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Li L, Zheng Z, Lan W, Tang N, Zhang D, Ling J, Wu Y, Yang P, Fu L, Liu J, Zhang J, Yu P, Huang T. Role of Exosomes in Cardiovascular Disease: A Key Regulator of Intercellular Communication in Cardiomyocytes. ACS OMEGA 2025; 10:18145-18169. [PMID: 40385188 PMCID: PMC12079207 DOI: 10.1021/acsomega.4c11423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/27/2025] [Accepted: 04/22/2025] [Indexed: 05/20/2025]
Abstract
In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.
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Affiliation(s)
- Liuxin Li
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Zhidong Zheng
- Department of Endocrinology and Metabolism, second Affiliated Hospital
of Nanchang University, Nanchang, People’s Republic of China, The second Clinical Medical College, Nanchang University, Nanchang 330006, Republic of China
| | - Wenyu Lan
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Nan Tang
- The
Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Deju Zhang
- Food
and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong 0000, Hong Kong
| | - Jitao Ling
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Yuting Wu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Pingping Yang
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Linhua Fu
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jianping Liu
- Department
of Endocrinology and Metabolism, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
| | - Jing Zhang
- Department
of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical
College, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Peng Yu
- Department
of Metabolism and Endocrinology, The Second
Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Tieqiu Huang
- Department
of Cardiovascular Medicine, The Second Affiliated Hospital, Jiangxi
Medical College, Nanchang University, Nanchang 330006, Jiangxi,China
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Li J, Liu L, Chen Y, Huang Y, Yang L. Exosomes derived from human umbilical cord mesenchymal stem cells attenuate senescence of peritoneal mesothelial cells by inhibiting oxidative stress. Int Immunopharmacol 2025; 158:114813. [PMID: 40354711 DOI: 10.1016/j.intimp.2025.114813] [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: 11/01/2024] [Revised: 05/04/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
OBJECTIVE Aging is a natural process that affects cellular function. In peritoneal dialysis (PD), chronic exposure to dialysate induces oxidative stress (OS) in peritoneal mesothelial cells (PMCs), leading to cellular aging, fibrosis, and reduced dialysis efficacy. Mesenchymal stem cells (MSCs) have shown potential in alleviating cellular aging. This study investigates the role of exosomes (hUMSC-Exos) derived from human umbilical cord MSCs (hUMSCs) in mitigating PMC senescence and explores the underlying mechanisms. METHODS Human peritoneal mesothelial cells (HMrSV5) were cultured with 2.5 % glucose to induce senescence. Aging markers were assessed via Western blotting, β-galactosidase staining, and cell cycle analysis. hUMSC-Exos were characterized using Western blot, electron microscopy, and nanoparticle tracking analysis. Their uptake by HMrSV5 cells was confirmed through fluorescence microscopy. Various concentrations of hUMSC-Exos were tested, and OS levels were evaluated using reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assays. The impact of the OS inhibitor N-acetyl-L-cysteine (NAC) on aging markers was also examined. RESULTS HMrSV5 cells treated with 2.5 % glucose exhibited increased expression of P53, P21, and P16, along with G0/G1 cell cycle arrest. Treatment with 150 μg/mL hUMSC-Exos reduced aging markers, decreased ROS and MDA levels, and increased SOD activity. Similar effects were observed with NAC treatment. CONCLUSION hUMSC-Exos alleviate PMCs aging by inhibiting OS, highlighting their potential to improve PD outcomes.
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Affiliation(s)
- Jia Li
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Lixin Liu
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Yiman Chen
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Yuling Huang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China; Department of International Physical Examination Center, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
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Kananivand M, Nouri F, Yousefi MH, Pajouhi A, Ghorbani H, Afkhami H, Razavi ZS. Mesenchymal stem cells and their exosomes: a novel approach to skin regeneration via signaling pathways activation. J Mol Histol 2025; 56:132. [PMID: 40208456 DOI: 10.1007/s10735-025-10394-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/06/2025] [Indexed: 04/11/2025]
Abstract
Accelerating wound healing is a crucial objective in surgical and regenerative medicine. The wound healing process involves three key stages: inflammation, cell proliferation, and tissue repair. Mesenchymal stem cells (MSCs) have demonstrated significant therapeutic potential in promoting tissue regeneration, particularly by enhancing epidermal cell migration and proliferation. However, the precise molecular mechanisms underlying MSC-mediated wound healing remain unclear. This review highlights the pivotal role of MSCs and their exosomes in wound repair, with a specific focus on critical signaling pathways, including PI3K/Akt, WNT/β-catenin, Notch, and MAPK. These pathways regulate essential cellular processes such as proliferation, differentiation, and angiogenesis. Moreover, in vitro and in vivo studies reveal that MSCs accelerate wound closure, enhance collagen deposition, and modulate immune responses, contributing to improved tissue regeneration. Understanding these mechanisms provides valuable insights into MSC-based therapeutic strategies for enhancing wound healing.
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Affiliation(s)
- Maryam Kananivand
- Medical Department, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Nouri
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University (SRBIAU), Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
| | - Ali Pajouhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hakimeah Ghorbani
- Department of Sciences, Faculty of Biological Sciences, Tabriz University of Sciences, Tabriz, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran.
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Du ZH, Chu WX, Peng X, Wu LL, Liu Y, Yu GY, Ding C. SHED-Derived Exosomes Ameliorate Sjögren's Syndrome-Induced Hyposalivation by Suppressing Th1 Cell Response via the miR-29a-3p/T-bet Axis. ACS APPLIED MATERIALS & INTERFACES 2025; 17:5752-5761. [PMID: 39803988 PMCID: PMC11788986 DOI: 10.1021/acsami.4c16595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025]
Abstract
Background: Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods: SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results: SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion: SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.
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Affiliation(s)
- Zhi-hao Du
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Wei-xia Chu
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
- Shanghai
General Hospital, Shanghai 200080, P. R. China
| | - Xin Peng
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Li-ling Wu
- Department
of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular
Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular
Receptors Research, Peking University School
of Basic Medical Sciences, Beijing 100191, P. R. China
| | - Yan Liu
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Guang-yan Yu
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Chong Ding
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
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Zheng B, Wang X, Guo M, Tzeng CM. Current Development of Mesenchymal Stem Cell-Derived Extracellular Vesicles. Cell Transplant 2025; 34:9636897241297623. [PMID: 39874070 PMCID: PMC11775985 DOI: 10.1177/09636897241297623] [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: 06/22/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 01/30/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells with self-renewal. They play a critical role in cell therapy due to their powerful immunomodulatory and regenerative effects. Recent studies suggest that one of the key therapeutic mechanisms of MSCs seems to derive from their paracrine product, called extracellular vesicles (EVs). The EVs contain much DNA, messenger RNA (mRNA), microRNA, and protein components, which can exert intracellular communication to target cells. In clinical applications, the MSC-EVs have been widely used in tissue repair and immune disorder diseases. However, there are serval issues need to be considered such as how to accomplish the large-scale production of EVs and how to verify the exact mechanism of EVs. In this review, we summarize the current progress of MSC-EVs and discuss the challenges and future of MSC-EVs.
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Affiliation(s)
- Bingyi Zheng
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Xueting Wang
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Meizhai Guo
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Chi-Meng Tzeng
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
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Wang S, Li X, Wang T, Sun Z, Feng E, Jin Y. Overexpression of USP35 enhances the protective effect of hUC-MSCs and their extracellular vesicles in oxygen-glucose deprivation/reperfusion-induced SH-SY5Y cells via stabilizing FUNDC1. Commun Biol 2024; 7:1330. [PMID: 39406943 PMCID: PMC11480199 DOI: 10.1038/s42003-024-07024-5] [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: 11/21/2023] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Ischemia-reperfusion (IR) injury is associated with neurological disorders such as stroke. The therapeutic potential of human umbilical cord mesenchymal stem cells (hUC-MSCs) and their secreted extracellular vesicles (EVs) in alleviating IR injury across various cell types including neuronal cells has been documented. However, the underlying mechanisms through which hUC-MSCs and hUC-MSC-EVs protect neuronal cells from IR-triggered damage are not well understood. In this study, we co-cultured SH-SY5Y neuroblastoma cells with hUC-MSCs or hUC-MSC-EVs and subjected them to oxygen-glucose deprivation/reperfusion (OGD/R) treatment. Our findings indicate that both hUC-MSCs and hUC-MSC-EVs significantly improved viability, reduced apoptosis, promoted autophagy of OGD/R-induced SH-SY5Y cells, and decreased mitochondrial reactive oxygen species levels within them. Furthermore, the neuroprotective effect of hUC-MSCs and hUC-MSC-EVs in OGD/R-induced SH-SY5Y cells was enhanced by overexpressing USP35, a deubiquitinase. Mechanistically, USP35 interacted with and stabilized FUNDC1, a positive regulator of mitochondrial metabolism. Knockdown of FUNDC1 in USP35-overexpressing hUC-MSCs and their secreted EVs eliminated the augmented neuroprotective function induced by excess USP35. In conclusion, these findings underscore the crucial role of USP35 in enhancing the neuroprotective function of hUC-MSCs and their secreted EVs, achieved through the stabilization of FUNDC1 in OGD/R-induced SH-SY5Y cells.
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Affiliation(s)
- Shuo Wang
- Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Xigong Li
- Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Tianjiao Wang
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310051, People's Republic of China
| | - Zeyu Sun
- Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Erwei Feng
- Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Yongming Jin
- Department of Orthopedics Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People's Republic of China.
