1
|
Chen D, Chen Z, Yuan J, Chen G, Chen Y, He K, Hu Y, Ye L, Yang Y. Research landscape and trends of human umbilical cord mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2025; 16:259. [PMID: 40437553 PMCID: PMC12121053 DOI: 10.1186/s13287-025-04379-2] [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: 02/19/2025] [Accepted: 05/02/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) have gained significant attention for their potential in cellular regeneration and functional rehabilitation. Nevertheless, the rapid expansion of research in this field makes it challenging for emerging trends and strategic priorities, potentially impeding scientific advancement. This study employs bibliometric analysis to systematically evaluate the research landscape and highlight pivotal research trajectories of hUCMSC-Exos. METHODS Publications on hUCMSC-Exos from 2012 to 2024 were retrieved from the Web of Science Core Collection (WoSCC). Quantitative bibliometric analysis was implemented through integrated utilization of VOSviewer, CiteSpace, and Bibliometrix analytical tools. RESULTS China and its institutions led global publication output, with Qian Hui from Jiangsu University identified as the most prolific author. STEM CELL RESEARCH & THERAPY emerged as a high-impact journal in this domain. Current research predominantly focuses on immunomodulation, regenerative medicine, pharmaceutical delivery systems, and clinical model development. Future research directions are expected to explore angiogenesis, spinal cord injury, and immunomodulation. CONCLUSIONS This study maps the evolving landscape of hUCMSC-Exos research, emphasizing its applications in regenerative medicine. By synthesizing current and emerging paradigms, these findings provide insights into therapeutic potential, novel mechanisms, and pathways for clinical translation.
Collapse
Affiliation(s)
- Desheng Chen
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zeping Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiabin Yuan
- Department of Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guanzi Chen
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yutao Chen
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Kaiming He
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yongwei Hu
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Linsen Ye
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
2
|
Du J, Wu J, Song Q, Li S, Hong Y, Anwar A, Fu Q, Liu J. Mesenchymal stem cell exosomes regulate TGFβ/Smad3 by decreasing the METTL3-NEAT1 axis to inhibit scar progression after breast surgery. J Mol Histol 2025; 56:161. [PMID: 40392368 DOI: 10.1007/s10735-025-10441-3] [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: 03/11/2025] [Accepted: 04/25/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Scars are traces of tissue loss left behind by connective tissue overgrowth and repair. Studies in recent years have shown that mesenchymal stem cell exosomes (MSC-Exo) have the ability to inhibit and repair cutaneous scarring, but their specific role in post-breast surgery scar formation and the mechanisms behind it remain enigmatic. METHODS Extraction and characterization of exosomes from mesenchymal stem cells (MSCs). Western Blot and RT-qPCR were used to evaluate the expression of fibrillar protein and TGF-β/Smad3 in mammary hypertrophic scar fibroblasts (MHSFs) stimulated with MSC-Exo, sh-METTL3, sh-NEAT1 and their negative controls. Construction of a mouse model of proliferative scar formation using mechanical tension and detection of fibronectin and pathway protein expression using Western Blot and RT-qPCR. Pathologic changes of mammary scarring in mice using HE staining, Masson staining and immunofluorescence. RESULTS Both in vitro and in vivo, MSC-Exo, sh-METTL3 and sh-NEAT1 were shown to decrease the expression of COL1A1, COL3A1, α-SMA, fibronectin, TGF-β, p-Smad2/Smad2, p-Smad3/Smad3, by Western Blot and RT-qPCR. In addition, improved lesions and reduced collagen deposition were observed in mice by HE and Masson assays. CONCLUSIONS In summary, our study revealed that exosomes of MSCs function through the m6A methyltransferase METTL3, which regulates the NEAT1/TGF-β/Smad3 axis to slow down the rate of scar formation after breast surgery.
