1
|
Yeh H, Gupta K, Lu YH, Srinivasan A, Delila L, Yen NTH, Nyam-Erdene A, Burnouf T. Platelet Extracellular Vesicles as Natural Delivery Vehicles for Mitochondrial Dysfunction Therapy? ACS Biomater Sci Eng 2025; 11:2601-2621. [PMID: 40280866 PMCID: PMC12076291 DOI: 10.1021/acsbiomaterials.5c00473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
Mitochondria are vital for energy production, metabolic regulation, and cellular signaling. Their dysfunction is strongly implicated in neurological, cardiovascular, and muscular degenerative diseases, where energy deficits and oxidative stress accelerate disease progression. Platelet extracellular vesicles (PEVs), once called "platelet dust", have emerged as promising agents for mitigating mitochondrial dysfunction. Like other extracellular vesicles (EVs), PEVs carry diverse molecular cargo and surface markers implicated in disease processes and therapeutic efficacy. Notably, they may possibly contain intact or partially functional mitochondrial components, making them tentatively attractive for targeting mitochondrial damage. Although direct research on PEVs-mediated mitochondrial rescue remains limited, current evidence suggests that PEVs can modulate diseases associated with mitochondrial dysfunction and potentially enhance mitochondrial health. This review explores the therapeutic potential of PEVs in neurodegenerative and cardiovascular disorders, highlighting their role in restoring mitochondrial health. By examining recent advancements in PEVs research, we aim to shed light on novel strategies for utilizing PEVs as therapeutic agents. Our goal is to underscore the importance of further fundamental and applied research into PEVs-based interventions, as innovative tools for combating a wide range of diseases linked to mitochondrial dysfunction.
Collapse
Affiliation(s)
- Hsien
Chang Yeh
- School
of Medicine, College of Medicine, Taipei
Medical University, Xin-Yi
Campus, Taipei City 110, Taiwan
| | - Kirti Gupta
- International
Graduate Program in Medicine, College of Medicine, Taipei Medical University, Xin-Yi Campus, Taipei 110, Taiwan
| | - Ya-Hsuan Lu
- School
of Biomedical Engineering, Taipei Medical
University, Shuang-Ho
Campus, New Taipei City 110, Taiwan
| | - Abinaya Srinivasan
- International
PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Shuang-Ho Campus, New Taipei
City 110, Taiwan
| | - Liling Delila
- Graduate
Institute of Biomedical Materials and Tissue Engineering, College
of Biomedical Engineering, Taipei Medical
University, Shuang-Ho
Campus, New Taipei City 110, Taiwan
| | - Nguyen Tran Hai Yen
- Graduate
Institute of Biomedical Materials and Tissue Engineering, College
of Biomedical Engineering, Taipei Medical
University, Shuang-Ho
Campus, New Taipei City 110, Taiwan
| | - Ariunjargal Nyam-Erdene
- International
PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Shuang-Ho Campus, New Taipei
City 110, Taiwan
| | - Thierry Burnouf
- International
PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Shuang-Ho Campus, New Taipei
City 110, Taiwan
- Graduate
Institute of Biomedical Materials and Tissue Engineering, College
of Biomedical Engineering, Taipei Medical
University, Shuang-Ho
Campus, New Taipei City 110, Taiwan
- International
PhD Program in Cell Therapy and Regeneration Medicine, College of
Medicine, Taipei Medical University, Taipei 110, Taiwan
| |
Collapse
|
2
|
Surico PL, Barone V, Singh RB, Coassin M, Blanco T, Dohlman TH, Basu S, Chauhan SK, Dana R, Di Zazzo A. Potential applications of mesenchymal stem cells in ocular surface immune-mediated disorders. Surv Ophthalmol 2025; 70:467-479. [PMID: 39097173 DOI: 10.1016/j.survophthal.2024.07.008] [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: 05/17/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.
Collapse
Affiliation(s)
- Pier Luigi Surico
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Vincenzo Barone
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Rohan Bir Singh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Tomas Blanco
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Thomas H Dohlman
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Sayan Basu
- Brien Holden Eye Research Centre (BHERC), L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy.
| |
Collapse
|
3
|
McMullan E, Joladarashi D, Kishore R. Unpacking Exosomes: A Therapeutic Frontier for Cardiac Repair. Curr Cardiol Rep 2025; 27:73. [PMID: 40111702 PMCID: PMC11925971 DOI: 10.1007/s11886-025-02225-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE OF REVIEW The rising global prevalence of cardiovascular disease is driving the need for innovative biotherapeutics. Recently, exosomes-extracellular vesicles involved in paracrine signaling have shown promise in aiding heart repair associated with cardiovascular conditions. Their therapeutic potential encompasses several beneficial mechanisms, including anti-fibrosis, anti-inflammation, pro-angiogenesis, anti-oxidation, and anti-apoptosis, all contributing to improved cardiac function. This review provides a comprehensive overview of exosomes and highlights the latest research on their effectiveness in addressing current challenges in regenerative cardiac medicine. RECENT FINDINGS Current approaches revolve around elucidating and enhancing how different cell types, cargo, and delivery methods impact healing in a pathological cardiovascular environment. The emerging field of therapeutic exosome research is promising for cardiac regeneration due to the beneficial effects of exosomal cargo. The expansion of mechanistic knowledge and the optimization of techniques are required before standard clinical application.
Collapse
Affiliation(s)
- Elena McMullan
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Darukeshwara Joladarashi
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Raj Kishore
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
| |
Collapse
|
4
|
Abbasi R, Alamdari-Mahd G, Maleki-Kakelar H, Momen-Mesgin R, Ahmadi M, Sharafkhani M, Rezaie J. Recent advances in the application of engineered exosomes from mesenchymal stem cells for regenerative medicine. Eur J Pharmacol 2025; 989:177236. [PMID: 39753159 DOI: 10.1016/j.ejphar.2024.177236] [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: 10/25/2024] [Revised: 12/14/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025]
Abstract
Exosomes, cell-derived vesicles produced by cells, are fascinating and drawing growing interest in biomedical exploration due to their exceptional properties. There is intriguing evidence that exosomes are involved in major biological processes, including diseases and regeneration. Exosomes from mesenchymal stem cells (MSCs) have shown promising outcomes in regenerative medicine. Numerous studies suggest that exosomes have several advantages over conventional synthetic nanocarriers, opening novel frontiers for innovative drug delivery. Regenerative medicine has demonstrated the profound therapeutic outcomes of engineered or loaded exosomes from MSCs. Different methods are being used to modify or/load exosomes. These exosomes can improve cell signaling pathways for bone and cartilage diseases, liver diseases, nerve tissues, kidney diseases, skin tissue, and cardiovascular diseases. Despite extensive research, clinical translation of these exosomes remains a challenge. The optimization of cargo loading methods, efficiency, physiological stability, and the isolation and characterization of exosomes present some challenges. The upcoming examination should include the development of large-scale, quality-controllable production approaches, the modification of drug loading approaches, and numerous in vivo investigations and clinical trials. Here, we provided an informative overview of the extracellular vesicles and modification/loading methods of exosomes. We discuss the last exosome research on regeneration disorders, highlighting the therapeutic applications of MSCs-derived exosomes. We also highlight future directions and challenges, underscoring the significance of addressing the main questions in the field.
Collapse
Affiliation(s)
- Reza Abbasi
- Department of Biology, Urmia University, Urmia, Iran
| | - Ghazal Alamdari-Mahd
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Hadi Maleki-Kakelar
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | | | - Mahdi Ahmadi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohaddeseh Sharafkhani
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| |
Collapse
|
5
|
Wang Y, Li G, Li G, Pan Y, Liu Z. BCL-2 overexpression exosomes promote the proliferation and migration of mesenchymal stem cells in hypoxic environment for skin injury in rats. J Biol Eng 2025; 19:7. [PMID: 39825412 PMCID: PMC11740716 DOI: 10.1186/s13036-024-00471-y] [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: 09/08/2024] [Accepted: 12/04/2024] [Indexed: 01/20/2025] Open
Abstract
OBJECTIVE The direction of this study was to detect and analyze the specific mechanism of anti-apoptosis in mesenchymal stem cells (MSCs) cells caused by high expression of BCL2. METHODS Bioinformatics was completed in Link omics. GO analysis and KEGG analysis were carried out, and the grope tool of Link omics database was used to evaluate PPI information and other core path analysis information. The cultured cells were divided into MSC + normoxic group (MSCs were cultured in conventional medium, including 10% depleted serum of fetal bovine exosomes, 37 °C, 5% CO2 and 95% air) and Exo-BCL-2 + MSC + normoxic group (a certain concentration of purified BCL-2 exosomes was co-cultured with MSC in conventional medium, 37 °C, 5% CO2 and 95% air), Exo-BCL-2 + MSC + hypoxia group (a certain concentration of purified BCL-2 exosomes and MSC were co-cultured in hypoxia medium at 37 °C, 80% CO2 and 20% air), MSC + hypoxia group (MSCs were cultured in hypoxia medium with 10% depleted serum of fetal bovine exosomes, 37 °C, 80% CO2 and 20% air), exo WT + MSC + normoxic group (co-cultured with MSC in conventional medium at 37 °C, 5% CO2 and 95% air) and exoWT + MSC + hypoxic group (co-cultured with MSC in hypoxic medium at 37 °C, 80% CO2 and 20%). Cell proliferation ability was monitored by cell proliferation test. Cell migration test was used to check the migration capacity of MSCs. The expressions of apoptosis-related proteins BCL-2, caspase3 and caspase9, Runx2, ALP and PPAR-γ were analyzed by western blot. Tissue damage was scored by H&E and Ma Song trichrome staining. Masson staining was used to evaluate the collagen volume fraction of the wound. The expressions of KRT14, α-SMA, CD31 and PCNA in rat trauma tissues were analyzed by immunofluorescence staining. The horizontal of apoptosis-related proteins in skin lesions was checked by Western blot. The horizontal of inflammatory factors TNF-α and IL-6 in traumatic tissue of rats were detected by ELISA. RESULTS From KEGG's results, we can see that BCL2-2 was closely related to base excision and repair, cell cycle, steroid biosynthesis and other pathways. When cultured for 48h and 72h, the proliferation ability and migration number of MSCs in MSC + hypoxia group were lower than MSC + normoxic group, but the expressions of caspase3 and caspase9 were higher. The proliferation ability and migration number of MSCs in Exo-BCL-2 + MSC + hypoxia group and MSC + hypoxia group were lower than those in Exo-BCL-2 + MSC + normoxic group and MSC + normoxic group, and the horizontal of caspase3 and caspase9 were lower. Exo-BCL-2 + MSC + normoxic group increased the proliferation capacity and migration number of MSCs, but decreased the expression of caspase3 and caspase9. Compared with Exo-BCL-2 + MSC + normoxia and Exo-BCL-2 + MSC + normoxia, the proliferation ability and migration quantity of MSCs in exo WT + MSC + normoxia and exo WT + MSC + hypoxia groups were lower, and the horizontal of caspase3 and caspase9 proteins was higher. CONCLUSION Bioinformatics analysis shows that BCL2-2 plays a worthwhile role in the process of cell apoptosis and proliferation. Exosomes with high expression of BCL-2 can encourage the proliferation of MSC in hypoxic environment. The wound treated with MSCs-BCL-2 promotes the compose of new blood vessels and granulation tissue in the wound, the redifferentiation of epithelial cells and the remodeling of collagen, which has a high therapeutic prospect for chronic wounds and skin regeneration.