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Yu M, Jin Y, Yuan K, Liu B, Zhu N, Zhang K, Li S, Tai Z. Effects of exosomes and inflammatory response on tumor: a bibliometrics study and visualization analysis via CiteSpace and VOSviewer. J Cancer Res Clin Oncol 2024; 150:405. [PMID: 39210153 PMCID: PMC11362500 DOI: 10.1007/s00432-024-05915-y] [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: 06/23/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Tumor is a new organism formed by abnormal hyperplasia of local tissue cells under the action of various tumorigenic factors. Inflammation plays a decisive role in inducing tumorigenesis, promoting tumor development, invasion and migration. More and more evidence indicate that exosomes are involved in regulating the formation of tumor microenvironment in the process of proinflammatory carcinogenesis, leading to the stimulation of anti-tumor immune response or systemic immunosuppression, and exosomes play a crucial role in the development of tumor. METHODS The articles on tumor-derived exosomes and inflammatory responses from January 2005 to January 2024 were collected through Web of Science (WOS), and the inclusion criteria were "Article", "Review Article" and "Early Access". Articles obtained after excluding "Book Chapters", "Editorial Material", "Proceeding Paper", "Meeting Abstract" and "Retracted Publication". Bibliometrics and visualization analysis were carried out on the obtained articles using CiteSpace6.2.R6 and VOSviewer1.6.20. RESULTS Total of 703 articles were included. The number of published documents showed a fluctuating growth trend year by year. A total of 61 countries have participated in the research on the effects of exosomes and inflammatory responses on tumors, among which China and the United States have the largest influence in this field. The obtained articles have been published in 60 journals around the world, among which PLOS ONE and NAT REV IMMUNOL are the journals with the most published articles and the highest co-citations respectively. The article from French author THERY C was cited the most (202 times). As a major researcher on the basic function of exosomes, THERY C established the gold standard for extraction, separation and identification of exosomes, and found that exosomes promote tumor metastasis through direct regulation of miRNA. Her research has had a huge impact on the field. Keyword co-occurrence analysis indicate that extracellular vesicles, inflammation, cancer, miRNAs, mesenchymal stem cells, drug delivery, gastric cancer and circulating endothelial microparticles are the research hotspot at present stage. The main keywords of the cluster analysis show that extracellular vesicles, human papilloma virus, myeloid cells, tumor macro-environment are the current research hotspots and frontier. The research hotspots have developed over time from the time chart of keywords and clustering, especially after 2016, exosomes have established extensive links with drug delivery, cancer treatment, inflammatory response and other fields. Tumor-derived exosomes stimulate receptor cells to secrete pro-inflammatory cytokines and growth factors, enabling immune and inflammatory cells to perceive the intracellular environment of cancer cells even when cancer cells do not express any tumor-specific antigens. For example, in anoxic environment, cancer cells can secrete exosomes containing pro-inflammatory factors to promote the invasion and metastasis of cancer cells. In the complex tumor microenvironment, both tumor cells and various stromal cells will secrete specific exosomes, and promote the development of tumors through various ways, so that tumor cells have drug resistance, and bring adverse effects on the clinical treatment of tumor patients. MicroRNAs and long noncoding RNA as hot keywords play important roles in regulating and mediating tumor development, and their specificity makes them important biomarkers for cancer prediction and diagnosis. Highlighting word analysis shows that microRNAs secreted by leukemia patients can effectively promote the proliferation of malignant cells and the development of cardiovascular diseases. At the same time, exosomes can induce the secretion of some microRNAs in patients, leading to cardiac repair and regeneration. Therefore, the detection and screening of microRNAs plays a crucial role in predicting the incidence of cardiovascular diseases in patients. CONCLUSION Exosomes have attracted increasing attention due to their significant heterogeneity and ability to regulate the tumor immune microenvironment. However, tumor cell-derived exosomes accelerate tumor progression by enhancing immunosuppression and inflammation, increasing oxidative stress, and promoting angiogenesis, which may lead to poor prognosis.
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Affiliation(s)
- Miao Yu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Yaxuan Jin
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Kaize Yuan
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Bohao Liu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Na Zhu
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Ke Zhang
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China
| | - Shuying Li
- North China University of Science and Technology (Hebei Key Laboratory for Chronic Diseases), Tangshan, China.
| | - Zhihui Tai
- North China University of Science and Technology Affiliated Hospital, Tangshan, China.
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Quarato ER, Salama NA, Calvi LM. Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging. Curr Osteoporos Rep 2024; 22:416-432. [PMID: 38782850 DOI: 10.1007/s11914-024-00874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE OF THE REVIEW In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease. RECENT FINDINGS Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.
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Affiliation(s)
- Emily R Quarato
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
| | - Noah A Salama
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
| | - Laura M Calvi
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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Zhao W, Li K, Li L, Wang R, Lei Y, Yang H, Sun L. Mesenchymal Stem Cell-Derived Exosomes as Drug Delivery Vehicles in Disease Therapy. Int J Mol Sci 2024; 25:7715. [PMID: 39062956 PMCID: PMC11277139 DOI: 10.3390/ijms25147715] [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: 06/07/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Exosomes are small vesicles containing proteins, nucleic acids, and biological lipids, which are responsible for intercellular communication. Studies have shown that exosomes can be utilized as effective drug delivery vehicles to accurately deliver therapeutic substances to target tissues, enhancing therapeutic effects and reducing side effects. Mesenchymal stem cells (MSCs) are a class of stem cells widely used for tissue engineering, regenerative medicine, and immunotherapy. Exosomes derived from MSCs have special immunomodulatory functions, low immunogenicity, the ability to penetrate tumor tissues, and high yield, which are expected to be engineered into efficient drug delivery systems. Despite the promising promise of MSC-derived exosomes, exploring their optimal preparation methods, drug-loading modalities, and therapeutic potential remains challenging. Therefore, this article reviews the related characteristics, preparation methods, application, and potential risks of MSC-derived exosomes as drug delivery systems in order to find potential therapeutic breakthroughs.
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Affiliation(s)
- Wenzhe Zhao
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
| | - Kaixuan Li
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
| | - Liangbo Li
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
| | - Ruichen Wang
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
| | - Yang Lei
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
| | - Hui Yang
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
| | - Leming Sun
- School of Life Sciences, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment in Special Environment, Northwestern Polytechnical University, Xi’an 710072, China; (W.Z.); (K.L.); (L.L.); (R.W.); (Y.L.)
- Dongguan Sanhang Innovation Institute, Dongguan 523808, China
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10
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Guerricchio L, Barile L, Bollini S. Evolving Strategies for Extracellular Vesicles as Future Cardiac Therapeutics: From Macro- to Nano-Applications. Int J Mol Sci 2024; 25:6187. [PMID: 38892376 PMCID: PMC11173118 DOI: 10.3390/ijms25116187] [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: 04/12/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Cardiovascular disease represents the foremost cause of mortality and morbidity worldwide, with a steadily increasing incidence due to the growth of the ageing population. Cardiac dysfunction leading to heart failure may arise from acute myocardial infarction (MI) as well as inflammatory- and cancer-related chronic cardiomyopathy. Despite pharmacological progress, effective cardiac repair represents an unmet clinical need, with heart transplantation being the only option for end-stage heart failure. The functional profiling of the biological activity of extracellular vesicles (EVs) has recently attracted increasing interest in the field of translational research for cardiac regenerative medicine. The cardioprotective and cardioactive potential of human progenitor stem/cell-derived EVs has been reported in several preclinical studies, and EVs have been suggested as promising paracrine therapy candidates for future clinical translation. Nevertheless, some compelling aspects must be properly addressed, including optimizing delivery strategies to meet patient needs and enhancing targeting specificity to the cardiac tissue. Therefore, in this review, we will discuss the most relevant aspects of the therapeutic potential of EVs released by human progenitors for cardiovascular disease, with a specific focus on the strategies that have been recently implemented to improve myocardial targeting and administration routes.
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Affiliation(s)
- Laura Guerricchio
- Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy;
| | - Lucio Barile
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, CH-6500 Bellinzona, Switzerland;
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland
| | - Sveva Bollini
- Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy;
- Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
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11
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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.
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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.
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12
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Wu Y, Peng W, Chen S, Zeng X, Zhu J, Zhu P. CAV1 Protein Encapsulated in Mouse BMSC-Derived Extracellular Vesicles Alleviates Myocardial Fibrosis Following Myocardial Infarction by Blocking the TGF-β1/SMAD2/c-JUN Axis. J Cardiovasc Transl Res 2024; 17:523-539. [PMID: 38092988 DOI: 10.1007/s12265-023-10472-9] [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: 06/28/2023] [Accepted: 11/27/2023] [Indexed: 07/03/2024]
Abstract
Extracellular vesicles (EVs) derived from mouse bone marrow mesenchymal stem cells (mBMSCs) convey the CAV1 protein, influencing the TGF-β1/SMAD2/c-JUN pathway and thus the molecular mechanisms underlying myocardial fibrosis (MF) post-myocardial infarction (MI). Through various experimental methods, including transmission electron microscopy, Nanosight analysis, Western blot, ELISA, and qRT-PCR, we isolated, purified, and identified EVs originating from mBMSCs. Bioinformatics and experimental findings show a reduced expression of CAV1 in myocardial fibrosis tissue. Furthermore, our findings suggest that mBMSC-EVs can deliver CAV1 to cardiac fibroblasts (CFs) and that silencing CAV1 in mBMSC-EVs promotes CF fibrosis. In vivo studies further corroborated these findings. In conclusion, mBMSC-EVs mitigate myocardial fibrosis in MI mice by delivering the CAV1 protein, inhibiting the TGF-β1/SMAD2/c-JUN pathway.
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Affiliation(s)
- Yijin Wu
- Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106 Zhongshan Er Road, Yuexiu District, Guangzhou, 510100, China
| | - Wenying Peng
- Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, China
| | - Siyao Chen
- Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, China
| | - Xiaodong Zeng
- Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, China
| | - Jiade Zhu
- Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106 Zhongshan Er Road, Yuexiu District, Guangzhou, 510100, China
| | - Ping Zhu
- Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106 Zhongshan Er Road, Yuexiu District, Guangzhou, 510100, China.
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13
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Amaro-Prellezo E, Gómez-Ferrer M, Hakobyan L, Ontoria-Oviedo I, Peiró-Molina E, Tarazona S, Salguero P, Ruiz-Saurí A, Selva-Roldán M, Vives-Sanchez R, Sepúlveda P. Extracellular vesicles from dental pulp mesenchymal stem cells modulate macrophage phenotype during acute and chronic cardiac inflammation in athymic nude rats with myocardial infarction. Inflamm Regen 2024; 44:25. [PMID: 38807194 PMCID: PMC11134765 DOI: 10.1186/s41232-024-00340-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/23/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND/AIMS Extracellular vesicles (EVs) derived from dental pulp mesenchymal stem cells (DP-MSCs) are a promising therapeutic option for the treatment of myocardial ischemia. The aim of this study is to determine whether MSC-EVs could promote a pro-resolving environment in the heart by modulating macrophage populations. METHODS EVs derived from three independent biopsies of DP-MSCs (MSC-EVs) were isolated by tangential flow-filtration and size exclusion chromatography and were characterized by omics analyses. Biological processes associated with these molecules were analyzed using String and GeneCodis platforms. The immunomodulatory capacity of MSC-EVs to polarize macrophages towards a pro-resolving or M2-like phenotype was assessed by evaluating surface markers, cytokine production, and efferocytosis. The therapeutic potential of MSC-EVs was evaluated in an acute myocardial infarction (AMI) model in nude rats. Infarct size and the distribution of macrophage populations in the infarct area were evaluated 7 and 21 days after intramyocardial injection of MSC-EVs. RESULTS Lipidomic, proteomic, and miRNA-seq analysis of MSC-EVs revealed their association with biological processes involved in tissue regeneration and regulation of the immune system, among others. MSC-EVs promoted the differentiation of pro-inflammatory macrophages towards a pro-resolving phenotype, as evidenced by increased expression of M2 markers and decreased secretion of pro-inflammatory cytokines. Administration of MSC-EVs in rats with AMI limited the extent of the infarcted area at 7 and 21 days post-infarction. MSC-EV treatment also reduced the number of pro-inflammatory macrophages within the infarct area, promoting the resolution of inflammation. CONCLUSION EVs derived from DP-MSCs exhibited similar characteristics at the omics level irrespective of the biopsy from which they were derived. All MSC-EVs exerted effective pro-resolving responses in a rat model of AMI, indicating their potential as therapeutic agents for the treatment of inflammation associated with AMI.