Collapse
Affiliation(s)
- Juan Du
- Department of Thyroid and Breast Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Jincheng Wu
- Department of Thyroid and Breast Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Qinqin Song
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Shuangru Li
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Youwang Hong
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Aizaz Anwar
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Quanyou Fu
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China
| | - Jisong Liu
- Department of Burn and Plastic Surgery, The Third People's Hospital of Bengbu Affiliated to Bengbu Medical University, Bengbu, 233000, Anhui, China.
| |
Collapse
|
3
|
Zhou M, Pei B, Cai P, Yi C, Akanyibah FA, Lyu C, Mao F. Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages. Stem Cell Res Ther 2025; 16:233. [PMID: 40346712 PMCID: PMC12065267 DOI: 10.1186/s13287-025-04365-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 04/24/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD), a chronic immune disorder, has increasing global incidence and poor treatment outcome. Abnormal macrophage function is implicated in the pathophysiology of IBD. In this study, we investigated the mechanism by which human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) inhibit inflammation in IBD mouse and macrophage inflammation models. METHODS We established a dextran sodium sulfate (DSS)-induce BALB/c mice model of IBD and treated with hucMSC-Ex via tail vein to evaluate their repair effect on IBD mice. An in vitro macrophage inflammation model was established using lipopolysaccharide (LPS) and Nigericin (Nig) by stimulating mouse macrophage RAW264.7 and human myeloid leukemia mononuclear (THP-1) cells to assess the repair effect of hucMSC-Ex on macrophage inflammation. EX 527, an effective inhibitor of silent information regulator of transcription 1 (SIRT1), was employed in both the in vivo and in vitro models to explore the effect of hucMSC-Ex on the SIRT1-FXR (farnesoid X receptor) pathway in macrophages during the attenuation of inflammation. RESULTS HucMSC-Ex effectively inhibited inflammation in both the in vivo and in vitro models by up-regulating the expressions of SIRT1 and FXR, which reduced the acetylation level of FXR and inhibited the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. The addition of EX 527 further proved that hucMSC-Ex can reduce the acetylation of FXR by activating the SIRT1-FXR pathway, and the decrease of FXR acetylation was directly related to the inhibition of the activity of the NLRP3 inflammasome. CONCLUSION HucMSC-Ex alleviates IBD by reducing the acetylation level of FXR through activating the SIRT1-FXR pathway in macrophages and directly negatively regulating the activation of NLRP3 inflammasomes, thus inhibiting the occurrence of the inflammatory process.
Collapse
Affiliation(s)
- Mengjiao Zhou
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, No.8 Dianli Road, Zhenjiang, Jiangsu, 212002, P. R. China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, 212013, P. R. China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, Jiangsu, 223800, P. R. China
| | - Peipei Cai
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, No.8 Dianli Road, Zhenjiang, Jiangsu, 212002, P. R. China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang, Jiangsu, 212028, P. R. China
| | - Francis Atim Akanyibah
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, No.8 Dianli Road, Zhenjiang, Jiangsu, 212002, P. R. China
| | - Changkun Lyu
- School of Medical Technology, Shangqiu Medical College Shangqiu, Shangqiu, Henan, 476100, P. R. China
| | - Fei Mao
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, No.8 Dianli Road, Zhenjiang, Jiangsu, 212002, P. R. China.
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, 212013, P. R. China.
| |
Collapse
|
4
|
Lu W, Yan L, Peng L, Wang X, Tang X, Du J, Lin J, Zou Z, Li L, Ye J, Zhou L. Efficacy and safety of mesenchymal stem cell therapy in acute on chronic liver failure: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2025; 16:197. [PMID: 40254564 PMCID: PMC12010635 DOI: 10.1186/s13287-025-04303-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Acute-on-chronic liver failure has become a serious global health burden, which is characterized by an acute deterioration of liver function, rapidly evolving organ failure, and high short-term mortality in patients with chronic liver disease. The pathogenesis includes extensive hepatic necrosis, which is related to intense systemic inflammation and subsequently causes the inflammatory cytokine storm, resulting in portal hypertension, organ dysfunction, and organ failure. Mesenchymal stem cells can function as seed cells to remodel and repair damaged liver tissues, thus showing potential therapeutic alternatives for patients with chronic liver disease. However, standard treatment protocols for mesenchymal stem cells in acute-on-chronic liver failure patients have not been established. METHODS We conducted a detailed search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library to find randomized controlled trials published before October 23, 2021. We formulated criteria for the literature screening according to the PICOS principle (Population, Intervention, Comparison, Outcome, Study design). Subsequently, the bias risk assessment tool was used to assess the quality of all enrolled studies. Finally, outcome measurements including the model of end-stage liver disease score, albumin, total bilirubin, coagulation function, and aminotransferase were extracted for statistical analysis. RESULTS A total of 7 clinical trials were included. The results of enrolled studies indicated that patients with acute-on-chronic liver failure who received mesenchymal stem cells inoculation showed a decreased MELD score in 4 weeks and 24 weeks, compared with counterparts who received conventional treatment. Reciprocally, mesenchymal stem cells inoculation improved the ALB levels in 4 weeks and 24 weeks. For secondary indicators, mesenchymal stem cells treatment significantly reduced INR levels and ALT levels, compared with the control group. Our results showed no significant differences in the incidence of adverse reactions or serious adverse events monitored in patients after mesenchymal stem cells inoculation. CONCLUSION This meta-analysis indicated that mesenchymal stem cell infusion is effective and safe in the treatment of patients with acute-on-chronic liver failure. Without increasing the incidence of adverse events or serious adverse events, MSC treatment improved liver function including a decrease in MELD score and an increase in ALB levels in patients with acute-on-chronic liver failure. However, large-cohort randomized controlled trials with longer follow-up periods are required to further confirm our conclusions.