Collapse
Affiliation(s)
- Ying Wang
- Department of Traumatic Clinic, Shanghai East Hospital of Tongji University, Shanghai, 200120, China
| | - Guang Li
- Department of Traumatic Clinic, Shanghai East Hospital of Tongji University, Shanghai, 200120, China
| | - Guofeng Li
- Department of Traumatic Clinic, Shanghai East Hospital of Tongji University, Shanghai, 200120, China
| | - Yutao Pan
- Department of Traumatic Clinic, Shanghai East Hospital of Tongji University, Shanghai, 200120, China
| | - Zhongmin Liu
- Department of Traumatic Clinic, Shanghai East Hospital of Tongji University, Shanghai, 200120, China.
| |
Collapse
|
6
|
Kundu D, Shin SY, Chilian WM, Dong F. The Potential of Mesenchymal Stem Cell-Derived Exosomes in Cardiac Repair. Int J Mol Sci 2024; 25:13494. [PMID: 39769256 PMCID: PMC11727646 DOI: 10.3390/ijms252413494] [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: 11/27/2024] [Revised: 12/12/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and effectively repairing the heart following myocardial injuries remains a significant challenge. Research has increasingly shown that exosomes derived from mesenchymal stem cells (MSC-Exo) can ameliorate myocardial injuries and improve outcomes after such injuries. The therapeutic benefits of MSC-Exo are largely due to their capacity to deliver specific cargo, including microRNAs and proteins. MSC-Exo can modulate various signaling pathways and provide several beneficial effects, including cytoprotection, inflammation modulation, and angiogenesis promotion to help repair the damaged myocardium. In this review, we summarize the cardioprotective effects of MSC-Exo in myocardial injury, the underlying molecular mechanism involved in the process, and various approaches studied to enhance their efficacy based on recent findings.
Collapse
Affiliation(s)
| | | | | | - Feng Dong
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA; (D.K.); (S.Y.S.); (W.M.C.)
| |
Collapse
|
7
|
Sadovskaya A, Petinati N, Shipounova I, Drize N, Smirnov I, Pobeguts O, Arapidi G, Lagarkova M, Karaseva L, Pokrovskaya O, Kuzmina L, Vasilieva A, Aleshina O, Parovichnikova E. Damage of the Bone Marrow Stromal Precursors in Patients with Acute Leukemia at the Onset of the Disease and During Treatment. Int J Mol Sci 2024; 25:13285. [PMID: 39769050 PMCID: PMC11677965 DOI: 10.3390/ijms252413285] [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: 10/25/2024] [Revised: 12/06/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
In patients with acute leukemia (AL), malignant cells and therapy modify the properties of multipotent mesenchymal stromal cells (MSCs) and their descendants, reducing their ability to maintain normal hematopoiesis. The aim of this work was to elucidate the alterations in MSCs at the onset and after therapy in patients with AL. The study included MSCs obtained from the bone marrow of 78 AL patients (42 AML and 36 ALL) and healthy donors. MSC growth characteristics, gene expression pattern, proteome and secretome were studied using appropriate methods. The concentration of MSCs in the bone marrow, proliferative potential, the expression of several genes, proteomes and secretomes were altered in AL-MSCs. Stromal progenitors had been affected differently in ALL and AML patients. In remission, MSC functions remain impaired despite the absence of tumor cells and the maintenance of benign hematopoietic cells. AL causes crucial and, to a large extent, irreversible changes in bone marrow MSCs.
Collapse
Affiliation(s)
- Aleksandra Sadovskaya
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
- Federal State Budget Educational Institution of Higher Education, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
| | - Nataliya Petinati
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Irina Shipounova
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Nina Drize
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Igor Smirnov
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Olga Pobeguts
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Georgiy Arapidi
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Maria Lagarkova
- Federal State Budget Educational Institution of Higher Education, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Luiza Karaseva
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Olga Pokrovskaya
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Larisa Kuzmina
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Anastasia Vasilieva
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Olga Aleshina
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| | - Elena Parovichnikova
- National Medical Research Center for Hematology, Moscow 125167, Russia (N.P.); (E.P.)
| |
Collapse
|
8
|
Liu X, Hyun Kim J, Li X, Liu R. Application of mesenchymal stem cells exosomes as nanovesicles delivery system in the treatment of breast cancer. Int J Pharm 2024; 666:124732. [PMID: 39304093 DOI: 10.1016/j.ijpharm.2024.124732] [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: 05/28/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.
Collapse
Affiliation(s)
- Xiaofan Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - June Hyun Kim
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea
| | - Xuemei Li
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
| | - Rui Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea.
| |
Collapse
|
9
|
Zhao L, Zhao BH, Ruze A, Li QL, Deng AX, Gao XM. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev 2024; 80:121-137. [PMID: 39438226 DOI: 10.1016/j.cytogfr.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024]
Abstract
The role of macrophage migration inhibitory factor (MIF) as a multifunctional cytokine in immunomodulation and inflammatory response is increasingly appreciated. Ischemic heart disease (IHD), the leading cause of global mortality, remains a focal point of research owing to its intricate pathophysiology. MIF has been identified as a critical player in IHD, where it exerts distinct roles. On one hand, MIF plays a protective role by enhancing energy metabolism through activation of AMPK, resisting oxidative stress, inhibiting activation of the JNK pathway, and maintaining intracellular calcium ion homeostasis. Additionally, MIF exerts protective effects through mesenchymal stem cells and exosomes. On the other hand, MIF can assume a pro-inflammatory role, which contributes to the exacerbation of IHD's development and progression. Furthermore, MIF levels significantly increase in IHD patients, and its genetic polymorphisms are positively correlated with prevalence and severity. These findings position MIF as a potential biomarker and therapeutic target in the management of IHD. This review summarizes the structure, source, signaling pathways and biological functions of MIF and focuses on its roles and clinical characteristics in IHD. The genetic variants of MIF associated with IHD is also discussed, providing more understandings of its complex interplay in the disease's pathology.
Collapse
Affiliation(s)
- Ling Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Bang-Hao Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Amanguli Ruze
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Qiu-Lin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - An-Xia Deng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China; Xinjiang Key Laboratory of Cardiovascular Disease, Urumqi, China.
| |
Collapse
|
10
|
Ma YN, Hu X, Karako K, Song P, Tang W, Xia Y. Exploring the multiple therapeutic mechanisms and challenges of mesenchymal stem cell-derived exosomes in Alzheimer's disease. Biosci Trends 2024; 18:413-430. [PMID: 39401895 DOI: 10.5582/bst.2024.01306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Alzheimer's disease (AD) is a severe neurodegenerative disorder, and the current treatment options are limited. Mesenchymal stem cell-derived exosomes (MSC-Exos) have garnered significant attention due to their unique biological properties, showcasing tremendous potential as an acellular alternative therapy for AD. MSC-Exos exhibit excellent biocompatibility and low immunogenicity, enabling them to effectively cross the blood-brain barrier (BBB) and deliver therapeutic molecules directly to target cells. They are highly efficacious in delivering nucleic acid-based drugs. Moreover, the production process of MSC-Exos benefits from a high proliferation capacity and multilineage differentiation potential, allowing for production while maintaining a stable composition. Despite the significant theoretical advantages of MSC-Exos, their clinical use still faces multiple challenges, including cross-contamination during isolation and purification processes, the complexity of their components, and the presence of potential adverse paracrine factors. Future research needs to focus on optimizing separation and purification techniques, enhancing delivery methods to improve therapeutic efficacy, and performing detailed analyses of the components of MSC-Exos. In summary, MSC-Exos hold promise as an effective option for the treatment of AD and other neurodegenerative diseases, driving their clinical research and use in related fields.
