2022; 11:e2101557. [PMID: 34706168 PMCID: PMC8891029 DOI: 10.1002/adhm.202101557] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/28/2021] [Indexed: 12/22/2022]
Abstract
Extracellular vesicles (EVs) are carriers of biological signals through export and delivery of RNAs and proteins. Of increasing interest is the use of EVs as a platform for delivery of biomolecules. Preclinical studies have effectively used EVs to treat a number of diseases. Uniquely, endogenous machinery within cells can be manipulated in order to produce desirable loading of cargo within secreted EVs. In order to inform the development of such approaches, an understanding of the cellular mechanisms by which cargo is sorted to EVs is required. Here, the current knowledge of cargo sorting within EVs is reviewed. Here is given an overview of recent bioengineering approaches that leverage these advances. Methods of externally manipulating EV cargo are also discussed. Finally, a perspective on the current challenges of EVs as a drug delivery platform is offered. It is proposed that standardized bioengineering methods for therapeutic EV preparation will be required to create a well-defined clinical product.
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Affiliation(s)
- Bryan Z. Wang
- Department of Biomedical Engineering, 622 West 168th Street VC12-234, 10032, U.S.A
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
| | - Lori Luo
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, 622 West 168th Street VC12-234, 10032, U.S.A
- Department of Medicine, 622 West 168th Street VC12-234, 10032, U.S.A
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Bone Marrow Mesenchymal Stem Cells and Their Derived Extracellular Vesicles Attenuate Non-Alcoholic Steatohepatitis-Induced Cardiotoxicity via Modulating Cardiac Mechanisms. Life (Basel) 2022; 12:life12030355. [PMID: 35330106 PMCID: PMC8952775 DOI: 10.3390/life12030355] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 106 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.
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Morales-Mantilla DE, Kain B, Le D, Flores AR, Paust S, King KY. Hematopoietic stem and progenitor cells improve survival from sepsis by boosting immunomodulatory cells. eLife 2022; 11:74561. [PMID: 35166205 PMCID: PMC8846591 DOI: 10.7554/elife.74561] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5–7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50–60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.
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Affiliation(s)
- Daniel E Morales-Mantilla
- Graduate Program in Immunology, Baylor College of Medicine, Houston, United States.,Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States
| | - Bailee Kain
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States.,Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States
| | - Duy Le
- Graduate Program in Immunology, Baylor College of Medicine, Houston, United States.,Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States
| | - Anthony R Flores
- Division of Infectious Diseases, Department of Pediatrics, UTHSC/McGovern Medical School, Houston, United States
| | - Silke Paust
- The Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, United States
| | - Katherine Y King
- Graduate Program in Immunology, Baylor College of Medicine, Houston, United States.,Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States.,Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, United States
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Wang Q, Xu N, Wang Y, Zhang X, Liu L, Zhou H, Wang H, Zhang X, Tang X, Fu C, Miao M, Wu D. Allogeneic Stem Cell Transplantation Combined With Transfusion of Mesenchymal Stem Cells in Primary Myelofibrosis: A Multicenter Retrospective Study. Front Oncol 2022; 11:792142. [PMID: 35141151 PMCID: PMC8818875 DOI: 10.3389/fonc.2021.792142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Allogeneic stem cell transplantation (allo-SCT) remains the only effective curative therapy for primary myelofibrosis. Utilization and efficacy of allo-SCT are limited by lethal complications, including engraftment failure, and acute (aGVHD) and chronic graft-versus-host disease (cGVHD). Several clinical trials have explored the use of mesenchymal stem cells (MSCs) in allo-SCT to prevent hematopoietic stem cell (HSC) engraftment failure and control GVHD. METHODS Clinical data of 17 patients with primary myelofibrosis who underwent allo-SCT combined with ex vivo expanded MSC transfusion in four centers from February 2011 to December 2018 were retrospectively analyzed. RESULTS All patients received myeloablative conditioning regimen. The median number of transplanted nucleated cells (NCs) per kilogram body weight was 11.18 × 108 (range: 2.63-16.75 × 108), and the median number of CD34+ cells was 4.72 × 106 (range: 1.32-8.4 × 106). MSCs were transfused on the day of transplant or on day 7 after transplant. The median MSC infusion number was 6.5 × 106 (range: 0.011-65 × 106). None of the patients experienced primary or secondary graft failure in the study. The median time to neutrophil engraftment was 13 days (range: 11-22 days), and the median time to platelet engraftment was 21 days (range: 12-184 days). The median follow-up time was 40.3 months (range: 1.8-127.8 months). The estimated relapse-free survival (RFS) at 5 years was 79.1%, and overall survival (OS) at 5 years was 64.7%. Analysis showed that the cumulative incidence of aGVHD grade II to IV was 36% (95% CI: 8%-55%) and that of grade III to IV was 26% (95% CI: 0%-45%) at day 100. The cumulative incidence of overall cGVHD at 2 years for the entire study population was 63% (95% CI: 26%-81%). The cumulative incidence of moderate to severe cGVHD at 2 years was 17% (95% CI: 0%-42%). Seven patients died during the study, with 5 patients succumbing from non-relapse causes and 2 from disease relapse. CONCLUSION The findings of the study indicate that allo-SCT combined with MSC transfusion may represent an effective treatment option for primary myelofibrosis.