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Affiliation(s)
- Elena Amaro-Prellezo
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
| | - Marta Gómez-Ferrer
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
| | - Lusine Hakobyan
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
- Department of Analytical Chemistry, Faculty of Chemistry, University of Valencia, Valencia, 46100, Spain
| | - Imelda Ontoria-Oviedo
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
| | - Esteban Peiró-Molina
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
- Hospital Universitari I Politècnic La Fe, Valencia, 46026, Spain
| | - Sonia Tarazona
- Department of Applied Statistics and Operations Research and Quality, Universitat Politècnica de València, Valencia, 46022, Spain
| | - Pedro Salguero
- Department of Applied Statistics and Operations Research and Quality, Universitat Politècnica de València, Valencia, 46022, Spain
| | - Amparo Ruiz-Saurí
- Department of Pathology, University of Valencia, Valencia, 46010, Spain
| | - Marta Selva-Roldán
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
| | - Rosa Vives-Sanchez
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain
| | - Pilar Sepúlveda
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Avda. Fernando Abril Martorell 106, Valencia, 46026, Spain.
- Hospital Universitari I Politècnic La Fe, Valencia, 46026, Spain.
- Department of Pathology, University of Valencia, Valencia, 46010, Spain.
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), III Institute of Health, Madrid, Carlos, Spain.
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14
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Gu J, You J, Liang H, Zhan J, Gu X, Zhu Y. Engineered bone marrow mesenchymal stem cell-derived exosomes loaded with miR302 through the cardiomyocyte specific peptide can reduce myocardial ischemia and reperfusion (I/R) injury. J Transl Med 2024; 22:168. [PMID: 38368334 PMCID: PMC10874538 DOI: 10.1186/s12967-024-04981-7] [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: 10/28/2023] [Accepted: 02/12/2024] [Indexed: 02/19/2024] Open
Abstract
BACKGROUND MicroRNA (miRNA)-based therapies have shown great potential in myocardial repair following myocardial infarction (MI). MicroRNA-302 (miR302) has been reported to exert a protective effect on MI. However, miRNAs are easily degraded and ineffective in penetrating cells, which limit their clinical applications. Exosomes, which are small bioactive molecules, have been considered as an ideal vehicle for miRNAs delivery due to their cell penetration, low immunogenicity and excellent stability potential. Herein, we explored cardiomyocyte-targeting exosomes as vehicles for delivery of miR302 into cardiomyocyte to potentially treat MI. METHODS To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered exosomes with cardiomyocyte specific peptide (CMP, WLSEAGPVVTVRALRGTGSW). Afterwards, the engineered exosomes were characterized and identified using transmission electron microscope (TEM) and Nanoparticle Tracking Analysis (NTA). Later on, the miR302 mimics were loaded into the engineered exosomes via electroporation technique. Subsequently, the effect of the engineered exosomes on myocardial ischemia and reperfusion (I/R) injury was evaluated in vitro and in vivo, including MTT, ELISA, real-time quantitative polymerase chain reaction (PCR), western blot, TUNNEL staining, echocardiogram and hematoxylin and eosin (HE) staining. RESULTS Results of in vitro experimentation showed that DSPE-PEG-CMP-EXO could be more efficiently internalized by H9C2 cells than unmodified exosomes (blank-exosomes). Importantly, compared with the DSPE-PEG-CMP-EXO group, DSPE-PEG-CMP-miR302-EXO significantly upregulated the expression of miR302, while exosomes loaded with miR302 could enhance proliferation of H9C2 cells. Western blot results showed that the DSPE-PEG-CMP-miR302-EXO significantly increased the protein level of Ki67 and Yap, which suggests that DSPE-PEG-CMP-miR302-EXO enhanced the activity of Yap, the principal downstream effector of Hippo pathway. In vivo, DSPE-PEG-CMP-miR302-EXO improved cardiac function, attenuated myocardial apoptosis and inflammatory response, as well as reduced infarct size significantly. CONCLUSION In conclusion, our findings suggest that CMP-engineered exosomes loaded with miR302 was internalized by H9C2 cells, an in vitro model for cardiomyocytes coupled with potential enhancement of the therapeutic effects on myocardial I/R injury.
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Affiliation(s)
- Jianjun Gu
- Department of Cardiology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, 98 Nantong West Road, Yangzhou, Jiangsu, China
| | - Jia You
- Department of Internal Medicine, Yangzhou Maternal and Child Health Care Hospital, Yangzhou, 225001, Jiangsu, China
| | - Hao Liang
- Department of Cardiology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, 98 Nantong West Road, Yangzhou, Jiangsu, China
| | - Jiacai Zhan
- Department of Cardiology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, 98 Nantong West Road, Yangzhou, Jiangsu, China
| | - Xiang Gu
- Department of Cardiology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, 98 Nantong West Road, Yangzhou, Jiangsu, China
| | - Ye Zhu
- Department of Cardiology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
- Department of Cardiology, Northern Jiangsu People's Hospital, 98 Nantong West Road, Yangzhou, Jiangsu, China.
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15
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Miron RJ, Zhang Y. Understanding exosomes: Part 1-Characterization, quantification and isolation techniques. Periodontol 2000 2024; 94:231-256. [PMID: 37740431 DOI: 10.1111/prd.12520] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 09/24/2023]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with a diameter in the range of 30-150 nm. Their use has gained great momentum recently due to their ability to be utilized as diagnostic tools with a vast array of therapeutic applications. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be investigated. This review article first focuses on understanding exosomes, including their cellular origin, biogenesis, function, and characterization. Thereafter, overviews of the quantification methods and isolation techniques are given with discussion over their potential use as novel therapeutics in regenerative medicine.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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16
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Jiang J, Zhang X, Wang H, Spanos M, Jiang F, Ni L, Li J, Li G, Lin Y, Xiao J. Closer to The Heart: Harnessing the Power of Targeted Extracellular Vesicle Therapies. Adv Biol (Weinh) 2024; 8:e2300141. [PMID: 37953665 DOI: 10.1002/adbi.202300141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 09/08/2023] [Indexed: 11/14/2023]
Abstract
Extracellular vesicles (EVs) have emerged as novel diagnostic and therapeutic approaches for cardiovascular diseases. EVs derived from various origins exhibit distinct effects on the cardiovascular system. However, the application of native EVs is constrained due to their poor stabilities and limited targeting capabilities. Currently, targeted modification of EVs primarily involves genetic engineering, chemical modification (covalent, non-covalent), cell membrane modification, and biomaterial encapsulation. These techniques enhance the stability, biological activity, target-binding capacity, and controlled release of EVs at specific cells and tissues. The diverse origins of cardioprotective EVs are covered, and the applications of cardiac-targeting EV delivery systems in protecting against cardiovascular diseases are discussed. This review summarizes the current stage of research on the potential of EV-based targeted therapies for addressing cardiovascular disorders.
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Affiliation(s)
- Jizong Jiang
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Xinxin Zhang
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Hongyun Wang
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Michail Spanos
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Fei Jiang
- Department of Nursing, Union Hospital, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Lingyan Ni
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Jin Li
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Guoping Li
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Yanjuan Lin
- Department of Nursing, Union Hospital, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Junjie Xiao
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China
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17
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Ma J, Wang W, Zhang W, Xu D, Ding J, Wang F, Peng X, Wang D, Li Y. The recent advances in cell delivery approaches, biochemical and engineering procedures of cell therapy applied to coronary heart disease. Biomed Pharmacother 2023; 169:115870. [PMID: 37952359 DOI: 10.1016/j.biopha.2023.115870] [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: 08/13/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
Cell therapy is an important topic in the field of regeneration medicine that is gaining attention within the scientific community. However, its potential for treatment in coronary heart disease (CHD) has yet to be established. Several various strategies, types of cells, routes of distribution, and supporting procedures have been tried and refined to trigger heart rejuvenation in CHD. However, only a few of them result in a real considerable promise for clinical usage. In this review, we give an update on techniques and clinical studies of cell treatment as used to cure CHD that are now ongoing or have been completed in the previous five years. We also highlight the emerging efficacy of stem cell treatment for CHD. We specifically examine and comment on current breakthroughs in cell treatment applied to CHD, including the most effective types of cells, transport modalities, engineering, and biochemical approaches used in this context. We believe the current review will be helpful for the researcher to distill this information and design future studies to overcome the challenges faced by this revolutionary approach for CHD.
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Affiliation(s)
- Jingru Ma
- Department of Clinical Laboratory, the Second Hospital of Jilin University, Changchun 13000, China
| | - Wenhai Wang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Wenbin Zhang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Dexin Xu
- Department of Orthopedics, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Jian Ding
- Department of Electrodiagnosis, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Fang Wang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Xia Peng
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Dahai Wang
- Department of Rehabilitation, Jilin Province FAW General Hospital, Changchun 130000, China
| | - Yanwei Li
- Department of General Practice and Family Medicine, the Second Hospital of Jilin University, Changchun 130000, China.
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18
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Li Q, Feng Q, Zhou H, Lin C, Sun X, Ma C, Sun L, Guo G, Wang D. Mechanisms and therapeutic strategies of extracellular vesicles in cardiovascular diseases. MedComm (Beijing) 2023; 4:e454. [PMID: 38124785 PMCID: PMC10732331 DOI: 10.1002/mco2.454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Cardiovascular disease (CVD) significantly impacts global society since it is the leading cause of death and disability worldwide, and extracellular vesicle (EV)-based therapies have been extensively investigated. EV delivery is involved in mediating the progression of CVDs and has great potential to be biomarker and therapeutic molecular carrier. Besides, EVs from stem cells and cardiac cells can effectively protect the heart from various pathologic conditions, and then serve as an alternative treatment for CVDs. Moreover, the research of using EVs as delivery carriers of therapeutic molecules, membrane engineering modification of EVs, or combining EVs with biomaterials further improves the application potential of EVs in clinical treatment. However, currently there are only a few articles summarizing the application of EVs in CVDs. This review provides an overview of the role of EVs in the pathogenesis and diagnosis of CVDs. It also focuses on how EVs promote the repair of myocardial injury and therapeutic methods of CVDs. In conclusion, it is of great significance to review the research on the application of EVs in the treatment of CVDs, which lays a foundation for further exploration of the role of EVs, and clarifies the prospect of EVs in the treatment of myocardial injury.