Collapse
Affiliation(s)
- Ya-Nan Ma
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Xiqi Hu
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Kenji Karako
- Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Peipei Song
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Wei Tang
- Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Ying Xia
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| |
Collapse
|
11
|
Essien SA, Ahuja I, Eisenhoffer GT. Apoptotic extracellular vesicles carrying Mif regulate macrophage recruitment and compensatory proliferation in neighboring epithelial stem cells during tissue maintenance. PLoS Biol 2024; 22:e3002194. [PMID: 39495793 DOI: 10.1371/journal.pbio.3002194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 11/20/2024] [Accepted: 08/27/2024] [Indexed: 11/06/2024] Open
Abstract
Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss to maintain tissue homeostasis. While apoptotic cell-derived extracellular vesicles (AEVs) can transmit instructional cues to mediate communication with neighboring cells, the molecular mechanisms that induce cell division are not well understood. Here, we show that macrophage migration inhibitory factor (Mif)-containing AEVs regulate compensatory proliferation via ERK signaling in epithelial stem cells of larval zebrafish. Time-lapse imaging showed efferocytosis of AEVs from dying epithelial stem cells by healthy neighboring stem cells. Proteomic and ultrastructure analysis of purified AEVs identified Mif localization on the AEV surface. Pharmacological inhibition or genetic mutation of Mif, or its cognate receptor CD74, decreased levels of phosphorylated ERK and compensatory proliferation in the neighboring epithelial stem cells. Disruption of Mif activity also caused decreased numbers of macrophages patrolling near AEVs, while depletion of the macrophage lineage resulted in a reduced proliferative response by the epithelial stem cells. We propose that AEVs carrying Mif directly stimulate epithelial stem cell repopulation and guide macrophages to cell non-autonomously induce localized proliferation to sustain overall cell numbers during tissue maintenance.
Collapse
Affiliation(s)
- Safia A Essien
- Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ivanshi Ahuja
- Department of Biosciences, Rice University, Houston, Texas, United States of America
| | - George T Eisenhoffer
- Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| |
Collapse
|
12
|
Liu C, Zhang D, Long K, Qi W, Pang L, Li J, Cheng KKY, Cai Y. From exosomes to mitochondria and myocardial infarction: Molecular insight and therapeutic challenge. Pharmacol Res 2024; 209:107468. [PMID: 39426469 DOI: 10.1016/j.phrs.2024.107468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/21/2024] [Accepted: 10/14/2024] [Indexed: 10/21/2024]
Abstract
Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.
Collapse
Affiliation(s)
- Chang Liu
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Dengwen Zhang
- Department of Anesthesiology, Heyuan People's Hospital, Guangdong, China; Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, China
| | - Kekao Long
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Wensheng Qi
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Lei Pang
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China
| | - Jia Li
- Department of Neurology, Wuhan No.1 Hospital, Hubei, China
| | - Kenneth King-Yip Cheng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
| | - Yin Cai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong SAR, China; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong SAR, China.
| |
Collapse
|
13
|
Abid AI, Conzatti G, Toti F, Anton N, Vandamme T. Mesenchymal stem cell-derived exosomes as cell free nanotherapeutics and nanocarriers. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 61:102769. [PMID: 38914247 DOI: 10.1016/j.nano.2024.102769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/18/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.
Collapse
Affiliation(s)
- Ali Imran Abid
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France
| | - Guillaume Conzatti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
| | - Florence Toti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Nicolas Anton
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Thierry Vandamme
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
| |
Collapse
|
14
|
Yuce K. The Application of Mesenchymal Stem Cells in Different Cardiovascular Disorders: Ways of Administration, and the Effectors. Stem Cell Rev Rep 2024; 20:1671-1691. [PMID: 39023739 DOI: 10.1007/s12015-024-10765-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2024] [Indexed: 07/20/2024]
Abstract
The heart is an organ with a low ability to renew and repair itself. MSCs have cell surface markers such as CD45-, CD34-, CD31-, CD4+, CD11a+, CD11b+, CD15+, CD18+, CD25+, CD49d+, CD50+, CD105+, CD73+, CD90+, CD9+, CD10+, CD106+, CD109+, CD127+, CD120a+, CD120b+, CD124+, CD126+, CD140a+, CD140b+, adherent properties and the ability to differentiate into cells such as adipocytes, osteoblasts and chondrocytes. Autogenic, allogeneic, normal, pretreated and genetically modified MSCs and secretomes are used in preclinical and clinical studies. MSCs and their secretomes (the total released molecules) generally have cardioprotective effects. Studies on cardiovascular diseases using MSCs and their secretomes include myocardial infraction/ischemia, fibrosis, hypertrophy, dilated cardiomyopathy and atherosclerosis. Stem cells or their secretomes used for this purpose are administered to the heart via intracoronary (Antegrade intracoronary and retrograde coronary venous injection), intramyocardial (Transendocardial and epicardial injection) and intravenous routes. The protective effects of MSCs and their secretomes on the heart are generally attributed to their differentiation into cardiomyocytes and endothelial cells, their immunomodulatory properties, paracrine effects, increasing blood vessel density, cardiac remodeling, and ejection fraction and decreasing apoptosis, the size of the wound, end-diastolic volume, end-systolic volume, ventricular myo-mass, fibrosis, matrix metalloproteins, and oxidative stress. The present review aims to assist researchers and physicians in selecting the appropriate cell type, secretomes, and technique to increase the chance of success in designing therapeutic strategies against cardiovascular diseases.
Collapse
Affiliation(s)
- Kemal Yuce
- Physiology, Department of Basic Medical Sciences, Medicine Faculty, Selcuk University, Konya, Türkiye.
| |
Collapse
|
15
|
Yan H, Ding H, Xie RX, Liu ZQ, Yang XQ, Xie LL, Liu CX, Liu XD, Chen LY, Huang XP. Research progress of exosomes from different sources in myocardial ischemia. Front Cardiovasc Med 2024; 11:1436764. [PMID: 39350967 PMCID: PMC11440518 DOI: 10.3389/fcvm.2024.1436764] [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: 05/22/2024] [Accepted: 08/16/2024] [Indexed: 10/04/2024] Open
Abstract
Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.
Collapse
Affiliation(s)
- Huan Yan
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Huang Ding
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Ruo-Xi Xie
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Zhi-Qing Liu
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Xiao-Qian Yang
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Ling-Li Xie
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Cai-Xia Liu
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Xiao-Dan Liu
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Li-Yuan Chen
- Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Xiao-Ping Huang
- Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| |
Collapse
|
16
|
Yang L, Liu N, Yang Y. Astragaloside IV-induced BMSC exosomes promote neovascularization and protect cardiac function in myocardial infarction mice via the miR-411/HIF-1α axis. J Liposome Res 2024; 34:452-463. [PMID: 38088046 DOI: 10.1080/08982104.2023.2293844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/07/2023] [Indexed: 12/26/2023]
Abstract
This study focused on investigating the mechanism of the astragaloside IV-induced bone marrow mesenchymal stem cell exosome (AS-IV-MSC-exo)/microRNA(miR)-411/HIF-1α axis in affecting vascular neovascularization and protecting cardiac function in myocardial infarction (MI) mice. Exosomes (MSC-exo and AS-IV-MSC-exo) were separated by differential centrifugation and then characterized. MI mouse models were established by left anterior descending coronary artery ligation. Echocardiography was used to evaluate cardiac function. HE staining and Masson staining were performed to observe myocardial histopathology. Capillary density in the myocardium via immunohistochemistry and quantified the expression of vascular endothelial growth factor (VEGF) via RT-qPCR. The expression of miR-411 and HIF-1α was tested by RT-qPCR and western blot and the targeting relationship of miR-411 and HIF-1α was verified by bioinformatics website and dual luciferase reporter gene assay. Exosomes with lipid bi-layer membrane structure, expressing exosomal surface marker proteins, and being taken up by cardiomyocytes could be successfully isolated utilizing ultracentrifugation. Intramyocardial injection of MSC-exo could restore cardiac function, decrease myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice; the effect of AS-IV-MSC-exo was more significant. The ability of AS-IV-MSC-exo to restore cardiac function, lower myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice was diminished when miR-411 expression in AS-IV-MSC-exo was reduced. Mechanistically, miR-411 was found to target and inhibit HIF-1α expression. Overexpression of HIF-1α impaired the impact of AS-IV-MSC-exo on improving cardiac function and promoting neovascularization in MI mice. AS-IV-MSC-exo improves cardiac function and promoted neovascularization via the miR-411/HIF-1α axis, thereby ameliorating MI.
Collapse
Affiliation(s)
- Lei Yang
- School of Medicine, Zhumadian Key Laboratory of Chronic Disease Research and Translational Medicine, Huanghuai University, Zhumadian, People's Republic of China
- Department of Scientific Research Section, Zhumadian Central Hospital, Affiliated Hospital of Huanghuai University, Zhumadian, People's Republic of China
| | - Nuan Liu
- School of Medicine, Zhumadian Key Laboratory of Chronic Disease Research and Translational Medicine, Huanghuai University, Zhumadian, People's Republic of China
- Department of Scientific Research Section, Zhumadian Central Hospital, Affiliated Hospital of Huanghuai University, Zhumadian, People's Republic of China
- Institute of Cardiovascular and Cerebrovascular Diseases, Huanghuai University, Zhumadian, People's Republic of China
| | - Yang Yang
- Department of Scientific Research Section, Zhumadian Central Hospital, Affiliated Hospital of Huanghuai University, Zhumadian, People's Republic of China
| |
Collapse
|
17
|
Song J, Wang L, Wang L, Guo X, He Q, Cui C, Hu H, Zang N, Yang M, Yan F, Liang K, Wang C, Liu F, Sun Y, Sun Z, Lai H, Hou X, Chen L. Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling. Stem Cells Transl Med 2024; 13:776-790. [PMID: 38864709 PMCID: PMC11328933 DOI: 10.1093/stcltm/szae038] [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: 11/21/2023] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to β-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.