Collapse
Affiliation(s)
- Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Longxiang Yan
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lulu Peng
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Du
- School of Rehabilitation Medicine, Gannan Medical University, GanZhou City, Jiangxi, 341000, PR China
| | - Jing Lin
- The First Clinical College of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
- Key Laboratory for Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China.
| |
Collapse
|
5
|
Chu T, Xiao Z, Xun C, Yang C, Lu M, Wang Y, Chen H, Chen P. Peptidomic profiling of mesenchymal stem cell-derived extracellular vesicles and anti-inflammatory activity of degraded peptides. Int Immunopharmacol 2025; 152:114452. [PMID: 40096816 DOI: 10.1016/j.intimp.2025.114452] [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: 01/08/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/19/2025]
Abstract
Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are key paracrine mediators involved in various autoimmune diseases. While current research on EVs predominantly focuses on their protein and nucleic acid components, small peptides received less attention. In this study, we found IFN-γ-treated MSC-EVs, as engineered EVs, exhibit better anti-inflammatory effects both in vitro and in vivo. Through LC-MS/MS and bioinformatics analysis, we identified four peptides-C3-1, C3-2, B2M-1, and IFIT3-1-that are highly expressed in IFN-γ-treated MSCs-EVs. These peptides significantly mitigate the proliferation inhibition of HUVEC cells induced by H₂O₂ and enhance their migratory capacity. Furthermore, they downregulate the expression of inflammatory cytokines TNF-α and IL-6 in H₂O₂-induced oxidative stress models of HUVEC and LPS-induced inflammatory models of RAW264.7 macrophages. The peptides also upregulate p-AKT and HIF-1α, with C3-1 demonstrating superior anti-inflammatory efficacy in both cell models. Consistent with the in vitro findings, in vivo experiments revealed that C3-1 reduces LPS-induced inflammatory cell infiltration in liver tissue and restores hepatocyte structural integrity, as evidenced by HE-stained liver sections. Western blot analysis further confirmed that C3-1 upregulates p-AKT expression and suppresses inflammatory cytokines. Collectively, these findings suggest that C3-1 exerts its anti-inflammatory effects via activation of the AKT signaling pathway and regulation of TNF-α and IL-6. This study not only highlights the anti-inflammatory potential of IFN-γ-treated MSC-derived EVs but also identifies C3-1 as a promising candidate for anti-inflammatory drug development. Notably, this is the first study to identify degraded peptides within EVs, providing a foundation for future research in this area.
Collapse
Affiliation(s)
- Tianqi Chu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Platform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China
| | - Zixuan Xiao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Chengfeng Xun
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Hunan Academy of Forestry, Changsha 410081, China
| | - Chunyan Yang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Mengqi Lu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Yuqiu Wang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Haiyan Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Platform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; East China Institute of Digital Medical Engineering, Shangrao 334000, China.
| | - Ping Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Platform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China.