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Affiliation(s)
- Qirong Li
- Department of CardiologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
- Laboratory Animal CenterCollege of Animal ScienceJilin UniversityChangchunChina
| | - Qiang Feng
- Laboratory Animal CenterCollege of Animal ScienceJilin UniversityChangchunChina
| | - Hengzong Zhou
- Laboratory Animal CenterCollege of Animal ScienceJilin UniversityChangchunChina
| | - Chao Lin
- School of Grain Science and TechnologyJilin Business and Technology CollegeChangchunChina
| | - Xiaoming Sun
- School of Grain Science and TechnologyJilin Business and Technology CollegeChangchunChina
| | - Chaoyang Ma
- Hepatology Hospital of Jilin ProvinceChangchunChina
| | - Liqun Sun
- Department of PathogenobiologyJilin University Mycology Research CenterCollege of Basic Medical SciencesJilin UniversityChangchunChina
| | - Gongliang Guo
- Department of CardiologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Dongxu Wang
- Laboratory Animal CenterCollege of Animal ScienceJilin UniversityChangchunChina
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19
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Lee CS, Lee M, Na K, Hwang HS. Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications. Mol Pharm 2023; 20:5278-5311. [PMID: 37867343 DOI: 10.1021/acs.molpharmaceut.3c00376] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Recently, stem cells and their secretomes have attracted great attention in biomedical applications, particularly extracellular vesicles (EVs). EVs are secretomes of cells for cell-to-cell communication. They play a role as intercellular messengers as they carry proteins, nucleic acids, lipids, and therapeutic agents. They have also been utilized as drug-delivery vehicles due to their biocompatibility, low immunogenicity, stability, targetability, and engineerable properties. The therapeutic potential of EVs can be further enhanced by surface engineering and modification using functional molecules such as aptamers, peptides, and antibodies. As a consequence, EVs hold great promise as effective delivery vehicles for enhancing treatment efficacy while avoiding side effects. Among various cell types that secrete EVs, stem cells are ideal sources of EVs because stem cells have unique properties such as self-renewal and regenerative potential for transplantation into damaged tissues that can facilitate their regeneration. However, challenges such as immune rejection and ethical considerations remain significant hurdles. Stem cell-derived EVs have been extensively explored as a cell-free approach that bypasses many challenges associated with cell-based therapy in cancer therapy and tissue regeneration. In this review, we summarize and discuss the current knowledge of various types of stem cells as a source of EVs, their engineering, and applications of EVs, focusing on cancer therapy and tissue engineering.
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Affiliation(s)
- Chung-Sung Lee
- Department of Pharmaceutical Engineering, Soonchunhyang University, Asan 31538, Republic of Korea
| | - Min Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, California 90095, United States
- Department of Bioengineering, University of California, Los Angeles, California 90095, United States
| | - Kun Na
- Department of BioMedical-Chemical Engineering, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Hee Sook Hwang
- Department of Pharmaceutical Engineering, Dankook University, Cheonan 31116, Republic of Korea
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Neves KB, Rios FJ, Sevilla‐Montero J, Montezano AC, Touyz RM. Exosomes and the cardiovascular system: role in cardiovascular health and disease. J Physiol 2023; 601:4923-4936. [PMID: 35306667 PMCID: PMC10953460 DOI: 10.1113/jp282054] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/15/2022] [Indexed: 11/16/2023] Open
Abstract
Exosomes, which are membrane-bound extracellular vesicles (EVs), are generated in the endosomal compartment of almost all eukaryotic cells. They are formed upon the fusion of multivesicular bodies and the plasma membrane and carry proteins, nucleic acids, lipids and other cellular constituents from their parent cells. Multiple factors influence their production including cell stress and injury, humoral factors, circulating toxins, and oxidative stress. They play an important role in intercellular communication, through their ability to transfer their cargo (proteins, lipids, RNAs) from one cell to another. Exosomes have been implicated in the pathophysiology of various diseases including cardiovascular disease (CVD), cancer, kidney disease, and inflammatory conditions. In addition, circulating exosomes may act as biomarkers for diagnostic and prognostic strategies for several pathological processes. In particular exosome-containing miRNAs have been suggested as biomarkers for the diagnosis and prognosis of myocardial injury, stroke and endothelial dysfunction. They may also have therapeutic potential, acting as vectors to deliver therapies in a targeted manner, such as the delivery of protective miRNAs. Transfection techniques are in development to load exosomes with desired cargo, such as proteins or miRNAs, to achieve up-regulation in the host cell or tissue. These advances in the field have the potential to assist in the detection and monitoring progress of a disease in patients during its early clinical stages, as well as targeted drug delivery.
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Affiliation(s)
- Karla B. Neves
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowUK
| | - Francisco J. Rios
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowUK
| | - Javier Sevilla‐Montero
- Biomedical Research Institute La Princesa Hospital (IIS‐IP)Department of MedicineSchool of MedicineUniversidad Autónoma of Madrid (UAM)MadridSpain
| | | | - Rhian M. Touyz
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowUK
- Research Institute of the McGill University Health Centre (RI‐MUHC)McGill UniversityMontrealCanada
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21
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Russo E, Alberti G, Corrao S, Borlongan CV, Miceli V, Conaldi PG, Di Gaudio F, La Rocca G. The Truth Is Out There: Biological Features and Clinical Indications of Extracellular Vesicles from Human Perinatal Stem Cells. Cells 2023; 12:2347. [PMID: 37830562 PMCID: PMC10571796 DOI: 10.3390/cells12192347] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 10/14/2023] Open
Abstract
The potential of perinatal tissues to provide cellular populations to be used in different applications of regenerative medicine is well established. Recently, the efforts of researchers are being addressed regarding the evaluation of cell products (secreted molecules or extracellular vesicles, EVs) to be used as an alternative to cellular infusion. The data regarding the effective recapitulation of most perinatal cells' properties by their secreted complement point in this direction. EVs secreted from perinatal cells exhibit key therapeutic effects such as tissue repair and regeneration, the suppression of inflammatory responses, immune system modulation, and a variety of other functions. Although the properties of EVs from perinatal derivatives and their significant potential for therapeutic success are amply recognized, several challenges still remain that need to be addressed. In the present review, we provide an up-to-date analysis of the most recent results in the field, which can be addressed in future research in order to overcome the challenges that are still present in the characterization and utilization of the secreted complement of perinatal cells and, in particular, mesenchymal stromal cells.
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Affiliation(s)
- Eleonora Russo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Giusi Alberti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Simona Corrao
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Cesar V. Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA;
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Francesca Di Gaudio
- Department of Health Promotion, Maternal-Infantile Care, Excellence Internal and Specialist Medicine “G. D’Alessandro” (PROMISE), University of Palermo, 90127 Palermo, Italy;
| | - Giampiero La Rocca
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
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22
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Bragança J, Pinto R, Silva B, Marques N, Leitão HS, Fernandes MT. Charting the Path: Navigating Embryonic Development to Potentially Safeguard against Congenital Heart Defects. J Pers Med 2023; 13:1263. [PMID: 37623513 PMCID: PMC10455635 DOI: 10.3390/jpm13081263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023] Open
Abstract
Congenital heart diseases (CHDs) are structural or functional defects present at birth due to improper heart development. Current therapeutic approaches to treating severe CHDs are primarily palliative surgical interventions during the peri- or prenatal stages, when the heart has fully developed from faulty embryogenesis. However, earlier interventions during embryonic development have the potential for better outcomes, as demonstrated by fetal cardiac interventions performed in utero, which have shown improved neonatal and prenatal survival rates, as well as reduced lifelong morbidity. Extensive research on heart development has identified key steps, cellular players, and the intricate network of signaling pathways and transcription factors governing cardiogenesis. Additionally, some reports have indicated that certain adverse genetic and environmental conditions leading to heart malformations and embryonic death may be amendable through the activation of alternative mechanisms. This review first highlights key molecular and cellular processes involved in heart development. Subsequently, it explores the potential for future therapeutic strategies, targeting early embryonic stages, to prevent CHDs, through the delivery of biomolecules or exosomes to compensate for faulty cardiogenic mechanisms. Implementing such non-surgical interventions during early gestation may offer a prophylactic approach toward reducing the occurrence and severity of CHDs.
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Affiliation(s)
- José Bragança
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal
| | - Rute Pinto
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Bárbara Silva
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- PhD Program in Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, Universidade do Algarve, 8005-139 Faro, Portugal
| | - Nuno Marques
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Helena S. Leitão
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Mónica T. Fernandes
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- School of Health, University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
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23
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Neuber S, Ermer MR, Emmert MY, Nazari-Shafti TZ. Treatment of Cardiac Fibrosis with Extracellular Vesicles: What Is Missing for Clinical Translation? Int J Mol Sci 2023; 24:10480. [PMID: 37445658 PMCID: PMC10342089 DOI: 10.3390/ijms241310480] [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: 05/31/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Heart failure is the leading cause of morbidity and mortality and currently affects more than 60 million people worldwide. A key feature in the pathogenesis of almost all forms of heart failure is cardiac fibrosis, which is characterized by excessive accumulation of extracellular matrix components in the heart. Although cardiac fibrosis is beneficial in the short term after acute myocardial injury to preserve the structural and functional integrity of the heart, persistent cardiac fibrosis contributes to pathological cardiac remodeling, leading to mechanical and electrical dysfunction of the heart. Despite its high prevalence, standard therapies specifically targeting cardiac fibrosis are not yet available. Cell-based approaches have been extensively studied as potential treatments for cardiac fibrosis, but several challenges have been identified during clinical translation. The observation that extracellular vesicles (EVs) derived from stem and progenitor cells exhibit some of the therapeutic effects of the parent cells has paved the way to overcome limitations associated with cell therapy. However, to make EV-based products a reality, standardized methods for EV production, isolation, characterization, and storage must be established, along with concrete evidence of their safety and efficacy in clinical trials. This article discusses EVs as novel therapeutics for cardiac fibrosis from a translational perspective.
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Affiliation(s)
- Sebastian Neuber
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany; (M.R.E.); (M.Y.E.); (T.Z.N.-S.)
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 13353 Berlin, Germany
| | - Miriam R. Ermer
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany; (M.R.E.); (M.Y.E.); (T.Z.N.-S.)
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Maximilian Y. Emmert
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany; (M.R.E.); (M.Y.E.); (T.Z.N.-S.)
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 13353 Berlin, Germany
- Institute for Regenerative Medicine, University of Zurich, 8044 Zurich, Switzerland
| | - Timo Z. Nazari-Shafti
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany; (M.R.E.); (M.Y.E.); (T.Z.N.-S.)
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 13353 Berlin, Germany
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24
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Yuan J, Yang H, Liu C, Shao L, Zhang H, Lu K, Wang J, Wang Y, Yu Q, Zhang Y, Yu Y, Shen Z. Microneedle Patch Loaded with Exosomes Containing MicroRNA-29b Prevents Cardiac Fibrosis after Myocardial Infarction. Adv Healthc Mater 2023; 12:e2202959. [PMID: 36739582 DOI: 10.1002/adhm.202202959] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/18/2023] [Indexed: 02/06/2023]
Abstract
Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA-29b (miR-29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR-29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR-29b and downregulate the expression of fibrosis-related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications.