Collapse
Affiliation(s)
- Jia Song
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Lingshu Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Liming Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Xinghong Guo
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Qin He
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chen Cui
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Huiqing Hu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Nan Zang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Mengmeng Yang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fei Yan
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Kai Liang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chuan Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fuqiang Liu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Yujing Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Zheng Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Hong Lai
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Xinguo Hou
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Li Chen
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| |
Collapse
|
18
|
Li J, Wang T, Hou X, Li Y, Zhang J, Bai W, Qian H, Sun Z. Extracellular vesicles: opening up a new perspective for the diagnosis and treatment of mitochondrial dysfunction. J Nanobiotechnology 2024; 22:487. [PMID: 39143493 PMCID: PMC11323404 DOI: 10.1186/s12951-024-02750-8] [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: 11/14/2023] [Accepted: 08/02/2024] [Indexed: 08/16/2024] Open
Abstract
Mitochondria are crucial organelles responsible for energy generation in eukaryotic cells. Oxidative stress, calcium disorders, and mitochondrial DNA abnormalities can all cause mitochondrial dysfunction. It is now well documented that mitochondrial dysfunction significantly contributes to the pathogenesis of numerous illnesses. Hence, it is vital to investigate innovative treatment methods targeting mitochondrial dysfunction. Extracellular vesicles (EVs) are cell-derived nanovesicles that serve as intercellular messengers and are classified into small EVs (sEVs, < 200 nm) and large EVs (lEVs, > 200 nm) based on their sizes. It is worth noting that certain subtypes of EVs are rich in mitochondrial components (even structurally intact mitochondria) and possess the ability to transfer them or other contents including proteins and nucleic acids to recipient cells to modulate their mitochondrial function. Specifically, EVs can modulate target cell mitochondrial homeostasis as well as mitochondria-controlled apoptosis and ROS generation by delivering relevant substances. In addition, the artificial modification of EVs as delivery carriers for therapeutic goods targeting mitochondria is also a current research hotspot. In this article, we will focus on the ability of EVs to modulate the mitochondrial function of target cells, aiming to offer novel perspectives on therapeutic approaches for diverse conditions linked to mitochondrial dysfunction.
Collapse
Affiliation(s)
- Jiali Li
- Department of Gerontology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Tangrong Wang
- Department of Gerontology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Xiaomei Hou
- The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, 450000, China
| | - Yu Li
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jiaxin Zhang
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Wenhuan Bai
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Hui Qian
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Zixuan Sun
- Department of Gerontology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China.
| |
Collapse
|
19
|
Zhao J, Shen F, Hu YM, Yin K, Chen Y, Chen YJ, Hu QC, Liang L. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer. Open Life Sci 2024; 19:20220899. [PMID: 39071494 PMCID: PMC11282918 DOI: 10.1515/biol-2022-0899] [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: 07/27/2023] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 07/30/2024] Open
Abstract
This study aimed to determine the prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer (HER2+ BC). Transcriptome sequencing and clinicopathological data were downloaded from the Cancer Genome Atlas. The 10X single cell sequencing dataset was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus. Exosomes-Related Genes were extracted from the ExoCarta and Gene Set Enrichment Analysis databases. FGF9, SF3B4, and EPCAM were found and deemed the most accurate predictive signatures. Patients with HER2+ BC were subtyped into three groupings by exosome prognostic gene (EPGs). The expression of SF3B4 was positively linked with the infiltration of macrophages, neutrophils, and CD4+ T cells. The expression characteristics of EPGs were associated with the biological process of "response to xenobiotic stimuli." Interactions were relatively high between malignant epithelial cells and fibroblasts, endothelial cells, monocytes, and macrophages. Malignant epithelial cells interact more with fibroblasts and endothelial cells. The migration inhibitory factor pathway was the primary outgoing signaling pattern, while the C-C motif chemokine ligand pathway was the primary incoming signaling pattern for communication between malignant epithelial cells and macrophages. This study described the role of exosome signatures in the prognosis and microenvironment of HER2+ BC and provided a basis for future research.
Collapse
Affiliation(s)
- Ji Zhao
- Department of Breast Surgery, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People’s Republic of China
| | - Feng Shen
- Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, People’s Republic of China
| | - Yue-Mei Hu
- Department of Pathology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People’s Republic of China
| | - Kai Yin
- Department of Breast Surgery, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People’s Republic of China
| | - Ying Chen
- Department of Radiation Oncology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Changning District, Shanghai, 200336, People’s Republic of China
| | - Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital (Xiamen), Fudan University, No. 668, Jinhu Road, Huli District, Xiamen, 361015, People’s Republic of China
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Xuhui District, Shanghai200032, People’s Republic of China
| | - Qun-Chao Hu
- Department of Radiation Oncology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Changning District, Shanghai, 200336, People’s Republic of China
| | - Li Liang
- Department of Medical Oncology, Zhongshan Hospital Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People’s Republic of China
| |
Collapse
|
20
|
Akbar N, Razzaq SS, Salim A, Haneef K. Mesenchymal Stem Cell-Derived Exosomes and Their MicroRNAs in Heart Repair and Regeneration. J Cardiovasc Transl Res 2024; 17:505-522. [PMID: 37875715 DOI: 10.1007/s12265-023-10449-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023]
Abstract
Mesenchymal stem cells (MSCs) can be differentiated into cardiac, endothelial, and smooth muscle cells. Therefore, MSC-based therapeutic approaches have the potential to deal with the aftermaths of cardiac diseases. However, transplanted stem cells rarely survive in damaged myocardium, proposing that paracrine factors other than trans-differentiation may involve in heart regeneration. Apart from cytokines/growth factors, MSCs secret small, single-membrane organelles named exosomes. The MSC-secreted exosomes are enriched in lipids, proteins, nucleic acids, and microRNA (miRNA). There has been an increasing amount of data that confirmed that MSC-derived exosomes and their active molecule microRNA (miRNAs) regulate signaling pathways involved in heart repair/regeneration. In this review, we systematically present an overview of MSCs, their cardiac differentiation, and the role of MSC-derived exosomes and exosomal miRNAs in heart regeneration. In addition, biological functions regulated by MSC-derived exosomes and exosomal-derived miRNAs in the process of heart regeneration are reviewed.
Collapse
Affiliation(s)
- Nukhba Akbar
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Syeda Saima Razzaq
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Kanwal Haneef
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan.
| |
Collapse
|
21
|
Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Collapse
Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| |
Collapse
|
22
|
Yu T, Xu Q, Chen X, Deng X, Chen N, Kou MT, Huang Y, Guo J, Xiao Z, Wang J. Biomimetic nanomaterials in myocardial infarction treatment: Harnessing bionic strategies for advanced therapeutics. Mater Today Bio 2024; 25:100957. [PMID: 38322664 PMCID: PMC10844134 DOI: 10.1016/j.mtbio.2024.100957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 02/08/2024] Open
Abstract
Myocardial infarction (MI) and its associated poor prognosis pose significant risks to human health. Nanomaterials hold great potential for the treatment of MI due to their targeted and controlled release properties, particularly biomimetic nanomaterials. The utilization of biomimetic strategies based on extracellular vesicles (EVs) and cell membranes will serve as the guiding principle for the development of nanomaterial therapy in the future. In this review, we present an overview of research progress on various exosomes derived from mesenchymal stem cells, cardiomyocytes, or induced pluripotent stem cells in the context of myocardial infarction (MI) therapy. These exosomes, utilized as cell-free therapies, have demonstrated the ability to enhance the efficacy of reducing the size of the infarcted area and preventing ischaemic reperfusion through mechanisms such as oxidative stress reduction, polarization modulation, fibrosis inhibition, and angiogenesis promotion. Moreover, EVs can exert cardioprotective effects by encapsulating therapeutic agents and can be engineered to specifically target the infarcted myocardium. Furthermore, we discuss the use of cell membranes derived from erythrocytes, stem cells, immune cells and platelets to encapsulate nanomaterials. This approach allows the nanomaterials to camouflage themselves as endogenous substances targeting the region affected by MI, thereby minimizing toxicity and improving biocompatibility. In conclusion, biomimetic nano-delivery systems hold promise as a potentially beneficial technology for MI treatment. This review serves as a valuable reference for the application of biomimetic nanomaterials in MI therapy and aims to expedite the translation of NPs-based MI therapeutic strategies into practical clinical applications.
Collapse
Affiliation(s)
- Tingting Yu
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Qiaxin Xu
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Xu Chen
- Department of Clinical Pharmacy, Daqing Oilfield General Hospital, Daqing, 163000, China
| | - Xiujiao Deng
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Nenghua Chen
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Man Teng Kou
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Yanyu Huang
- Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA
| | - Jun Guo
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
- Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Zeyu Xiao
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, 510630, China
| | - Jinghao Wang
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| |
Collapse
|
23
|
Chia SPS, Pang JKS, Soh BS. Current RNA strategies in treating cardiovascular diseases. Mol Ther 2024; 32:580-608. [PMID: 38291757 PMCID: PMC10928165 DOI: 10.1016/j.ymthe.2024.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/22/2023] [Accepted: 01/23/2024] [Indexed: 02/01/2024] Open
Abstract
Cardiovascular disease (CVD) continues to impose a significant global health burden, necessitating the exploration of innovative treatment strategies. Ribonucleic acid (RNA)-based therapeutics have emerged as a promising avenue to address the complex molecular mechanisms underlying CVD pathogenesis. We present a comprehensive review of the current state of RNA therapeutics in the context of CVD, focusing on the diverse modalities that bring about transient or permanent modifications by targeting the different stages of the molecular biology central dogma. Considering the immense potential of RNA therapeutics, we have identified common gene targets that could serve as potential interventions for prevalent Mendelian CVD caused by single gene mutations, as well as acquired CVDs developed over time due to various factors. These gene targets offer opportunities to develop RNA-based treatments tailored to specific genetic and molecular pathways, presenting a novel and precise approach to address the complex pathogenesis of both types of cardiovascular conditions. Additionally, we discuss the challenges and opportunities associated with delivery strategies to achieve targeted delivery of RNA therapeutics to the cardiovascular system. This review highlights the immense potential of RNA-based interventions as a novel and precise approach to combat CVD, paving the way for future advancements in cardiovascular therapeutics.