| |
Collapse
|
6
|
Choi MS, Hong JS, Lee DH, Jang YJ, Kim JH, Lee YS. Anti-liver fibrotic effects of small extracellular vesicle microRNAs from human umbilical cord-derived mesenchymal stem cells and their differentiated hepatocyte-like cells. Biotechnol Lett 2025; 47:38. [PMID: 40175803 DOI: 10.1007/s10529-025-03579-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 04/04/2025]
Abstract
OBJECTIVE The aim of this study is to identify therapeutic cargos within mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) for the treatment of liver fibrosis, a condition that poses significant health risks. RESULTS sEVs from human umbilical cord-derived MSCs (UCMSCs) and their differentiated hepatocyte-like cells (hpUCMSCs) were found to alleviate liver fibrosis in mouse models, reduce fibrogenic gene expression in the liver, and inhibit hepatic stellate cell (HSC) activation, a central driver of liver fibrosis, in vitro. Deep sequencing identified differentially abundant microRNAs (miRNAs) (high-abundance: 57, low-abundance: 22) in both UCMSC- and hpUCMSC-derived sEVs, compared to HeLa cell-derived sEVs, which lack anti-liver fibrotic activity. Functional enrichment analysis of the high-abundance sEV miRNA targets revealed their involvement in transcriptional regulation, apoptosis, and cancer-related pathways, all of which are linked to liver fibrosis and hepatocellular carcinoma. Notably, many of the top 10 most abundant miRNAs reduced pro-fibrotic marker levels in activated HSCs in vitro. CONCLUSION The therapeutic potential of the high-abundance miRNAs shared by UCMSC- and hpUCMSC-derived sEVs in treating liver fibrosis is highlighted.
Collapse
Affiliation(s)
- Min-Seok Choi
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Jae-Sang Hong
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Do-Hoon Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Seegene Inc., Songpa-Gu, Seoul, 05548, Republic of Korea
| | - Yu Jin Jang
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
- Peace Lab California, Cell and Gene Therapy Manufacturing, I Peace, Inc., Palo Alto, CA, 94303, USA
| | - Jong-Hoon Kim
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Young Sik Lee
- College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
| |
Collapse
|
7
|
Iswarya R, Krishnadas S, Dharmalingam K, Gowri Priya C. Human trabecular meshwork stem cell-derived small extracellular vesicles enhance trabecular meshwork cell survival and proliferation. Exp Eye Res 2025; 253:110281. [PMID: 39961413 DOI: 10.1016/j.exer.2025.110281] [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: 08/24/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
Glaucoma is an optic neuropathy, one of the leading causes of irreversible blindness worldwide. Previous studies in animal models have shown that transplantation of trabecular meshwork stem cells (TMSCs-adult tissue-resident stem cells of TM) promotes TM regeneration and restores intraocular pressure through paracrine signaling. One of the major paracrine signal mediators is the extracellular vesicles. Given the advantages of sEV over cell-based therapies, the current work aims to investigate the potential of TMSC-derived small extracellular vesicles (sEV) in promoting TM cell survival and proliferation using in vitro experiments. TM cells were cultured in TM media and stem cell growth media (SCGM). Phenotypic and functional (sphere formation) characterization of cultured cells revealed that the SCGM maintained stemness with greater functional efficacy. sEV from TM cell (TM media) and TMSC (SCGM) conditioned media were isolated using the ultracentrifugation method. Characterization of sEV demonstrated that the sEV were within the size range of 30-200 nm and poly-dispersive spherical in shape. The TM and TMSC sEV express common exosomal marker syntenin, TM specific exosomal markers-emilin and neuropilin. To check the uptake specificity, the labelled sEV were incubated with different cell types. The varying degrees of uptake of the labelled sEV by TM cells, HLEB3 and 3T3 cell lines implied that TM and TMSC sEV might have varied surface components. The regenerative efficacy of the sEV was assessed in vitro by scratch wound assay, immunostaining for proliferation marker Ki67, and 5'-Bromo-2'-deoxyuridine incorporation assay. The TMSC sEV exhibited better wound healing efficacy by inducing TM cell proliferation. Furthermore, evaluation of the antioxidant potential depicted that the TMSC sEV enhanced TM cell viability under chronic oxidative stress by significantly reducing the intracellular reactive oxygen species. Taken together, our study demonstrated for the first time that the TMSC sEV enhanced TM cell proliferation as well as migration in vitro and attenuated oxidative stress-induced cell death by reducing intracellular reactive oxygen species. Further studies in animal models will pave the way for the potential application of TMSC sEV in glaucoma treatment.