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Affiliation(s)
- Jianping Yuan
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
- Department of Thoracic and Cardiovascular Surgery, Baotou Central Hospital, Baotou, 014040, P. R. China
| | - Hong Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Chunxia Liu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Haixin Zhang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Kunyan Lu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Jingjing Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Yuanyuan Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Qian Yu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China
| | - Yanxia Zhang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Yunsheng Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215007, P. R. China
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25
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Williams T, Salmanian G, Burns M, Maldonado V, Smith E, Porter RM, Song YH, Samsonraj RM. Versatility of mesenchymal stem cell-derived extracellular vesicles in tissue repair and regenerative applications. Biochimie 2023; 207:33-48. [PMID: 36427681 DOI: 10.1016/j.biochi.2022.11.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/29/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent somatic cells that have been widely explored in the field of regenerative medicine. MSCs possess the ability to secrete soluble factors as well as lipid bound extracellular vesicles (EVs). MSCs have gained increased interest and attention as a result of their therapeutic properties, which are thought to be attributed to their secretome. However, while the use of MSCs as whole cells pose heterogeneity concerns and survival issues post-transplantation, such limitations are absent in cell-free EV-based treatments. EVs derived from MSCs are promising therapeutic agents for a range of clinical conditions and disorders owing to their immunomodulatory, pro-regenerative, anti-inflammatory, and antifibrotic activity. Recent successes with preclinical studies using EVs for repair and regeneration of damaged tissues such as cardiac tissue, lung, liver, pancreas, bone, skin, cornea, and blood diseases are discussed in this review. We also discuss delivery strategies of EVs using biomaterials as delivery vehicles through systemic or local administration. Despite its effectiveness in preclinical investigations, the application of MSC-EV in clinical settings will necessitate careful consideration surrounding issues such as: i) scalability and isolation, ii) biodistribution, iii) targeting specific tissues, iv) quantification and characterization, and v) safety and efficacy of dosage. The future of EVs in regenerative medicine is promising yet still needs further investigation on enhancing the efficacy, scalability, and potency for clinical applications.
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Affiliation(s)
- Taylor Williams
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Ghazaleh Salmanian
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Morgan Burns
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Vitali Maldonado
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Emma Smith
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Ryan M Porter
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Young Hye Song
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA; Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR, USA
| | - Rebekah Margaret Samsonraj
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA; Interdisciplinary Graduate Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR, USA; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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26
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Moeinabadi‐Bidgoli K, Rezaee M, Hossein‐Khannazer N, Babajani A, Aghdaei HA, Arki MK, Afaghi S, Niknejad H, Vosough M. Exosomes for angiogenesis induction in ischemic disorders. J Cell Mol Med 2023; 27:763-787. [PMID: 36786037 PMCID: PMC10003030 DOI: 10.1111/jcmm.17689] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/19/2023] [Accepted: 01/26/2023] [Indexed: 02/15/2023] Open
Abstract
Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, they are considered as cell-free therapeutics. Besides, exosomes do not rise cell therapy concerns such as teratoma formation, alloreactivity and thrombotic events. In addition, exosomes are stored and utilized more convenient. Interestingly, exosomes could be an ideal complementary therapeutic tool for ischemic disorders. In this review, we discussed therapeutic functions of exosomes in ischemic disorders including angiogenesis induction through various mechanisms with specific attention to vascular endothelial growth factor pathway. Furthermore, different delivery routes of exosomes and different modification strategies including cell preconditioning, gene modification and bioconjugation, were highlighted. Finally, pre-clinical and clinical investigations in which exosomes were used were discussed.
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Affiliation(s)
- Kasra Moeinabadi‐Bidgoli
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Malihe Rezaee
- School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Nikoo Hossein‐Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Amirhesam Babajani
- Oncopathology Research CenterIran University of Medical SciencesTehranIran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastroenterology Disorders Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Siamak Afaghi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Hassan Niknejad
- Oncopathology Research CenterIran University of Medical SciencesTehranIran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Experimental Cancer Medicine, Institution for Laboratory MedicineKarolinska InstituteStockholmSweden
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27
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Chen X, Yu W, Zhang J, Fan X, Liu X, Liu Q, Pan S, Dixon RAF, Li P, Yu P, Shi A. Therapeutic angiogenesis and tissue revascularization in ischemic vascular disease. J Biol Eng 2023; 17:13. [PMID: 36797776 PMCID: PMC9936669 DOI: 10.1186/s13036-023-00330-2] [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: 11/08/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Ischemic vascular disease is a major healthcare problem. The keys to treatment lie in vascular regeneration and restoration of perfusion. However, current treatments cannot satisfy the need for vascular regeneration to restore blood circulation. As biomedical research has evolved rapidly, a variety of potential alternative therapeutics has been explored widely, such as growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. This review will comprehensively describe the main pathogenesis of vascular injury in ischemic vascular disease, the therapeutic function of the above three treatment strategies, the corresponding potential challenges, and future research directions.
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Affiliation(s)
- Xinyue Chen
- grid.412455.30000 0004 1756 5980The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Wenlu Yu
- grid.260463.50000 0001 2182 8825School of Ophthalmology and Optometry of Nanchang University, Nanchang, 330006 China
| | - Jing Zhang
- grid.412455.30000 0004 1756 5980Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Xiao Fan
- grid.412455.30000 0004 1756 5980Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Xiao Liu
- grid.412536.70000 0004 1791 7851Department of Cardiovascular Medicine, The Second Affiliated Hospital of Sun Yat Sen University, Guangzhou, 51000 Guangdong China
| | - Qi Liu
- grid.416470.00000 0004 4656 4290Wafic Said Molecular Cardiology Research Laboratory, The Texas Heart Institute, Houston, TX USA
| | - Su Pan
- grid.416470.00000 0004 4656 4290Wafic Said Molecular Cardiology Research Laboratory, The Texas Heart Institute, Houston, TX USA
| | - Richard A. F. Dixon
- grid.416470.00000 0004 4656 4290Wafic Said Molecular Cardiology Research Laboratory, The Texas Heart Institute, Houston, TX USA
| | - Pengyang Li
- grid.224260.00000 0004 0458 8737Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA USA
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China. .,Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
| | - Ao Shi
- School of Medicine, St. George University of London, London, UK. .,School of Medicine, University of Nicosia, Nicosia, Cyprus.
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28
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Zhang R, Mesquita T, Cho JH, Li C, Sanchez L, Holm K, Akhmerov A, Liu W, Li Y, Ibrahim AG, Cingolani E. Systemic Delivery of Extracellular Vesicles Attenuates Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction. JACC Clin Electrophysiol 2023; 9:147-158. [PMID: 36858679 PMCID: PMC11073791 DOI: 10.1016/j.jacep.2022.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) is a common comorbidity in heart failure with preserved ejection fraction (HFpEF) patients. To date, treatments for HFpEF-related AF have been limited to anti-arrhythmic drugs and ablation. Here we examined the effects of immortalized cardiosphere-derived extracellular vesicles (imCDCevs) in rats with HFpEF. OBJECTIVES This study sought to investigate the mechanisms of AF in HFpEF and probe the potential therapeutic efficacy of imCDCevs in HFpEF-related AF. METHODS Dahl salt-sensitive rats were fed a high-salt diet for 7 weeks to induce HFpEF and randomized to receive imCDCevs (n = 18) or vehicle intravenously (n = 14). Rats fed a normal-salt diet were used as control animals (n = 26). A comprehensive characterization of atrial remodeling was conducted using functional and molecular techniques. RESULTS HFpEF-verified animals showed significantly higher AF inducibility (84%) compared with control animals (15%). These changes were associated with prolonged action potential duration, slowed conduction velocity (connexin 43 lateralization), and fibrotic remodeling in the left atrium of HFpEF compared with control animals. ImCDCevs reversed adverse electrical remodeling (restoration of action potential duration to control levels and reorganization of connexin 43) and reduced AF inducibility (33%). In addition, fibrosis, inflammation, and oxidative stress, which are major pathological AF drivers, were markedly attenuated in imCDCevs-treated animals. Importantly, these effects occurred without changes in blood pressure and diastolic function. CONCLUSIONS Thus, imCDCevs attenuated adverse remodeling, and prevented AF in a rat model of HFpEF.
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Affiliation(s)
- Rui Zhang
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Thassio Mesquita
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jae Hyung Cho
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chang Li
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Lizbeth Sanchez
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kevin Holm
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Akbarshakh Akhmerov
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Weixin Liu
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Yigang Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ahmed G Ibrahim
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Eugenio Cingolani
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
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Yin X, Jiang LH. Extracellular vesicles: Targeting the heart. Front Cardiovasc Med 2023; 9:1041481. [PMID: 36704471 PMCID: PMC9871562 DOI: 10.3389/fcvm.2022.1041481] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023] Open
Abstract
Cardiovascular diseases rank the highest incidence and mortality worldwide. As the most common type of cardiovascular disease, myocardial infarction causes high morbidity and mortality. Recent studies have revealed that extracellular vesicles, including exosomes, show great potential as a promising cell-free therapy for the treatment of myocardial infarction. However, low heart-targeting efficiency and short plasma half-life have hampered the clinical translation of extracellular vesicle therapy. Currently, four major types of strategies aiming at enhancing target efficiency have been developed, including modifying EV surface, suppressing non-target absorption, increasing the uptake efficiency of target cells, and utilizing a hydrogel patch. This presented review summarizes the current research aimed at EV heart targeting and discusses the challenges and opportunities in EV therapy, which will be beneficial for the development of effective heart-targeting strategies.
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Affiliation(s)
- Xin Yin
- Faculty of Life Sciences and Technology, Kunming University of Science and Technology, Kunming, China,Department of Ultrasound, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China,The First People’s Hospital of Yunnan, Kunming, Yunnan, China
| | - Li-Hong Jiang
- Department of Ultrasound, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China,The First People’s Hospital of Yunnan, Kunming, Yunnan, China,*Correspondence: Li-Hong Jiang,
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30
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Zhu F, Chen Y, Li J, Yang Z, Lin Y, Jiang B, Shao L, Hu S, Shen Z. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Myocardial Infarction Injury via miR-24-3p-Promoted M2 Macrophage Polarization. Adv Biol (Weinh) 2022; 6:e2200074. [PMID: 35818695 DOI: 10.1002/adbi.202200074] [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: 03/23/2022] [Revised: 06/22/2022] [Indexed: 01/28/2023]
Abstract
Exosomes derived from human umbilical cord mesenchymal stem cells (UMSC-Exos) have shown encouraging effects in regulating inflammation and attenuating myocardial injury. Macrophages are regulated dynamically in response to environmental cues. However, the underlying mechanisms by which UMSC-Exos regulate macrophage polarization are still not well understood. Herein, it is aimed to explore the effects of UMSC-Exos on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). These results show that UMSC-Exos improve cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. RNA-sequencing results identify Plcb3 as a key gene involved in UMSC-Exo-facilitated M2 macrophage polarization. Further bioinformatic analysis identifies exosomal miR-24-3p as a potential effector mediating Plcb3 downregulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhances M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in the inflammatory environment. Furthermore, reducing miR-24-3p expression in UMSC-Exos attenuates the effects of UMSC-Exos on M2 macrophage polarization. This study demonstrates that the cardiac therapeutic effects of UMSC-Exos are at least partially through promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanistically, exosomal miR-24-3p is found to inhibit Plcb3 expression and NF-κB pathway activation to promote M2 macrophage polarization.