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Affiliation(s)
- Qingyuan Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Na Xu
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Wang
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Beijing, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xi Zhang
- Xinqiao Hospital, Army Military Medical University, Chongqing, China
| | - Limin Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Huifen Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Hong Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Xiang Zhang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Xiaowen Tang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Chengcheng Fu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Miao Miao
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China
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Hosseini NF, Dalirfardouei R, Aliramaei MR, Najafi R. Stem cells or their exosomes: which is preferred in COVID-19 treatment? Biotechnol Lett 2022; 44:159-177. [PMID: 35043287 PMCID: PMC8765836 DOI: 10.1007/s10529-021-03209-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
It only took 8 months for the pneumonia caused by a previously unknown coronavirus to turn into a global pandemic of unprecedentedly far-reaching implications. Failure of the already discovered treatment measures opened up a new opportunity to evaluate the potentials of mesenchymal stem cells and their extracellular vesicles (EVs), exosomes in particular. Eventually, the initial success experienced after the use of MSCs in treating the new pneumonia by Lnge and his team backed up the idea of MSC-based therapies and pushed them closer to becoming a reality. However, MSC-related concerns regarding safety such as abnormal differentiation, spontaneous malignant and the formation of ectopic tissues have triggered the replacement of MSCs by their secreted exosomes. The issue has been further strengthened by the fact that the exosomes leave similar treatment impacts when compared to their parental cells. In recent years, much attention has been paid to the use of MSC-derived exosomes in the treatment of a variety of diseases. With a primary focus on COVID-19 and its current treatment methods, the present review looks into the potentials of MSCs and MSC-derived exosomes in battling the ongoing pandemic. Finally, the research will draw an analogy between exosomes and their parental cells, when it comes to the progresses and challenges in using exosomes as a large-scale treatment method.
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Affiliation(s)
- Nashmin Fayazi Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Dalirfardouei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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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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Lu CH, Chen YA, Ke CC, Chiu SJ, Jeng FS, Chen CC, Hsieh YJ, Yang BH, Chang CW, Wang FS, Liu RS. Multiplexed Molecular Imaging Strategy Integrated with RNA Sequencing in the Assessment of the Therapeutic Effect of Wharton's Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles for Osteoporosis. Int J Nanomedicine 2021; 16:7813-7830. [PMID: 34880610 PMCID: PMC8646890 DOI: 10.2147/ijn.s335757] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/05/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Osteoporosis is a result of an imbalance in bone remodeling. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been considered as a potentially promising treatment for osteoporosis. However, the therapeutic effect, genetic alterations, and in vivo behavior of exogenous EVs for osteoporosis in mice models remain poorly understood. Methods A multiplexed molecular imaging strategy was constructed by micro-positron emission tomography (µPET)/computed tomography (CT), µCT, and optical imaging modality which reflected the osteoblastic activity, microstructure, and in vivo behavior of EVs, respectively. RNA sequencing was used to analyze the cargo of EVs, and the bone tissues of ovariectomized (OVX) mice post EV treatment. Results The result of [18F]NaF µPET showed an increase in osteoblastic activity in the distal femur of EV-treated mice, and the bone structural parameters derived from µCT were also improved. In terms of in vivo behavior of exogenous EVs, fluorescent dye-labeled EVs could target the distal femur of mice, whereas the uptakes of bone tissues were not significantly different between OVX mice and healthy mice. RNA sequencing demonstrated upregulation of ECM-related genes, which might associate with the PI3K/AKT signaling pathway, in line with the results of microRNA analysis showing that mir-21, mir-29, mir-221, and let-7a were enriched in Wharton’s jelly-MSC-EVs and correlated to the BMP and PI3K/AKT signaling pathways. Conclusion The therapeutic effect of exogenous WJ-MSC-EVs in the treatment of osteoporosis was successfully assessed by a multiplexed molecular imaging strategy. The RNA sequencing demonstrated the possible molecular targets in the regulation of bone remodeling. The results highlight the novelty of diagnostic and therapeutic strategies of EV-based treatment for osteoporosis.