Collapse
Affiliation(s)
- Radhakrishnan Iswarya
- Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India; Department of Biotechnology, Aravind Medical Research Foundation, Alagappa University, Karaikudi, Tamil Nadu, India
| | - Subbaiah Krishnadas
- Glaucoma Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Madurai, Tamil Nadu, India
| | - Kuppamuthu Dharmalingam
- Department of Biotechnology, Aravind Medical Research Foundation, Alagappa University, Karaikudi, Tamil Nadu, India; Department of Proteomics, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India
| | - Chidambaranathan Gowri Priya
- Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu, India; Department of Biotechnology, Aravind Medical Research Foundation, Alagappa University, Karaikudi, Tamil Nadu, India.
| |
Collapse
|
8
|
Tandon R, Srivastava N. Unravelling exosome paradigm: Therapeutic, diagnostic and theranostics application and regulatory consideration. Life Sci 2025; 366-367:123472. [PMID: 39956185 DOI: 10.1016/j.lfs.2025.123472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 01/13/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.
Collapse
Affiliation(s)
- Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India.
| |
Collapse
|
9
|
Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res 2025; 70:103-124. [PMID: 38729561 PMCID: PMC11976416 DOI: 10.1016/j.jare.2024.05.004] [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: 08/15/2023] [Revised: 02/27/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of preclinical models and clinical trials for human diseases. In the context of MSC transplantation, it is widely recognized that the main mechanism for the regenerative potential of MSCs is not their differentiation, with in vivo data revealing transient and low engraftment rates. Instead, MSCs therapeutic effects are mainly attributed to its secretome, i.e., paracrine factors secreted by these cells, further offering a more attractive and innovative approach due to the effectiveness and safety of a cell-free product. AIM OF REVIEW In this review, we will discuss the potential benefits of MSC-derived secretome in regenerative medicine with particular focus on respiratory, hepatic, and neurological diseases. Both free and vesicular factors of MSC secretome will be detailed. We will also address novel potential strategies capable of improving their healing potential, namely by delivering important regenerative molecules according to specific diseases and tissue needs, as well as non-clinical and clinical studies that allow us to dissect their mechanisms of action. KEY SCIENTIFIC CONCEPTS OF REVIEW MSC-derived secretome includes both soluble and non-soluble factors, organized in extracellular vesicles (EVs). Importantly, besides depending on the cell origin, the characteristics and therapeutic potential of MSC secretome is deeply influenced by external stimuli, highlighting the possibility of optimizing their characteristics through preconditioning approaches. Nevertheless, the clarity around their mechanisms of action remains ambiguous, whereas the need for standardized procedures for the successful translation of those products to the clinics urges.
Collapse
Affiliation(s)
- Catarina M Trigo
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana S Rodrigues
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Sérgio P Camões
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Susana Solá
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana P Miranda
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
| |
Collapse
|
10
|
Alahmari LA, Ali LS, Fansa HA, Alshaya DS, Al-Salmi FA, El-Hallous EI, Eldesoqui M, Gad Elsaid F, Fayad E, El-Mansy AA, Alsharif G, Khalil DY, Mahmood MB, Khalil RY, Rashwan HM, El-Sawah SG. Antioxidant and Antiapoptotic Effects of Selenium And Nano Selenium-Loaded Exosomes on Hepatic Dysfunction of Type 1 Diabetic Rats. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2025; 343:211-219. [PMID: 39535481 DOI: 10.1002/jez.2881] [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: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Mesenchymal stem cells-derived exosomes (MSCs-EXs) applications have brought a key breakthrough in treating type 1 diabetes mellitus (T1DM) and its diabetic complications. However, various recent strategies aimed to construct prominent engineered EXs with greater precision and higher efficiency for diabetes syndrome were conducted. In this research, we seek to enhance the medicinal potentialities of MSCs-EXs on type 1 diabetic rats' hepatic complications, via loading with either selenium (Se) or nano selenium (NSe) particles. For consecutive 4-weeks, rats were divided into 8 groups as; control, EXs, EXs + Se, EXs + NSe, STZ-diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. The three diabetic-treated groups manifested a significant reduction in hepatic contents of oxidative stress (OS) (MDA, NO, and H2O2) inflammatory (IL-6, TNF-α, and TGF-β), and apoptotic (P53, BAX, caspase-3, and Bcl2) markers, with marked elevation in hepatic antioxidant levels (GSH, GPX, SOD, and CAT). Such results were supported by the marked diminish in serum total proteins, liver function enzymes (AST, ALT, and bilirubin), and both serum and liver lipid profile fractions. In addition, hepatic histological examination showed marked improvement in liver architecture of all treated diabetic rats' groups, compared to diabetic untreated rats. Significantly, diabetic rats with EXs loaded with NSe exhibited the most therapeutic superiority.