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Affiliation(s)
- Feng Zhu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Jingjing Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Ziying Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Yang Lin
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Boxuan Jiang
- School of Medicine, Nantong University, Nantong, 226007, China
| | - Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
| | - Shengshou Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China.,Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, 215000, China
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31
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Divband S, Tasharrofi N, Abroun S, Zomorrod MS. Human Umbilical Cord Mesenchymal Stem Cells-Derived Small Extracellular Vesicles Can Be Considered as Cell-Free Therapeutics for Angiogenesis Promotion. CELL JOURNAL 2022; 24:689-696. [PMID: 36377219 PMCID: PMC9663965 DOI: 10.22074/cellj.2022.8275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Indexed: 12/01/2022]
Abstract
OBJECTIVE Angiogenesis has critical roles in several physiological processes. Restoring angiogenesis in some pathological conditions such as a few vascular diseases can be a therapeutic approach to controlling this issue. Mesenchymal stem cells (MSCs) secrete specific intracellular products known as extracellular vesicles (EVs) with high therapeutic potential which compared to their source cells, do not have the limitations of cell therapy. The angiogenic effect of the human umbilical cord MSCs (hUCMSCs)-derived small EVs are evaluated in the present work. Aim of this research is to show that hUCMSCs-derived small EVs cause differentiation of genes involved in angiogenesis like FGFR-1, FGF, VEGF, and VEGFR-2. MATERIALS AND METHODS In this experimental study, MSCs were isolated from the human umbilical cord, and after confirming their identities, their secreted EVs (including exosomes) were extracted by ultracentrifugation. The isolated small EVs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), bicinchoninic acid assay (BCA), and Western Blotting. Then, the human umbilical vein endothelial cells (HUVECs) were treated with derived small EVs for 72 hours, and the expression of the angiogenic factors including FGFR-1, FGF, VEGF, and VEGFR-2 was evaluated by quantitative real-time-polymerase chain reaction (qPCR). Angiogenesis was also evaluated via a tube formation assay. RESULTS The results demonstrated that FGFR-1, FGF, VEGF, and VEGFR-2 could be elevated 2, 2, 3.5, and 2 times, respectively, in EVs treated HUVECs, and derivative EVs can encourage tube formation in HUVECs. CONCLUSION These findings imply that hUCMSCs-derived small EVs are valuable resources in promoting angiogenesis and are very promising in cell-free therapy.
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Affiliation(s)
- Somayeh Divband
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nooshin Tasharrofi
- Faculty of Pharmacy, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Saeid Abroun
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran,P.O.Box: 14115-111Department of Hematology and Cell TherapyFaculty of Medical SciencesTarbiat Modares
UniversityTehranIran
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Lv K, Wang Y, Lou P, Liu S, Zhou P, Yang L, Lu Y, Cheng J, Liu J. Extracellular vesicles as advanced therapeutics for the resolution of organ fibrosis: Current progress and future perspectives. Front Immunol 2022; 13:1042983. [PMCID: PMC9630482 DOI: 10.3389/fimmu.2022.1042983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
Organ fibrosis is a serious health challenge worldwide, and its global incidence and medical burden are increasing dramatically each year. Fibrosis can occur in nearly all major organs and ultimately lead to organ dysfunction. However, current clinical treatments cannot slow or reverse the progression of fibrosis to end-stage organ failure, and thus advanced anti-fibrotic therapeutics are urgently needed. As a type of naturally derived nanovesicle, native extracellular vesicles (EVs) from multiple cell types (e.g., stem cells, immune cells, and tissue cells) have been shown to alleviate organ fibrosis in many preclinical models through multiple effective mechanisms, such as anti-inflammation, pro-angiogenesis, inactivation of myofibroblasts, and fibrinolysis of ECM components. Moreover, the therapeutic potency of native EVs can be further enhanced by multiple engineering strategies, such as genetic modifications, preconditionings, therapeutic reagent-loadings, and combination with functional biomaterials. In this review, we briefly introduce the pathology and current clinical treatments of organ fibrosis, discuss EV biology and production strategies, and particularly focus on important studies using native or engineered EVs as interventions to attenuate tissue fibrosis. This review provides insights into the development and translation of EV-based nanotherapies into clinical applications in the future.
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Affiliation(s)
- Ke Lv
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yizhuo Wang
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Lou
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Shuyun Liu
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Pingya Zhou
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Yanrong Lu
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jingqiu Cheng
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jingping Liu
- National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jingping Liu,
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Emerging roles of ferroptosis in cardiovascular diseases. Cell Death Dis 2022; 8:394. [PMID: 36127318 PMCID: PMC9488879 DOI: 10.1038/s41420-022-01183-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 11/26/2022]
Abstract
The mechanism of cardiovascular diseases (CVDs) is complex and threatens human health. Cardiomyocyte death is an important participant in the pathophysiological basis of CVDs. Ferroptosis is a new type of iron-dependent programmed cell death caused by excessive accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS) and abnormal iron metabolism. Ferroptosis differs from other known cell death pathways, such as apoptosis, necrosis, necroptosis, autophagy and pyroptosis. Several compounds have been shown to induce or inhibit ferroptosis by regulating related key factors or signalling pathways. Recent studies have confirmed that ferroptosis is associated with the development of diverse CVDs and may be a potential therapeutic drug target for CVDs. In this review, we summarize the characteristics and related mechanisms of ferroptosis and focus on its role in CVDs, with the goal of inspiring novel treatment strategies.
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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.
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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,
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35
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Azaryan E, Karbasi S, Zarban A, Naseri M. Cell-free therapy based on stem cell-derived exosomes: A promising approach for wound healing. Wound Repair Regen 2022; 30:585-594. [PMID: 35927607 DOI: 10.1111/wrr.13043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/22/2022] [Accepted: 07/15/2022] [Indexed: 11/28/2022]
Abstract
There are several successive and overlapping phases in wound healing as a complex process. By the disruption of each of these phases, chronic non-healing wounds are resultant. Despite the present soothing surgeries, standard wound dressings and topical gels, the wound is often not completely closed. Today, stem cells have attracted a huge deal of attention therapeutically and pharmaceutically considering their unique features. However, they have some restrictions. Moreover, it is hoped to eliminate the limitations of cellular therapies based on their derivatives known as exosomes. Exosomes are extracellular vesicles secreted from cells. They have a diameter of almost 30-150 nm and miRNAs, mRNAs, and proteins that are possibly different from the source cell are included in exosomal contents. Such nanovesicles have a key role in the intercellular communication of pathological and physiological procedures. Exosome-based therapy is a new significant method for wound healing. By exosomes effects, wound management may be improved and a new therapeutic model may be highlighted for cell-free therapies with reduced side effects for the wound repair.
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Affiliation(s)
- Ehsaneh Azaryan
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
- Cellular and Molecular Research Center, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Samira Karbasi
- Department of Molecular Medicine, School of Medicine, Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Asghar Zarban
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
- Clinical Biochemistry Department, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohsen Naseri
- Cellular and Molecular Research Center, Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
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36
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Abstract
Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.
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Affiliation(s)
- Dhananjie Chandrasekera
- Department of Physiology, School of Biomedical Sciences, HeartOtago, University of Otago, 270, Great King Street, Dunedin, New Zealand.
| | - Rajesh Katare
- Department of Physiology, School of Biomedical Sciences, HeartOtago, University of Otago, 270, Great King Street, Dunedin, New Zealand.
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Zhang J, Peng Y, Guo M, Li C. Large-Scale Expansion of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Stirred Suspension Bioreactor Enabled by Computational Fluid Dynamics Modeling. Bioengineering (Basel) 2022; 9:bioengineering9070274. [PMID: 35877325 PMCID: PMC9312327 DOI: 10.3390/bioengineering9070274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/20/2022] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) hold great potential to generate novel and curative cell therapy products. However, the current large-scale cultivation of hUCMSCs is based on empirical geometry-dependent methods, limiting the generation of high-quantity and high-quality hUCMSCs for clinical therapy. Herein, we develop a novel scale-up strategy based on computational fluid dynamics (CFD) to effectively expand the hUCMSCs in a 3D tank bioreactor. Using a standardized hUCMSCs line on microcarriers, we successfully translated and expanded the hUCMSCs from a 200 mL spinner flask to a 1.5 L computer-controlled bioreactor by matching the shear environment and suspending the microcarrier. Experimental results revealed that the batch-cultured hUCMSCs in bioreactors with an agitation speed of 40 rpm shared a more favorable growth and physiological state, similar to that run at 45 rpm in a 200 mL spinner flask, showing comparability in both culture systems. Notably, the maximum cell density reached up to 27.3 × 105 cells/mL in fed-batch culture, 2.9 folds of that of batch culture and 20.2 times of seeding cells. As such, efficient process optimization and scale-up expansion of hUCMSCs were achieved in the microcarrier-based bioreactor system by the developed CFD simulation strategy, which provided an alternative toolbox to generate massive and standardized curative cell therapy products.
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Affiliation(s)
| | | | | | - Chao Li
- Correspondence: (M.G.); (C.L.)
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38
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Weber B, Franz N, Marzi I, Henrich D, Leppik L. Extracellular vesicles as mediators and markers of acute organ injury: current concepts. Eur J Trauma Emerg Surg 2022; 48:1525-1544. [PMID: 33533957 PMCID: PMC7856451 DOI: 10.1007/s00068-021-01607-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/19/2021] [Indexed: 12/15/2022]
Abstract
Due to the continued high incidence and mortality rate worldwide, there is a need to develop new strategies for the quick, precise, and valuable recognition of presenting injury pattern in traumatized and poly-traumatized patients. Extracellular vesicles (EVs) have been shown to facilitate intercellular communication processes between cells in close proximity as well as distant cells in healthy and disease organisms. miRNAs and proteins transferred by EVs play biological roles in maintaining normal organ structure and function under physiological conditions. In pathological conditions, EVs change the miRNAs and protein cargo composition, mediating or suppressing the injury consequences. Therefore, incorporating EVs with their unique protein and miRNAs signature into the list of promising new biomarkers is a logical next step. In this review, we discuss the general characteristics and technical aspects of EVs isolation and characterization. We discuss results of recent in vitro, in vivo, and patients study describing the role of EVs in different inflammatory diseases and traumatic organ injuries. miRNAs and protein signature of EVs found in patients with acute organ injury are also debated.