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Affiliation(s)
- Cheng-Hsiu Lu
- Industrial Ph.D. Program of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Core Facility for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yi-An Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan
| | - Chien-Chih Ke
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.,Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Sain-Jhih Chiu
- Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan
| | - Fong-Shya Jeng
- Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan
| | - Chao-Cheng Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Ju Hsieh
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.,Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Bang-Hung Yang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.,PET Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Wei Chang
- PET Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Feng-Sheng Wang
- Core Facility for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ren-Shyan Liu
- Industrial Ph.D. Program of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.,PET Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Nuclear Medicine, Cheng Hsin Hospital, Taipei, Taiwan
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Shen M, Chen T. Mesenchymal Stem Cell-Derived Exosomes and Their Potential Agents in Hematological Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4539453. [PMID: 34621464 PMCID: PMC8492257 DOI: 10.1155/2021/4539453] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSCs) are the most exploited stem cells with multilineage differentiation potential and immunomodulatory properties. Numerous lines of findings have reported their successful applications in a multitude of inflammatory conditions and immune disorders. However, it is currently discovered that these effects are mainly mediated in a paracrine manner by MSC-exosomes. Moreover, MSC-exosomes have been implicated in a wide variety of biological responses including immunomodulation, oxidative stress, tumor progression, and tissue regeneration. Meanwhile, they are reported to actively participate in various hematological diseases by the means of transferring different types of exosomal components to the target cells. Therefore, in this review, we briefly discuss the sources and biological features of MSCs and then illustrate the biogenesis and biological processes of MSC-exosomes. Of note, this paper especially highlights the latest research progress of MSC-exosomes in hematological diseases.
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Affiliation(s)
- Min Shen
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Tong Chen
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, China
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Extracellular vesicles tell all: How vesicle-mediated cellular communication shapes hematopoietic stem cell biology with increasing age. Exp Hematol 2021; 101-102:7-15. [PMID: 34407444 DOI: 10.1016/j.exphem.2021.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/06/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022]
Abstract
Extracellular vesicles (EVs) are small lipid bilayer particles containing biologically important cargo and impart regulatory changes in target cells. Despite the importance of EVs in cellular communication, there remains a gap in our understanding of how EVs influence HSC fate and, in turn, how aging and longevity are affected. This review summarizes the current literature dealing with how age-altered intercellular communication mediated by EVs influences HSC biology.
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Dunphy K, O’Mahoney K, Dowling P, O’Gorman P, Bazou D. Clinical Proteomics of Biofluids in Haematological Malignancies. Int J Mol Sci 2021; 22:ijms22158021. [PMID: 34360786 PMCID: PMC8348619 DOI: 10.3390/ijms22158021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/25/2022] Open
Abstract
Since the emergence of high-throughput proteomic techniques and advances in clinical technologies, there has been a steady rise in the number of cancer-associated diagnostic, prognostic, and predictive biomarkers being identified and translated into clinical use. The characterisation of biofluids has become a core objective for many proteomic researchers in order to detect disease-associated protein biomarkers in a minimally invasive manner. The proteomes of biofluids, including serum, saliva, cerebrospinal fluid, and urine, are highly dynamic with protein abundance fluctuating depending on the physiological and/or pathophysiological context. Improvements in mass-spectrometric technologies have facilitated the in-depth characterisation of biofluid proteomes which are now considered hosts of a wide array of clinically relevant biomarkers. Promising efforts are being made in the field of biomarker diagnostics for haematologic malignancies. Several serum and urine-based biomarkers such as free light chains, β-microglobulin, and lactate dehydrogenase are quantified as part of the clinical assessment of haematological malignancies. However, novel, minimally invasive proteomic markers are required to aid diagnosis and prognosis and to monitor therapeutic response and minimal residual disease. This review focuses on biofluids as a promising source of proteomic biomarkers in haematologic malignancies and a key component of future diagnostic, prognostic, and disease-monitoring applications.
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Affiliation(s)
- Katie Dunphy
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Kelly O’Mahoney
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
| | - Paul Dowling
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Peter O’Gorman
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
| | - Despina Bazou
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland; (K.O.); (P.O.)
- Correspondence:
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