Collapse
Affiliation(s)
- Layla A Alahmari
- Department of Community Health, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
| | - Lashin S Ali
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Physiology Department, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Hoda A Fansa
- Department of Basic Dental Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Department of Oral Biology, Faculty of Dentistry, Alexandria University, Egypt
| | - Dalal S Alshaya
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Fawziah A Al-Salmi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ehab I El-Hallous
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, Riyadh, Saudi Arabia
| | - Fahmy Gad Elsaid
- Department of Biology, College of Science, King Khalid University, Asir, Abha, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ahmed A El-Mansy
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan
- Department of Medical Histology & Cell Biology, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Ghadi Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia
- Department of Biomedical Research, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Dlovan Y Khalil
- Biology Department, Faculty of Science, Sulaimani University, Sulaimaniyah, Iraq
| | - Maryam Bakir Mahmood
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Rozhan Yassin Khalil
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Hanan M Rashwan
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Shady G El-Sawah
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| |
Collapse
|
11
|
Mincheva G, Moreno-Manzano V, Felipo V, Llansola M. Extracellular vesicles from mesenchymal stem cells improve liver injury in rats with mild liver damage. Underlying mechanisms and role of TGFβ. Life Sci 2025; 364:123429. [PMID: 39884339 DOI: 10.1016/j.lfs.2025.123429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/21/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Preventing the progression of liver damage to fibrosis would be beneficial for patients with steatotic liver disease (SLD). Mesenchymal stem cells (MSC) are a promising therapy for SLD and derived extracellular vesicles (EVs) could even improve the treatment's efficacy and safety. However, the mechanisms of MSC-EVs beneficial effects are not well known. It has been suggested that modifying the EVs cargo could improve their beneficial effects. The aims of this study were to assess if MSC-EVs reduce liver damage in a rat model of mild liver damage; to analyze the underlying mechanisms and to assess if silencing TGFβ enhances the beneficial effects of MSC-EVs. CCl4 was injected three times per week during four weeks to induce mild liver damage. EVs from human adipocyte MSC and from TGFβ-depleted MSC (siTGFβ-MSC-EVs) were injected in the tail vein. Steatosis, fibrosis, liver inflammation, macrophage infiltration and liver content of fibrotic markers, DAMPs, cytokines and bile acids were analyzed. Normal MSC-EVs reduce the CCL2 increase in liver, macrophage infiltration and the increases in the fibrosis markers collagen I and α-SMA. Treatment with siTGFβ-MSC-EVs, in addition, reduces liver steatosis, the increase of bile acids (mainly TCA), and DAMP HMGB1 levels, inducing a larger reduction of collagen I in liver of CCl4 rats. Treatment with MSCs-EVs effectively reduces early liver damage. Silencing of TGFβ in MSCs enhances the beneficial effects by additional mechanisms. Early treatment with MSC-EVs, especially after silencing TGFβ, could improve liver damage in SLD patients.