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Affiliation(s)
- Birte Weber
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Niklas Franz
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Ingo Marzi
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Dirk Henrich
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Liudmila Leppik
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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Liu W, Feng Y, Wang X, Ding J, Li H, Guan H, Chen Z. Human umbilical vein endothelial cells-derived exosomes enhance cardiac function after acute myocardial infarction by activating the PI3K/AKT signaling pathway. Bioengineered 2022; 13:8850-8865. [PMID: 35361041 PMCID: PMC9161948 DOI: 10.1080/21655979.2022.2056317] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Currently, acute myocardial infarction (AMI) is one of the leading causes of human health issues worldwide. The sudden and continuous occlusion of the coronary artery results in myocardial hypoxic-ischemic necrosis, which is accompanied by inflammatory infiltration and fibrosis, leading to pathological cardiac remodeling. Exosome-based therapy is a promising cell-free approach for repairing the ischemic myocardium. This study aimed to explore the effects and mechanism of human umbilical vein endothelial cells (HUVECs)-derived exosomes on AMI. The results indicated that the localized injection of HUVECs-derived exosomes in the infarcted area could significantly improve cardiac function in AMI mouse models. It could also ameliorate myocardial fibrosis and decrease infarct size after AMI. Additionally, HUVECs-derived exosomes had cardioprotective effects on the H9C2 cells in hypoxic culture conditions, including increased cell viability and decreased lactate dehydrogenase (LDH) release. In both the in-vivo and in-vitro experiments, HUVECs-derived exosomes could effectively inhibit cardiomyocyte apoptosis. The low expression levels of Bcl-2–associated X protein (Bax) and cleaved caspase-3, high expression levels of B-cell lymphoma 2 (Bcl-2), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) were detected in AMI mouse models treated with HUVECs-derived exosomes in-vivo. In conclusion, HUVECs-derived exosomes effectively enhanced cardiac function after AMI and inhibited cardiomyocyte apoptosis, which might be regulated through the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway.
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Affiliation(s)
- Wei Liu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Feng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuehua Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiaxing Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huili Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongquan Guan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhijian Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Huang Y, Chen L, Chen D, Fan P, Yu H. Exosomal microRNA-140-3p from human umbilical cord mesenchymal stem cells attenuates joint injury of rats with rheumatoid arthritis by silencing SGK1. Mol Med 2022; 28:36. [PMID: 35303795 PMCID: PMC8932126 DOI: 10.1186/s10020-022-00451-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 02/04/2022] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE Over the years, microRNAs (miRNAs) have been involved in the pathogenesis of rheumatoid arthritis (RA). We aim to investigate the role of human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomal miR-140-3p in RA development. METHODS Exosomes(exo) were isolated from human umbilical cord-derived mesenchymal stem cells (HUCMSCs), and this isolation was followed by the transfer of miR-140-3p. RA rat models were constructed by collagen II adjuvant and respectively treated with HUCMSCs-exo or HUCMSCs-exo carrying miR-140-3p mimic/inhibitor, and expression of miR-140-3p and serum- and glucocorticoid-inducible kinase 1 (SGK1) was assessed. Then, RA score and inflammation scoring, fibrosis degree and apoptosis, serum inflammatory response and oxidative stress in joint tissues were determined. The RA synovial fibroblasts (RASFs) were extracted from rats and identified. Conducted with relative treatment, the migration, proliferation and apoptosis in RASFs were determined. RESULTS MiR-140-3p was decreased while SGK1 was increased in RA rats. HUCMSCs-exo or upregulated exosomal miR-140-3p improved pathological changes and suppressed inflammation, oxidative stress and fibrosis in RA rats, and also constrained and RASF growth. Overexpression of SGK1 reversed the inhibition of RASF growth caused by overexpression of miR-140-3p. CONCLUSION Upregulated exosomal miR-140-3p attenuated joint injury of RA rats by silencing SGK1. This research provided further understanding of the role of exosomal miR-140-3p in RA development.
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Affiliation(s)
- Yijiang Huang
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West College Road, Wenzhou, 325000, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, China
| | - Liang Chen
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West College Road, Wenzhou, 325000, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, China
| | - Daosen Chen
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West College Road, Wenzhou, 325000, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, China
| | - Pei Fan
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West College Road, Wenzhou, 325000, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, China
| | - Huachen Yu
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West College Road, Wenzhou, 325000, China. .,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, China.
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Sharma A, Gupta S, Archana S, Verma RS. Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances. Stem Cell Rev Rep 2022; 18:1546-1602. [PMID: 35122226 DOI: 10.1007/s12015-021-10314-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 12/29/2022]
Abstract
Irreversible myocardium infarction is one of the leading causes of cardiovascular disease (CVD) related death and its quantum is expected to grow in coming years. Pharmacological intervention has been at the forefront to ameliorate injury-related morbidity and mortality. However, its outcomes are highly skewed. As an alternative, stem cell-based tissue engineering/regenerative medicine has been explored quite extensively to regenerate the damaged myocardium. The therapeutic modality that has been most widely studied both preclinically and clinically is based on adult multipotent mesenchymal stem cells (MSC) delivered to the injured heart. However, there is debate over the mechanistic therapeutic role of MSC in generating functional beating cardiomyocytes. This review intends to emphasize the role and use of MSC in cardiac regenerative therapy (CRT). We have elucidated in detail, the various aspects related to the history and progress of MSC use in cardiac tissue engineering and its multiple strategies to drive cardiomyogenesis. We have further discussed with a focus on the various therapeutic mechanism uncovered in recent times that has a significant role in ameliorating heart-related problems. We reviewed recent and advanced technologies using MSC to develop/create tissue construct for use in cardiac regenerative therapy. Finally, we have provided the latest update on the usage of MSC in clinical trials and discussed the outcome of such studies in realizing the full potential of MSC use in clinical management of cardiac injury as a cellular therapy module.
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Affiliation(s)
- Akriti Sharma
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - Santosh Gupta
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - S Archana
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - Rama Shanker Verma
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India.
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Khan K, Caron C, Mahmoud I, Derish I, Schwertani A, Cecere R. Extracellular Vesicles as a Cell-free Therapy for Cardiac Repair: a Systematic Review and Meta-analysis of Randomized Controlled Preclinical Trials in Animal Myocardial Infarction Models. Stem Cell Rev Rep 2022; 18:1143-1167. [PMID: 35107768 DOI: 10.1007/s12015-021-10289-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 12/14/2022]
Abstract
Stem cell therapy for cardiac regeneration has been gaining traction as a possible intervention for the reduction of the burden associated with MI and heart failure. However, stem cell therapies have several shortcomings, including poor engraftment, limited improvements in cardiac function, and possible teratogenicity. Recently, extracellular vesicles (EVs) from stem cell sources have been explored as a novel therapy to regenerate the injured myocardium in several animal MI trials. In this systematic review and meta-analysis, we investigate the use of stem cell-derived EVs for cardiac repair preclinical trials in animal MI models. Cochrane Library, Medline, Embase, PubMed, Scopus and Web of Science and grey literature (Canadian Agency for Drugs, Technologies in Health, and Google Scholar) were searched through August 20, 2020 and 37 articles were included in the final analysis. The overall effect size observed in EV-treated small animals after MI for ejection fraction (EF) was 10.85 [95 %CI: 8.79, 12.90] and for fractional shortening (FS) was 7.19 [95 %CI: 5.43, 8.96] compared to control-treated animals. The most abundant stem cell source used were mesenchymal stem cells which showed robust improvements in EF and FS (MD = 11.89 [95 % CI: 9.44, 14.34] and MD = 6.96 [95 % CI: 4.97, 8.96], respectively). Significant publication bias was detected for EF and FS outcomes. This study supports the use of EVs derived from stem cells as a novel therapy for cardiac repair after MI. Further investigation in larger animal studies may be necessary before clinical trials.PROSPERO registration number: CRD42019142218.
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Affiliation(s)
- Kashif Khan
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Christophe Caron
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Ibtisam Mahmoud
- McConnell Resource Centre, McGill University Health Centre, Montreal, Quebec, Canada
| | - Ida Derish
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Adel Schwertani
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Renzo Cecere
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada.
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Small Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhanced Proangiogenic Potential of Cardiac Fibroblasts via Angiopoietin-Like 4. Stem Cells Int 2022; 2022:3229289. [PMID: 35154329 PMCID: PMC8824744 DOI: 10.1155/2022/3229289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 01/13/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives. After myocardial hypoxic injury, it is important to enhance vascular formation and restore blood supply for injury repair. Previous studies have suggested that cardiac fibroblasts (CFs) play a crucial role in angiogenesis after myocardial injury. Small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells (hucMSCs) promote fibroblast-to-myofibroblast differentiation in inflammatory environment and have cardioprotective effects. It remains unknown whether sEVs regulate cardiac fibroblasts to promote angiogenesis after myocardial injury. Methods and Results. We isolated primary CFs from Sprague-Dawley rats (1–3 days old) and treated them with lipopolysaccharide (LPS) and LPS+sEVs. RNA sequencing analysis revealed that angiopoietin-like 4 (Angptl4) was increased in the LPS+sEVs group more than in the LPS group. After inhibition of Angptl4 expression in sEVs and CFs, cell proliferation, Transwell migration, and tube formation assays were used to detect the angiogenic activity of human umbilical vein endothelial cells. β-Catenin expression in CFs was detected by western blotting. The β-catenin inhibitor ICG001 was used to examine whether β-catenin was involved in the proangiogenic potential of CFs promoted by sEVs. sEVs enhanced the proangiogenic potential of CFs under inflammatory conditions, which was associated with β-catenin signaling. The proangiogenic potential of CFs was decreased when Angptl4 was knocked down in CFs and in hucMSCs. Conclusions. The sEVs regulated CFs to promote angiogenesis via Angptl4 in an inflammatory environment. This may provide a research basis for treating myocardial injury with sEVs.