Collapse
Affiliation(s)
- Shirley Pei Shan Chia
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Jeremy Kah Sheng Pang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Boon-Seng Soh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore.
| |
Collapse
|
24
|
Surico PL, Scarabosio A, Miotti G, Grando M, Salati C, Parodi PC, Spadea L, Zeppieri M. Unlocking the versatile potential: Adipose-derived mesenchymal stem cells in ocular surface reconstruction and oculoplastics. World J Stem Cells 2024; 16:89-101. [PMID: 38455097 PMCID: PMC10915950 DOI: 10.4252/wjsc.v16.i2.89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/06/2024] [Accepted: 01/29/2024] [Indexed: 02/26/2024] Open
Abstract
This review comprehensively explores the versatile potential of mesenchymal stem cells (MSCs) with a specific focus on adipose-derived MSCs. Ophthalmic and oculoplastic surgery, encompassing diverse procedures for ocular and periocular enhancement, demands advanced solutions for tissue restoration, functional and aesthetic refinement, and aging. Investigating immunomodulatory, regenerative, and healing capacities of MSCs, this review underscores the potential use of adipose-derived MSCs as a cost-effective alternative from bench to bedside, addressing common unmet needs in the field of reconstructive and regenerative surgery.
Collapse
Affiliation(s)
- Pier Luigi Surico
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, United States
- Department of Ophthalmology, Campus Bio-Medico University, Rome 00128, Italy
| | - Anna Scarabosio
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Giovanni Miotti
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Martina Grando
- Department of Internal Medicine, Azienda Sanitaria Friuli Occidentale, San Vito al Tagliamento 33078, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Pier Camillo Parodi
- Department of Plastic Surgery, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy.
| |
Collapse
|
25
|
Sadeghsoltani F, Hassanpour P, Safari MM, Haiaty S, Rahbarghazi R, Rahmati M, Mota A. Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle. J Cell Physiol 2024; 239:e31185. [PMID: 38219050 DOI: 10.1002/jcp.31185] [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: 10/09/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 01/15/2024]
Abstract
Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.
Collapse
Affiliation(s)
- Fatemeh Sadeghsoltani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Hassanpour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mir-Meghdad Safari
- Open Heart ICU of Shahid Madani Cardiovascular Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanya Haiaty
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Rahmati
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mota
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
26
|
Bansal S, Rahman M, Ravichandran R, Canez J, Fleming T, Mohanakumar T. Extracellular Vesicles in Transplantation: Friend or Foe. Transplantation 2024; 108:374-385. [PMID: 37482627 DOI: 10.1097/tp.0000000000004693] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
The long-term function of transplanted organs, even under immunosuppression, is hindered by rejection, especially chronic rejection. Chronic rejection occurs more frequently after lung transplantation, termed chronic lung allograft dysfunction (CLAD), than after transplantation of other solid organs. Pulmonary infection is a known risk factor for CLAD, as transplanted lungs are constantly exposed to the external environment; however, the mechanisms by which respiratory infections lead to CLAD are poorly understood. The role of extracellular vesicles (EVs) in transplantation remains largely unknown. Current evidence suggests that EVs released from transplanted organs can serve as friend and foe. EVs carry not only major histocompatibility complex antigens but also tissue-restricted self-antigens and various transcription factors, costimulatory molecules, and microRNAs capable of regulating alloimmune responses. EVs play an important role in antigen presentation by direct, indirect, and semidirect pathways in which CD8 and CD4 cells can be activated. During viral infections, exosomes (small EVs <200 nm in diameter) can express viral antigens and regulate immune responses. Circulating exosomes may also be a viable biomarker for other diseases and rejection after organ transplantation. Bioengineering the surface of exosomes has been proposed as a tool for targeted delivery of drugs and personalized medicine. This review focuses on recent studies demonstrating the role of EVs with a focus on exosomes and their dual role (immune activation or tolerance induction) after organ transplantation, more specifically, lung transplantation.
Collapse
Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
| | | | | | | | | | | |
Collapse
|
27
|
Caño-Carrillo S, Castillo-Casas JM, Franco D, Lozano-Velasco E. Unraveling the Signaling Dynamics of Small Extracellular Vesicles in Cardiac Diseases. Cells 2024; 13:265. [PMID: 38334657 PMCID: PMC10854837 DOI: 10.3390/cells13030265] [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: 12/29/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024] Open
Abstract
Effective intercellular communication is essential for cellular and tissue balance maintenance and response to challenges. Cellular communication methods involve direct cell contact or the release of biological molecules to cover short and long distances. However, a recent discovery in this communication network is the involvement of extracellular vesicles that host biological contents such as proteins, nucleic acids, and lipids, influencing neighboring cells. These extracellular vesicles are found in body fluids; thus, they are considered as potential disease biomarkers. Cardiovascular diseases are significant contributors to global morbidity and mortality, encompassing conditions such as ischemic heart disease, cardiomyopathies, electrical heart diseases, and heart failure. Recent studies reveal the release of extracellular vesicles by cardiovascular cells, influencing normal cardiac function and structure. However, under pathological conditions, extracellular vesicles composition changes, contributing to the development of cardiovascular diseases. Investigating the loading of molecular cargo in these extracellular vesicles is essential for understanding their role in disease development. This review consolidates the latest insights into the role of extracellular vesicles in diagnosis and prognosis of cardiovascular diseases, exploring the potential applications of extracellular vesicles in personalized therapies, shedding light on the evolving landscape of cardiovascular medicine.
Collapse
Affiliation(s)
| | | | | | - Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (S.C.-C.); (J.M.C.-C.); (D.F.)
| |
Collapse
|
28
|
Ahmed W, Huang S, Chen L. Engineered exosomes derived from stem cells: a new brain-targeted strategy. Expert Opin Drug Deliv 2024; 21:91-110. [PMID: 38258509 DOI: 10.1080/17425247.2024.2306877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/15/2024] [Indexed: 01/24/2024]
Abstract
INTRODUCTION Using engineered exosomes produced from stem cells is an experimental therapeutic approach for treating brain diseases. According to reports, preclinical research has demonstrated notable neurogenesis and angiogenesis effects using modified stem cell-derived exosomes. These biological nanoparticles have a variety of anti-apoptotic, anti-inflammatory, and antioxidant properties that make them very promising for treating nervous system disorders. AREAS COVERED This review examines different ways to enhance the delivery of modified stem cell-derived exosomes, how they infiltrate the blood-brain barrier (BBB), and how they facilitate their access to the brain. We would also like to determine whether these nanoparticles have the most significant transmission rates through BBB when targeting brain lesions. EXPERT OPINION Using engineered stem cell-derived exosomes for treating brain disorders has generated considerable attention toward clinical research and application. However, stem cell-derived exosomes lack consistency, and their mechanisms of action are uncertain. Therefore, upcoming research needs to prioritize examining the underlying mechanisms and strategies via which these nanoparticles combat neurological disorders.
Collapse
Affiliation(s)
- Waqas Ahmed
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Songze Huang
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lukui Chen
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
29
|
Yin X, Lin L, Fang F, Zhang B, Shen C. Mechanisms and Optimization Strategies of Paracrine Exosomes from Mesenchymal Stem Cells in Ischemic Heart Disease. Stem Cells Int 2023; 2023:6500831. [PMID: 38034060 PMCID: PMC10686715 DOI: 10.1155/2023/6500831] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/11/2023] [Accepted: 10/25/2023] [Indexed: 12/02/2023] Open
Abstract
The morbidity and mortality of myocardial infarction (MI) are increasing worldwide. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal and differentiation capabilities that are essential in tissue healing and regenerative medicine. However, the low implantation and survival rates of transplanted cells hinder the widespread clinical use of stem cells. Exosomes are naturally occurring nanovesicles that are secreted by cells and promote the repair of cardiac function by transporting noncoding RNA and protein. In recent years, MSC-derived exosomes have been promising cell-free treatment tools for improving cardiac function and reversing cardiac remodeling. This review describes the biological properties and therapeutic potential of exosomes and summarizes some engineering approaches for exosomes optimization to enhance the targeting and therapeutic efficacy of exosomes in MI.