Collapse
Affiliation(s)
- Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Victoria Moreno-Manzano
- Laboratory of Neuronal and Tissue Regeneration, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| |
Collapse
|
12
|
Mittal A, Jakhmola VR, Baweja S. Bioengineered extracellular vesicles: The path to precision medicine in liver diseases. LIVER RESEARCH (BEIJING, CHINA) 2025; 9:17-28. [PMID: 40206438 PMCID: PMC11977285 DOI: 10.1016/j.livres.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 04/11/2025]
Abstract
Extracellular vesicles (EVs) are membrane-bound entities secreted by each cell, categorized as, exosomes, microvesicles or apoptotic bodies based on their size and biogenesis. They serve as promising vectors for drug delivery due to their capacity to carry diverse molecular signatures reflective of their cell of origin. EV research has significantly advanced since their serendipitous discovery, with recent studies focusing on their roles in various diseases and their potential for targeted therapy. In liver diseases, EVs are particularly promising for precision medicine, providing diagnostic and therapeutic potential in conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, hepatocellular carcinoma, alcoholic liver disease, liver fibrosis, and acute liver failure. Despite challenges in isolation and characterization, engineered EVs have shown efficacy in delivering therapeutic agents with improved targeting and reduced side effects. As research progresses, EVs hold great promise to revolutionize precision medicine in liver diseases, offering targeted, efficient, and versatile therapeutic options. In this review, we summarize various techniques for loading EVs with therapeutic cargo including both passive and active methods, and the potential of bioengineered EVs loaded with various molecules, such as miRNAs, proteins, and anti-inflammatory drugs in ameliorating clinical pathologies of liver diseases.
Collapse
Affiliation(s)
| | | | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| |
Collapse
|
13
|
Wu K, Zhao W, Hou Z, Zhang W, Qin L, Qiu J, Wang D, Zhuang L, Xue X, Sun D. Ferritinophagy: multifaceted roles and potential therapeutic strategies in liver diseases. Front Cell Dev Biol 2025; 13:1551003. [PMID: 40070880 PMCID: PMC11893559 DOI: 10.3389/fcell.2025.1551003] [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: 12/24/2024] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Ferritinophagy, the selective autophagic degradation of ferritin to release iron, is emerging as a critical regulator of iron homeostasis and a key player in the pathogenesis of various liver diseases. This review comprehensively examines the mechanisms, regulation, and multifaceted roles of ferritinophagy in liver health and disease. Ferritinophagy is intricately regulated by several factors, including Nuclear Receptor Coactivator 4 (NCOA4), Iron regulatory proteins and signaling pathways such as mTOR and AMPK. These regulatory mechanisms ensure proper iron utilization and prevent iron overload, which can induce oxidative stress and ferroptosis. In liver diseases, ferritinophagy exhibits dual roles. In liver fibrosis, promoting ferritinophagy in hepatic stellate cells (HSCs) can induce cell senescence and reduce fibrosis progression. However, in non-alcoholic fatty liver disease (NAFLD), chronic ferritinophagy may exacerbate liver injury through iron overload and oxidative stress. In hepatocellular carcinoma (HCC), ferritinophagy can be harnessed as a novel therapeutic strategy by inducing ferroptosis in cancer cells. Additionally, ferritinophagy is implicated in drug-induced liver injury and sepsis-associated liver damage, highlighting its broad impact on liver pathology. This review also explores the crosstalk between ferritinophagy and other selective autophagy pathways, such as mitophagy and lipophagy, which collectively influence cellular homeostasis and disease progression. Understanding these interactions is essential for developing comprehensive therapeutic strategies targeting multiple autophagy pathways. In summary, ferritinophagy is a complex and dynamic process with significant implications for liver diseases. This review provides an in-depth analysis of ferritinophagy's regulatory mechanisms and its potential as a therapeutic target, emphasizing the need for further research to elucidate its role in liver health and disease.