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Chua JKE, Lim J, Foong LH, Mok CY, Tan HY, Tung XY, Ramasamy TS, Govindasamy V, Then KY, Das AK, Cheong SK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Progress and Remaining Hurdles in Developing Regulatory Compliant Quality Control Assays. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:191-211. [DOI: 10.1007/5584_2022_728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Xu Z, Tian N, Li S, Li K, Guo H, Zhang H, Jin H, An M, Yu X. Extracellular vesicles secreted from mesenchymal stem cells exert anti-apoptotic and anti-inflammatory effects via transmitting microRNA-18b in rats with diabetic retinopathy. Int Immunopharmacol 2021; 101:108234. [PMID: 34655847 DOI: 10.1016/j.intimp.2021.108234] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/14/2021] [Accepted: 10/04/2021] [Indexed: 12/28/2022]
Abstract
Diabetic retinopathy (DR) is a major cause of visual deficits and blindness in the working-age population and inflammatory response is a key event during DR. In this study, we investigated the anti-inflammatory properties of small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in a diabetic rat model and human retinal microvascular endothelial cells. After development of DR in rats subjected to diabetes induction with streptozotocin (STZ), the DR rats were treated with different concentrations of hUCMSC-sEVs. Our results showed that the treatment of the retinas of DR rats with hUCMSC-sEVs not only reduced the level of vascular leakage in the retinas of rats but also decreased the retinal thickness as well as the associated inflammation. Further, our in vitro evidences suggest that hUCMSC-sEVs repress high glucose (HG)-induced cell inflammation and apoptosis. Subsequently, we analyzed the differentially expressed microRNAs (miRNAs) in the hUCMSC-sEVs by microarray and performed in silico studies to predict the target mRNA of miR-18b. Our findings also revealed that the expression of miR-18b was significantly elevated in the retina of diabetic rats after sEV treatment. In addition, miR-18b was found to target mitogen-activated protein kinase kinase kinase 1 (MAP3K1), thereby inhibiting NF-κB p65 phosphorylation to alleviate DR. Overall, this study highlights the potential of hUCMSCs-sEVs as biomaterials for anti-inflammatory and anti-apoptotic effects in DR by transferring miR-18b.
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Affiliation(s)
- Zepeng Xu
- Department of Ophthalmology, Jiangmen Wuyi Hospital of TCM, Jiangmen 529000, Guangdong, China; The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Ni Tian
- Department of Ophthalmology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China.
| | - Songtao Li
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Kunmeng Li
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Haike Guo
- Department of Ophthalmology, Shanghai Heping Eye Hospital, Shanghai 200437, China
| | - Hongyang Zhang
- Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangzhou 510120, Guangdong, China
| | - Haiying Jin
- Department of Ophthalmology, Shanghai No. 10 People's Hospital, Shanghai 200040, China
| | - Meixia An
- Department of Ophthalmology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, Guangdong, China
| | - Xiaoyi Yu
- Department of Ophthalmology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
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Karn V, Ahmed S, Tsai LW, Dubey R, Ojha S, Singh HN, Kumar M, Gupta PK, Sadhu S, Jha NK, Kumar A, Pandit S, Kumar S. Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects. Biomedicines 2021; 9:biomedicines9101373. [PMID: 34680490 PMCID: PMC8533559 DOI: 10.3390/biomedicines9101373] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/19/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022] Open
Abstract
The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19.
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Affiliation(s)
- Vamika Karn
- Department of Biotechnology, Amity University, Mumbai 410221, India;
| | - Shaista Ahmed
- Faculty of Medical and Paramedical Sciences, Aix-Marseille University, 13005 Marseille, France;
| | - Lung-Wen Tsai
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
- Department of Information Technology Office, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Rajni Dubey
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi P.O. Box 17666, United Arab Emirates;
| | - Himanshu Naryan Singh
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA;
| | - Mukesh Kumar
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Soumi Sadhu
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India;
| | - Ashutosh Kumar
- Department of Anatomy, All India Institute of Medical Sciences, Patna 801507, India;
| | - Soumya Pandit
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Sanjay Kumar
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
- Correspondence: or ; Tel.: +91-120-4570-000
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Li M, Zhang HP, Wang XY, Chen ZG, Lin XF, Zhu W. Mesenchymal Stem Cell-Derived Exosomes Ameliorate Dermal Fibrosis in a Murine Model of Bleomycin-Induced Scleroderma. Stem Cells Dev 2021; 30:981-990. [PMID: 34428952 DOI: 10.1089/scd.2021.0112] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have become a promising therapeutic strategy for scleroderma. Exosomes derived from MSCs (MSC-exosomes) possess functional properties similar to those of their source cells. In this study, we aimed to explore the potential role of MSC-exosomes in the treatment of scleroderma. MSC-exosomes were isolated from human umbilical cords through ultracentrifugation and characterized. An experimental fibrosis model was established in BALB/c mice by a subcutaneous injection of bleomycin, followed by treatment with MSC-exosomes or MSC infusions once a week for a total of four doses. Using hematoxylin and eosin and Masson's trichrome staining and immunohistochemistry, hydroxyproline content, and quantitative real-time polymerase chain reaction analyses, we investigated the effects of MSC-exosomes on dermal fibrosis and explored the underlying mechanism. MSC-exosome treatment restored the dermal architecture, reduced dermal thickness, and partially increased subcutaneous adipose tissue thickness. In addition, MSC-exosomes inhibited the expression of collagen (COL)-I, COL-III, and α-smooth muscle actin. The transforming growth factor (TGF)-β/Smad signaling pathway was also suppressed in MSC-exosome-treated mice. Taken together, our results suggest that MSC-exosomes can attenuate myofibroblast activation and collagen deposition in dermal fibrosis by downregulating the TGF-β/Smad signaling pathway. Therefore, the use of MSC-exosomes may be a potential therapeutic approach for the treatment of scleroderma.
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Affiliation(s)
- Man Li
- Department of Dermatology and Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Hai-Ping Zhang
- Department of Dermatology and Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Xue-Yao Wang
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Zhi-Guo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Xue-Fei Lin
- Department of Dermatology and Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Wei Zhu
- Department of Dermatology and Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
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Wang B, Cao C, Han D, Bai J, Guo J, Guo Q, Li D, Zhang J, Zhang Z, Wang Y, Tang J, Shen D, Zhang J. Dysregulation of miR-342-3p in plasma exosomes derived from convalescent AMI patients and its consequences on cardiac repair. Biomed Pharmacother 2021; 142:112056. [PMID: 34435593 DOI: 10.1016/j.biopha.2021.112056] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 02/04/2023] Open
Abstract
Plasma exosomes derived from healthy people have been shown to be beneficial in terms of protecting against ischemia-reperfusion injury or acute myocardial infarction (AMI). However, a pathological condition may severely affect the constitution and biological activity of exosomes. In our study, we isolated plasma exosomes from healthy volunteers and convalescent AMI patients (3-7 d after onset). Compared to exosomes from healthy controls (Nor-Exo), exosomes from convalescent AMI patients (AMI-Exo) exhibited an impaired ability to repair damaged cardiomyocytes both in vitro and in vivo. miRNA sequencing and PCR analysis indicated that miR-342-3p was significantly downregulated in AMI-Exo. Moreover, miR-342-3p alleviated H2O2-induced injury and reduced apoptosis and autophagy in H9c2 cardiomyocytes, while in vivo restoration of miR-342-3p expression enhanced the reparative function of AMI-Exo. Further mechanistic studies revealed that the SOX6 and TFEB genes were two direct and functional targets of miR-342-3p. Taken together, during the early convalescent phase after AMI, dysregulated miR-342-3p in plasma exosomes might be responsible for their impaired cardioprotective potential. miR-342-3p contributed to exosome-mediated heart repair by inhibiting cardiomyocyte apoptosis and autophagy through targeting SOX6 and TFEB, respectively. Our work provided novel insights on the role of plasma exosomes in the natural process of cardiac repair after AMI and suggestions for therapy development.
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Affiliation(s)
- Bo Wang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Chang Cao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Dongjian Han
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Jing Bai
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Jiacheng Guo
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Qianqian Guo
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Demin Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Jianchao Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Zenglei Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Yunzhe Wang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China
| | - Junnan Tang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China.
| | - Deliang Shen
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China.
| | - Jinying Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, PR China.
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Sánchez-Sánchez R, Gómez-Ferrer M, Reinal I, Buigues M, Villanueva-Bádenas E, Ontoria-Oviedo I, Hernándiz A, González-King H, Peiró-Molina E, Dorronsoro A, Sepúlveda P. miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia. Front Cell Dev Biol 2021; 9:734143. [PMID: 34532322 PMCID: PMC8439391 DOI: 10.3389/fcell.2021.734143] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/02/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are an emerging alternative to cell-based therapies to treat many diseases. However, the complexity of producing homogeneous populations of EVs in sufficient amount hampers their clinical use. To address these limitations, we immortalized dental pulp-derived MSC using a human telomerase lentiviral vector and investigated the cardioprotective potential of a hypoxia-regulated EV-derived cargo microRNA, miR-4732-3p. We tested the compared the capacity of a synthetic miR-4732-3p mimic with EVs to confer protection to cardiomyocytes, fibroblasts and endothelial cells against oxygen-glucose deprivation (OGD). Results showed that OGD-induced cardiomyocytes treated with either EVs or miR-4732-3p showed prolonged spontaneous beating, lowered ROS levels, and less apoptosis. Transfection of the miR-4732-3p mimic was more effective than EVs in stimulating angiogenesis in vitro and in vivo and in reducing fibroblast differentiation upon transforming growth factor beta treatment. Finally, the miR-4732-3p mimic reduced scar tissue and preserved cardiac function when transplanted intramyocardially in infarcted nude rats. Overall, these results indicate that miR-4732-3p is regulated by hypoxia and exerts cardioprotective actions against ischemic insult, with potential application in cell-free-based therapeutic strategies.
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Affiliation(s)
- Rafael Sánchez-Sánchez
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Marta Gómez-Ferrer
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Ignacio Reinal
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Marc Buigues
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Estela Villanueva-Bádenas
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Imelda Ontoria-Oviedo
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Amparo Hernándiz
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Hernán González-King
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Esteban Peiró-Molina
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Akaitz Dorronsoro
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Pilar Sepúlveda
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
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MSCs-Derived Extracellular Vesicles Carrying miR-212-5p Alleviate Myocardial Infarction-Induced Cardiac Fibrosis via NLRC5/VEGF/TGF-β1/SMAD Axis. J Cardiovasc Transl Res 2021; 15:302-316. [PMID: 34508321 DOI: 10.1007/s12265-021-10156-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
The purpose of the present study was to define the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in the progression of myocardial infarction (MI)-induced cardiac fibrosis. An in vitro cell model of hypoxia-induced cardiac fibrosis was constructed in cardiac fibroblasts (CFs). miR-212-5p was poorly expressed in clinical pathological samples and animal models of cardiac fibrosis caused by MI, while miR-212-5p expression was enriched in EVs released from MSCs. EVs from MSCs were isolated, evaluated, and co-cultured with CFs. Dual-luciferase reporter gene assay revealed that miR-212-5p negatively targeted NLRC5 progression of cardiac fibrosis. Following loss- and gain-function assay, EVs expressing miR-212-5p protected against cardiac fibrosis evidenced by reduced levels of α-SMA, Collagen I, TGF-β1, and IL-1β. In vivo experiments further confirmed the above research results. Collectively, EVs from MSCs expressing miR-212-5p may attenuate MI by suppressing the NLRC5/VEGF/TGF-β1/SMAD axis.
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