Collapse
Affiliation(s)
- Xiaorong Yin
- Department of Clinical Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Lizhi Lin
- Department of Clinical Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Fang Fang
- Department of Cardiology, Jining Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Cheng Shen
- Department of Cardiology, Jining Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| |
Collapse
|
30
|
Hawthorne IJ, Dunbar H, Tunstead C, Schorpp T, Weiss DJ, Enes SR, Dos Santos CC, Armstrong ME, Donnelly SC, English K. Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma. Mol Ther 2023; 31:3243-3258. [PMID: 37735872 PMCID: PMC10638061 DOI: 10.1016/j.ymthe.2023.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
Collapse
Affiliation(s)
- Ian J Hawthorne
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Hazel Dunbar
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Courteney Tunstead
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Tamara Schorpp
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Daniel J Weiss
- Department of Medicine, 226 Health Sciences Research Facility, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
| | - Sara Rolandsson Enes
- Department of Experimental Medical Science, Faculty of Medicine, Lund University, 22100 Lund, Sweden
| | - Claudia C Dos Santos
- The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, Canada; Institute of Medical Sciences and Interdepartmental Division of Critical Care, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | | | - Karen English
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
| |
Collapse
|
31
|
Zhang H, Wan X, Tian J, An Z, Liu L, Zhao X, Zhou Y, Zhang L, Ge C, Song X. The therapeutic efficacy and clinical translation of mesenchymal stem cell-derived exosomes in cardiovascular diseases. Biomed Pharmacother 2023; 167:115551. [PMID: 37783149 DOI: 10.1016/j.biopha.2023.115551] [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: 06/19/2023] [Revised: 09/08/2023] [Accepted: 09/18/2023] [Indexed: 10/04/2023] Open
Abstract
Exosomes, mainly derived from mesenchymal stem cells, provide a good reference for cardiac function repair and clinical application in cardiac and vascular diseases by regulating cardiomyocyte viability, inflammatory levels, angiogenesis, and ventricular remodeling after a heart injury. This review presents the cardioprotective efficacy of mesenchymal stem cell-originated exosomes and explores the underlying molecular mechanisms. Furthermore, we expound on several efficient approaches to transporting exosomes into the heart in clinical application and comment on the advantages and disadvantages of each method.
Collapse
Affiliation(s)
- Huan Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Xueqi Wan
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China; The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, PR China
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Yuquan Zhou
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Lijun Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Changjiang Ge
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China.
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China.
| |
Collapse
|
32
|
Chen P, Pan Y, Ning X, Shi X, Zhong J, Fan X, Li W, Teng Y, Liu X, Yu B, Yang Y, Li H, Ou C. Targeted heart repair by Tβ4-loaded cardiac-resident macrophage-derived extracellular vesicles modified with monocyte membranes. Acta Biomater 2023; 169:372-386. [PMID: 37597679 DOI: 10.1016/j.actbio.2023.08.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/21/2023]
Abstract
Recent studies have demonstrated the critical role of cardiac-resident macrophages (cMacs) in the maintenance of physiological homeostasis. However, recruitment of circulating monocyte-derived macrophages decreases cMac levels post-myocardial infarction (MI). Transplanting cMacs is not an ideal option due to their low survival rates and the risk of immunological rejection. However, extracellular vesicle therapy has the potential to provide a feasible and safe alternative for cardiac repair. In this study, cell membrane-modified extracellular vesicles (MmEVs) were developed for heart repair by modifying cMac-derived extracellular vesicles (mEVs) with monocyte membranes, resulting in immune evasion and sequential targeted localization to damaged regions through expression of CD47 on MmEVs and strong affinity between monocyte membrane proteins and CCL2. Additionally, to fully exploit the potential clinical application of MmEVs and achieve a better curative effect, thymosin β4 (Tβ4) was loaded into the nanoparticles, resulting in Tβ4-MmEVs. In vitro experiments indicated that both the MmEVs and Tβ4-MmEVs promoted cardiomyocyte proliferation and endothelial cell migration. Animal experiments suggested that MI mice treated with MmEVs and Tβ4-MmEVs exhibited reduced myocardial fibrosis and increased vascular density compared to the control group. Thus, we posit that these targeted nanoparticles hold significant potential for MI adjuvant therapy and may open new avenues for cardiac repair and regeneration. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) derived from bioactive parent cell sources involved in pathological and repair processes for cardiovascular disease have emerged as a compelling strategy for regenerative therapy. In this study, we constructed monocyte membrane-modified extracellular vesicles loaded with a drug (Tβ4-MmEVs) for heart repair that exhibit extraordinary abilities of immune evasion and sequential localization to damaged regions owing to the presence of CD47 and the strong affinity between monocytes and damaged cardiomyocytes and endothelial cells. The bioactivities of Tβ4-MmEVs on enhancing cardiomyocyte and endothelial cell proliferation were validated both in vitro and in vivo. Effective development and implementation of therapeutically membrane-modified nanoparticles from homologous origins can provide a reference for adjuvant therapy in clinical MI management.
Collapse
Affiliation(s)
- Peier Chen
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Yuxuan Pan
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Xiaodong Ning
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Xu Shi
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Jianfeng Zhong
- Department of Cardiology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524003, China
| | - Xianglin Fan
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Weirun Li
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Yintong Teng
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Xueting Liu
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China
| | - Bin Yu
- Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yanhua Yang
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China.
| | - Hekai Li
- Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Caiwen Ou
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, Dongguan 523018, China.
| |
Collapse
|
33
|
Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. [PMID: 37587531 PMCID: PMC10433599 DOI: 10.1186/s40779-023-00472-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023] Open
Abstract
Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.
Collapse
Affiliation(s)
- Jia-Yi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ling-Feng Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Gao-Feng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Shi-Ji Fang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Zhao-Yu Li
- Department of Overseas Education College, Jimei University, Xiamen, 361021, Fujian, China
| | - Xu-Ran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Medicine II, Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
- Pulmonary and Critical Care, Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
| | - Xiao-Kun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Zhou-Guang Wang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China.
| |
Collapse
|
34
|
Zhang W, Wang T, Xue Y, Zhan B, Lai Z, Huang W, Peng X, Zhou Y. Research progress of extracellular vesicles and exosomes derived from mesenchymal stem cells in the treatment of oxidative stress-related diseases. Front Immunol 2023; 14:1238789. [PMID: 37646039 PMCID: PMC10461809 DOI: 10.3389/fimmu.2023.1238789] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/24/2023] [Indexed: 09/01/2023] Open
Abstract
There is growing evidence that mesenchymal stem cell-derived extracellular vesicles and exosomes can significantly improve the curative effect of oxidative stress-related diseases. Mesenchymal stem cell extracellular vesicles and exosomes (MSC-EVs and MSC-Exos) are rich in bioactive molecules and have many biological regulatory functions. In this review, we describe how MSC-EVs and MSC-Exos reduce the related markers of oxidative stress and inflammation in various systemic diseases, and the molecular mechanism of MSC-EVs and MSC-Exos in treating apoptosis and vascular injury induced by oxidative stress. The results of a large number of experimental studies have shown that both local and systemic administration can effectively inhibit the oxidative stress response in diseases and promote the survival and regeneration of damaged parenchymal cells. The mRNA and miRNAs in MSC-EVs and MSC-Exos are the most important bioactive molecules in disease treatment, which can inhibit the apoptosis, necrosis and oxidative stress of lung, heart, kidney, liver, bone, skin and other cells, and promote their survive and regenerate.
Collapse
Affiliation(s)
- Wenwen Zhang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tingyu Wang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yuanye Xue
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Bingbing Zhan
- School of Pharmaceutical Sciences, Guangdong Medical University, Dongguan, China
| | - Zengjie Lai
- The Second Clinical Medical College of Guangdong Medical University, Dongguan, China
| | - Wenjie Huang
- School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xinsheng Peng
- Biomedical Innovation Center, Guangdong Medical University, Dongguan, China
- Institute of Marine Medicine, Guangdong Medical University, Zhanjiang, China
| | - Yanfang Zhou
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| |
Collapse
|
35
|
Liu Y, Wang M, Yu Y, Li C, Zhang C. Advances in the study of exosomes derived from mesenchymal stem cells and cardiac cells for the treatment of myocardial infarction. Cell Commun Signal 2023; 21:202. [PMID: 37580705 PMCID: PMC10424417 DOI: 10.1186/s12964-023-01227-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/12/2023] [Indexed: 08/16/2023] Open
Abstract
Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury. Video Abstract.
Collapse
Affiliation(s)
- Yuchang Liu
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Minrui Wang
- School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yang Yu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Chunxiang Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- The Key Laboratory of Medical Electrophysiology of the Ministry of Education, Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Laboratory of Nucleic Acids in Medicine for National High-Level Talents, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| |
Collapse
|
36
|
Rehman A, Nigam A, Laino L, Russo D, Todisco C, Esposito G, Svolacchia F, Giuzio F, Desiderio V, Ferraro G. Mesenchymal Stem Cells in Soft Tissue Regenerative Medicine: A Comprehensive Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1449. [PMID: 37629738 PMCID: PMC10456353 DOI: 10.3390/medicina59081449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023]
Abstract
Soft tissue regeneration holds significant promise for addressing various clinical challenges, ranging from craniofacial and oral tissue defects to blood vessels, muscle, and fibrous tissue regeneration. Mesenchymal stem cells (MSCs) have emerged as a promising tool in regenerative medicine due to their unique characteristics and potential to differentiate into multiple cell lineages. This comprehensive review explores the role of MSCs in different aspects of soft tissue regeneration, including their application in craniofacial and oral soft tissue regeneration, nerve regeneration, blood vessel regeneration, muscle regeneration, and fibrous tissue regeneration. By examining the latest research findings and clinical advancements, this article aims to provide insights into the current state of MSC-based therapies in soft tissue regenerative medicine.
Collapse
Affiliation(s)
- Ayesha Rehman
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Aditya Nigam
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Luigi Laino
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
| | - Diana Russo
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
| | | | | | - Fabiano Svolacchia
- Departments of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00118 Rome, Italy;
| | - Federica Giuzio
- Department of Sciences, University of Basilicata, Via Nazario Sauro 85, 85100 Potenza, Italy;
- U.O.S.D. of Plastic Surgery A.O.R “San Carlo”, 85100 Potenza, Italy
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Giuseppe Ferraro
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
| |
Collapse
|
37
|
Pan LF, Niu ZQ, Ren S, Pei HH, Gao YX, Feng H, Sun JL, Zhang ZL. Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury? World J Stem Cells 2023; 15:654-664. [PMID: 37545754 PMCID: PMC10401421 DOI: 10.4252/wjsc.v15.i7.654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/11/2023] [Accepted: 06/27/2023] [Indexed: 07/25/2023] Open
Abstract
Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.
Collapse
Affiliation(s)
- Long-Fei Pan
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
| | - Ze-Qun Niu
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Song Ren
- Department of Geriatric Digestive Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Hong-Hong Pei
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Yan-Xia Gao
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Hui Feng
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Jiang-Li Sun
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Zheng-Liang Zhang
- Emergency Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| |
Collapse
|
38
|
Essien SA, Ahuja I, Eisenhoffer GT. Macrophage Migration Inhibitory Factor on Apoptotic Extracellular Vesicles Regulates Compensatory Proliferation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.14.544889. [PMID: 37398303 PMCID: PMC10312732 DOI: 10.1101/2023.06.14.544889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss to maintain tissue homeostasis. While apoptotic cell-derived extracellular vesicles (AEVs) can transmit instructional cues to mediate communication with neighboring cells, the molecular mechanisms that induce cell division are not well understood. Here we show that macrophage migration inhibitory factor (MIF)-containing AEVs regulate compensatory proliferation via ERK signaling in epithelial stem cells of larval zebrafish. Time-lapse imaging showed efferocytosis of AEVs from dying epithelial stem cells by healthy neighboring stem cells. Proteomic and ultrastructure analysis of purified AEVs identified MIF localization on the AEV surface. Pharmacological inhibition or genetic mutation of MIF, or its cognate receptor CD74, decreased levels of phosphorylated ERK and compensatory proliferation in the neighboring epithelial stem cells. Disruption of MIF activity also caused decreased numbers of macrophages patrolling near AEVs, while depletion of the macrophage lineage resulted in a reduced proliferative response by the epithelial stem cells. We propose that AEVs carrying MIF directly stimulate epithelial stem cell repopulation and guide macrophages to cell non-autonomously induce localized proliferation to sustain overall cell numbers during tissue maintenance.
Collapse
Affiliation(s)
- Safia A. Essien
- Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, TX
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ivanshi Ahuja
- Department of Biosciences, Rice University, Houston TX
| | - George T. Eisenhoffer
- Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UT Health Houston Graduate School of Biomedical Sciences, Houston, TX
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX
| |
Collapse
|
39
|
Sharma A. Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology. J Cell Physiol 2023; 238:687-697. [PMID: 36745675 DOI: 10.1002/jcp.30967] [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: 11/14/2022] [Revised: 01/02/2023] [Accepted: 01/20/2023] [Indexed: 02/07/2023]
Abstract
Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.
Collapse
Affiliation(s)
- Aman Sharma
- ExoCan Healthcare Technologies Ltd, Pune, India
| |
Collapse
|
40
|
Nian W, Fu C. Exosomes in Myocardial Infarction: Therapeutic Potential and Clinical Application. J Cardiovasc Transl Res 2023; 16:87-96. [PMID: 35672604 DOI: 10.1007/s12265-022-10284-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 10/18/2022]
Abstract
Myocardial infarction (MI) remains the leading fatal disease in the world, and with subsequent adverse ventricular remodeling often leading to the development of heart failure, finding new ways to improve the prognosis of MI is important. Exosomes are extracellular vesicles of 30-150 nm secreted by various cells in the body. It is now well recognized that exosomes play an important role in MI, and exosomes may become a new approach to post-MI treatment. It is valuable to study how exosomes are involved in post-MI progression and how exosomes can be modified to improve their effectiveness. In this review, we focus on summarizing the therapeutic potential of exosomes for MI and the current status of clinical applications to provide evidence for the formal use of exosomes in the clinic.
Collapse
Affiliation(s)
| | - Cong Fu
- Department of Cardiology, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College, 92# West Zhe Shan Road, Wuhu, Anhui, China. .,Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wan Nan Medical College, Wuhu, China.
| |
Collapse
|
41
|
Hallmarks of Cancer Affected by the MIF Cytokine Family. Cancers (Basel) 2023; 15:cancers15020395. [PMID: 36672343 PMCID: PMC9856758 DOI: 10.3390/cancers15020395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
New diagnostic methods and treatments have significantly decreased the mortality rates of cancer patients, but further improvements are warranted based on the identification of novel tumor-promoting molecules that can serve as therapeutic targets. The macrophage migration inhibitory factor (MIF) family of cytokines, comprising MIF and DDT (also known as MIF2), are overexpressed in almost all cancer types, and their high expressions are related to a worse prognosis for the patients. MIF is involved in 9 of the 10 hallmarks of cancer, and its inhibition by antibodies, nanobodies, or small synthetic molecules has shown promising results. Even though DDT is also proposed to be involved in several of the hallmarks of cancer, the available information about its pro-tumoral role and mechanism of action is more limited. Here, we provide an overview of the involvement of both MIF and DDT in cancer, and we propose that blocking both cytokines is needed to obtain the maximum anti-tumor response.
Collapse
|
42
|
Chang W, Li P. Bone marrow mesenchymal stromal cell-derived small extracellular vesicles: A novel therapeutic agent in ischemic heart diseases. Front Pharmacol 2023; 13:1098634. [PMID: 36686710 PMCID: PMC9849567 DOI: 10.3389/fphar.2022.1098634] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 12/22/2022] [Indexed: 01/07/2023] Open
Abstract
Myocardial injury is a major pathological factor that causes death in patients with heart diseases. In recent years, mesenchymal stromal cells (MSCs) have been generally used in treating many diseases in animal models and clinical trials. mesenchymal stromal cells have the ability to differentiate into osteocytes, adipocytes and chondrocytes. Thus, these cells are considered suitable for cardiac injury repair. However, mechanistic studies have shown that the secretomes of mesenchymal stromal cells, mainly small extracellular vesicles (sEVs), have better therapeutic effects than mesenchymal stromal cells themselves. In addition, small extracellular vesicles have easier quality control characteristics and better safety profiles. Therefore, mesenchymal stromal cell-small extracellular vesicles are emerging as novel therapeutic agents for damaged myocardial treatment. To date, many clinical trials and preclinical experimental results have demonstrated the beneficial effects of bone marrow-derived mesenchymal stromal cells (BMMSCs) and bone marrow-derived mesenchymal stromal cells-small extracellular vesicles on ischemic heart disease. However, the validation of therapeutic efficacy and the use of tissue engineering methods require an exacting scientific rigor and robustness. This review summarizes the current knowledge of bone marrow-derived mesenchymal stromal cells- or bone marrow-derived mesenchymal stromal cells-small extracellular vesicle-based therapy for cardiac injury and discusses critical scientific issues in the development of these therapeutic strategies.
Collapse
Affiliation(s)
- Wenguang Chang
- Institute for Translational Medicine, The Affiliated Hospital, College of Medicine, Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital, College of Medicine, Qingdao University, Qingdao, China
| |
Collapse
|
43
|
Adelipour M, Lubman DM, Kim J. Potential applications of mesenchymal stem cells and their derived exosomes in regenerative medicine. Expert Opin Biol Ther 2023; 23:491-507. [PMID: 37147781 PMCID: PMC10330313 DOI: 10.1080/14712598.2023.2211203] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/03/2023] [Indexed: 05/07/2023]
Abstract
INTRODUCTION Regenerative medicine involves the replacement of damaged cells, tissues, or organs to restore normal function. Mesenchymal stem cells (MSCs) and exosomes secreted by MSCs have unique advantages that make them a suitable candidate in the field of regenerative medicine. AREAS COVERED This article provides a comprehensive overview of regenerative medicine, focusing on the use of MSCs and their exosomes as potential therapies for replacing damaged cells, tissues, or organs. This article discusses the distinct advantages of both MSCs and their secreted exosomes, including their immunomodulatory effects, lack of immunogenicity, and recruitment to damaged areas. While both MSCs and exosomes have these advantages, MSCs also have the unique ability to self-renew and differentiate. This article also assesses the current challenges associated with the application of MSCs and their secreted exosomes in therapy. We have reviewed proposed solutions for improving MSC or exosome therapy, including ex-vivo preconditioning strategies, genetic modification, and encapsulation. Literature search was conducted using Google Scholar and PubMed databases. EXPERT OPINION Providing insight into the future development of MSC and exosome-based therapies and to encourage the scientific community to focus on the identified gaps, develop appropriate guidelines, and enhance the clinical application of these therapies.
Collapse
Affiliation(s)
- Maryam Adelipour
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
- Department of Biochemistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Jeongkwon Kim
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
| |
Collapse
|
44
|
Cui J, Li Y, Zhu M, Liu Y, Liu Y. Analysis of the Research Hotspot of Exosomes in Cardiovascular Disease: A Bibliometric-based Literature Review. Curr Vasc Pharmacol 2023; 21:316-345. [PMID: 37779407 DOI: 10.2174/0115701611249727230920042944] [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: 02/18/2023] [Revised: 08/21/2023] [Accepted: 08/29/2023] [Indexed: 10/03/2023]
Abstract
OBJECTIVE To investigate the current status and development trend of research on exosomes in cardiovascular disease (CVD) using bibliometric analysis and to elucidate trending research topics. METHODS Research articles on exosomes in CVD published up to April 2022 were retrieved from the Web of Science database. Data were organized using Microsoft Office Excel 2019. CiteSpace 6.1 and VOSviewer 1.6.18 were used for bibliometric analysis and result visualization. RESULTS Overall, 256 original research publications containing 190 fundamental research publications and 66 clinical research publications were included. "Extracellular vesicle" was the most frequent research keyword, followed by "microrna," "apoptosis," and "angiogenesis." Most publications were from China (187, 73.05%), followed by the United States (57, 22.27%), the United Kingdom (7, 2.73%), and Japan (7, 2.73%). A systematic review of the publications revealed that myocardial infarction and stroke were the most popular topics and that exosomes and their contents, such as microRNAs (miRNAs), play positive roles in neuroprotection, inhibition of autophagy and apoptosis, promotion of angiogenesis, and protection of cardiomyocytes. CONCLUSION Research on exosomes in CVD has attracted considerable attention, with China having the most published studies. Fundamental research has focused on CVD pathogenesis; exosomes regulate the progression of CVD through biological processes, such as the inflammatory response, autophagy, and apoptosis. Clinical research has focused on biomarkers for CVD; studies on using miRNAs in exosomes as disease markers for diagnosis could become a future trend.
Collapse
Affiliation(s)
- Jing Cui
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yiwen Li
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Mengmeng Zhu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yanfei Liu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
- Second Department of Geriatrics, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yue Liu
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
45
|
Okamura A, Yoshioka Y, Saito Y, Ochiya T. Can Extracellular Vesicles as Drug Delivery Systems Be a Game Changer in Cardiac Disease? Pharm Res 2022; 40:889-908. [PMID: 36577860 PMCID: PMC10126064 DOI: 10.1007/s11095-022-03463-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/13/2022] [Indexed: 12/29/2022]
Abstract
Cardiac diseases such as myocardial infarction and heart failure have been the leading cause of death worldwide for more than 20 years, and new treatments continue to be investigated. Heart transplantation, a curative treatment for severe cardiac dysfunction, is available to only a small number of patients due to the rarity of donors and high costs. Cardiac regenerative medicine using embryonic stem cells and induced pluripotent stem cells is expected to be a new alternative to heart transplantation, but it has problems such as induction of immune response, tumor formation, and low survival rate of transplanted cells. On the other hand, there has been a focus on cell-free therapy using extracellular vesicles (EVs) due to their high biocompatibility and target specificity. Exosomes, one type of EV, play a role in the molecular transport system in vivo and can be considered a drug delivery system (DDS) innate to all living things. Exosomes contain nucleic acids and proteins, which are transported from secretory cells to recipient cells. Molecules in exosomes are encapsulated in a lipid bilayer, which allows them to exist stably in body fluids without being affected by nuclease degradation enzymes. Therefore, the therapeutic use of exosomes as DDSs has been widely explored and is being used in clinical trials and other clinical settings. This review summarizes the current topics of EVs as DDSs in cardiac disease.
Collapse
Affiliation(s)
- Akihiko Okamura
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan.,Department of Cardiovascular Medicine, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Yusuke Yoshioka
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Yoshihiko Saito
- Department of Cardiovascular Medicine, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan.
| |
Collapse
|
46
|
An Z, Tian J, Liu Y, Zhao X, Yang X, Yong J, Liu L, Zhang L, Jiang W, Song X, Zhang H. Exosomes as a Cell-free Therapy for Myocardial Injury Following Acute Myocardial Infarction or Ischemic Reperfusion. Aging Dis 2022; 13:1770-1786. [PMID: 36465167 PMCID: PMC9662265 DOI: 10.14336/ad.2022.0416] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/16/2022] [Indexed: 08/13/2023] Open
Abstract
Exosomes, which contain miRNA, have been receiving growing attention in cardiovascular therapy because of their role in mediating cell-cell communication, autophagy, apoptosis, inflammation, and angiogenesis. Several studies have suggested that miRNA derived from exosomes can be used to detect myocardial infarctions (MI) in patients. Basic research also suggests that exosomes could serve as a potential therapeutic target for treating acute myocardial infarction. Ischemia/reperfusion (IR) injury is associated with adverse cardiac events after acute MI. We aim to review the potential benefits and mechanisms of exosomes in treating MI and IR injury.
Collapse
Affiliation(s)
- Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Yue Liu
- Cardiovascular disease center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Xueyao Yang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Jingwen Yong
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Lijun Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Wenjian Jiang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Hongjia Zhang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
47
|
Fu J, Niu H, Gao G, Wang L, Yu K, Guo R, Zhang J. Naringenin promotes angiogenesis of ischemic myocardium after myocardial infarction through miR-223-3p/IGF1R axis. Regen Ther 2022; 21:362-371. [PMID: 36161098 PMCID: PMC9471969 DOI: 10.1016/j.reth.2022.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 07/15/2022] [Accepted: 07/28/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Naringenin exerts a protective effect on myocardial ischemia and reperfusion. It has been reported that miR-223-3p is a potential target for the treatment of myocardial infarction (MI). In view of the unreported correlation between Naringenin and miR-223-3p, this study was designed to confirm that the ameliorative effects of Naringenin on MI is directly related to the regulation of miR-223-3p. Methods Through electrocardiogram detection, Masson pathological staining and immunohistochemistry of angiogenesis-related factors, alleviative effects of Naringenin on heart function, myocardial injury and angiogenesis in MI mice were observed individually. Hypoxic HUVECs were selected in the in vitro experimental model. The cell viability, angiogenesis and migration ability were analyzed to fathom out the pro-angiogenesis potential of Naringenin. The effect of Naringenin on miR-223-3p, as well as the downstream molecular mechanism was verified through bioinformatics analysis and rescue experiments. Results Naringenin improved heart functions of MI mice, reduced degree of myocardial fibrosis, stimulated expressions of angiogenic factors and down-regulated level of miR-223-3p in myocardial tissue. In in vitro experiments, Naringenin increased the viability of hypoxic HUVECs, as well as the abilities of tube formation and migration, and further inhibited the expression of miR-223-3p. In the rescue trial, miR-223-3p mimic reversed the therapeutic effect of Naringenin. Type 1 insulin-like growth factor receptor (IGF1R), as a downstream target gene of miR-223-3p, partially offset the cellular regulatory effects of miR-223-3p after overexpression of IGF1R. Conclusions Naringenin improves the angiogenesis of hypoxic HUVECs by regulating the miR-223-3p/IGF1R axis, and has the potential to promote myocardial angiogenesis in MI mice.
Collapse
Affiliation(s)
- Jinguo Fu
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Heping Niu
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Guangren Gao
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Lei Wang
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Kai Yu
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Run Guo
- Department of Cardiology, Cangzhou Central Hospital, China
| | - Jun Zhang
- Department of Cardiology, Cangzhou Central Hospital, China
| |
Collapse
|
48
|
Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome. Cell Death Dis 2022; 8:452. [DOI: 10.1038/s41420-022-01235-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 09/25/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
AbstractInflammation plays crucial roles in the regulation of pathophysiological processes involved in injury, repair and remodeling of the infarcted heart; hence, it has become a promising target to improve the prognosis of myocardial infarction (MI). Mesenchymal stem cells (MSCs) serve as an effective and innovative treatment option for cardiac repair owing to their paracrine effects and immunomodulatory functions. In fact, transplanted MSCs have been shown to accumulate at injury sites of heart, exerting multiple effects including immunomodulation, regulating macrophages polarization, modulating the activation of T cells, NK cells and dendritic cells and alleviating pyroptosis of non-immune cells. Many studies also proved that preconditioning of MSCs can enhance their inflammation-regulatory effects. In this review, we provide an overview on the current understanding of the mechanisms on MSCs and their secretome regulating inflammation and immune cells after myocardial infarction and shed light on the applications of MSCs in the treatment of cardiac infarction.
Collapse
|
49
|
Chen S, Yu Q, Song Y, Cui Z, Li M, Mei C, Cui H, Cao S, Zhu C. Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury. Front Pharmacol 2022; 13:951906. [PMID: 36160453 PMCID: PMC9493190 DOI: 10.3389/fphar.2022.951906] [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: 05/24/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Hepatic ischemia–reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage migration inhibitory factor (MIF) in hepatic I/R injury is unclear. Methods: We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia–reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored in vivo and in vitro. Results: MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress in vivo and in vitro, whereas MIF overexpression significantly aggravated liver injury. Via RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice. Conclusion: Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.
Collapse
Affiliation(s)
- Sanyang Chen
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
| | - Qiwen Yu
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yaodong Song
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
| | - Zongchao Cui
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
| | - Mengke Li
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
| | - Chaopeng Mei
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
| | - Huning Cui
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
| | - Shengli Cao
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Shengli Cao, ; Changju Zhu,
| | - Changju Zhu
- Department of Emergency Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, China
- *Correspondence: Shengli Cao, ; Changju Zhu,
| |
Collapse
|
50
|
Ma J, Lei P, Chen H, Wang L, Fang Y, Yan X, Yang Q, Peng B, Jin L, Sun D. Advances in lncRNAs from stem cell-derived exosome for the treatment of cardiovascular diseases. Front Pharmacol 2022; 13:986683. [PMID: 36147326 PMCID: PMC9486024 DOI: 10.3389/fphar.2022.986683] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality globally. Benefiting from the advantages of early diagnosis and precision medicine, stem cell-based therapies have emerged as promising treatment options for CVDs. However, autologous or allogeneic stem cell transplantation imposes a potential risk of immunological rejection, infusion toxicity, and oncogenesis. Fortunately, exosome can override these limitations. Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) in exosome from stem cell paracrine factors play critical roles in stem cell therapy and participate in numerous regulatory processes, including transcriptional silencing, transcriptional activation, chromosome modification, and intranuclear transport. Accordingly, lncRNAs can treat CVDs by directly acting on specific signaling pathways. This mini review systematically summarizes the key regulatory actions of lncRNAs from different stem cells on myocardial aging and apoptosis, ischemia-reperfusion injury, retinopathy, atherosclerosis, and hypertension. In addition, the current challenges and future prospects of lncRNAs treatment for CVDs are discussed.
Collapse
Affiliation(s)
- Jiahui Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Pengyu Lei
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Haojie Chen
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Lei Wang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Yimeng Fang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Xiaoqing Yan
- Department of Pharmacy, Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Bo Peng
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Libo Jin
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
| |
Collapse
|