Collapse
Affiliation(s)
- Kejia Wu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei Zhao
- Department of Anesthesiology, Xinyi People’s Hospital, Xinyi, Jiangsu, China
| | - Zeyu Hou
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weigang Zhang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Qin
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Junyi Qiu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Daobin Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lin Zhuang
- Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Xiaofeng Xue
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ding Sun
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
14
|
Ma J, Sun Q, Chen Y, Li J, Chen S, Luo L. Exosomes containing miR-148a-3p derived from mesenchymal stem cells suppress epithelial-mesenchymal transition in lens epithelial cells. Stem Cells Transl Med 2025; 14:szae091. [PMID: 40036306 PMCID: PMC11878568 DOI: 10.1093/stcltm/szae091] [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: 06/28/2024] [Accepted: 11/02/2024] [Indexed: 03/06/2025] Open
Abstract
Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is responsible for the development of fibrotic cataracts, which contribute to severe visual impairment. Recent evidence has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) can attenuate EMT in several tissues. However, the effect of MSC-Exo on EMT in LECs (LECs-EMT) has not been determined. In this study, we isolated exosomes from human umbilical cord MSCs (hucMSC-Exo) and evaluated their effect on LECs-EMT both in vitro and in vivo. HucMSC-Exo application significantly suppressed the expression of mesenchymal cell-associated genes while increasing the expression of epithelial cell-associated genes. Cell proliferation and migration of LECs undergoing EMT were inhibited after hucMSC-Exo treatment. The volume of EMT plaques in mice with injury-induced anterior subcapsular cataract (ASC) was significantly reduced in the hucMSC-Exo-treated group. Furthermore, miR-148a-3p was abundant in hucMSC-Exo. After transfection with miR-148a-3p inhibitor, the anti-fibrotic effect of hucMSC-Exo was attenuated in LECs-EMT. A dual-luciferase reporter assay identified PRNP as a direct target gene of miR-148a-3p. Furthermore, we verified that hucMSC-Exo inhibited LECs-EMT through the miR-148a-3p/PRNP axis and the potential downstream ERK signaling pathway. Taken together, our work reveals the inhibitory effect of hucMSC-Exo on LECs-EMT and the underlying mechanism involved, which may provide potential therapeutic options for fibrotic cataracts.
Collapse
Affiliation(s)
- Jingyu Ma
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, People’s Republic of China
| | - Qihang Sun
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong 999077, People’s Republic of China
| | - Yijia Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, People’s Republic of China
| | - Jinyan Li
- Department of Ophthalmology, The Key Laboratory of Advanced Interdisciplinary Studies Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, People’s Republic of China
| | - Shuyi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, People’s Republic of China
| | - Lixia Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, People’s Republic of China
| |
Collapse
|
15
|
Ma X, Peng L, Zhu X, Chu T, Yang C, Zhou B, Sun X, Gao T, Zhang M, Chen P, Chen H. Isolation, identification, and challenges of extracellular vesicles: emerging players in clinical applications. Apoptosis 2025; 30:422-445. [PMID: 39522104 DOI: 10.1007/s10495-024-02036-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Extracellular vesicles (EVs) serve as critical mediators of intercellular communication, encompassing exosomes, microvesicles, and apoptotic vesicles that play significant roles in diverse physiological and pathological contexts. Numerous studies have demonstrated that EVs derived from mesenchymal stem cells (MSC-EVs) play a pivotal role in facilitating tissue and organ repair, alleviating inflammation and apoptosis, enhancing the proliferation of endogenous stem cells within tissues and organs, and modulating immune function-these functions have been extensively utilized in clinical applications. The precise classification, isolation, and identification of MSC-EVs are essential for their clinical applications. This article provides a comprehensive overview of the biological properties of EVs, emphasizing both their advantages and limitations in isolation and identification methodologies. Additionally, we summarize the protein markers associated with MSC-EVs, emphasizing their significance in the treatment of various diseases. Finally, this article addresses the current challenges and dilemmas in developing clinical applications for MSC-EVs, aiming to offer valuable insights for future research.
Collapse
Affiliation(s)
- Xiaoxiao Ma
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Lanwei Peng
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiaohui Zhu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianqi Chu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Changcheng Yang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Bohao Zhou
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiangwei Sun
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianya Gao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Mengqi Zhang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Ping Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
| | - Haiyan Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
- East China Institute of Digital Medical Engineering, Shangrao, 334000, People's Republic of China.
| |
Collapse
|
16
|
Xu L, Shao Z, Fang X, Xin Z, Zhao S, Zhang H, Zhang Y, Zheng W, Yu X, Zhang Z, Sun L. Exploring precision treatments in immune-mediated inflammatory diseases: Harnessing the infinite potential of nucleic acid delivery. EXPLORATION (BEIJING, CHINA) 2025; 5:20230165. [PMID: 40040830 PMCID: PMC11875455 DOI: 10.1002/exp.20230165] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/22/2024] [Indexed: 03/06/2025]
Abstract
Immune-mediated inflammatory diseases (IMIDs) impose an immeasurable burden on individuals and society. While the conventional use of immunosuppressants and disease-modifying drugs has provided partial relief and control, their inevitable side effects and limited efficacy cast a shadow over finding a cure. Promising nucleic acid drugs have shown the potential to exert precise effects at the molecular level, with different classes of nucleic acids having regulatory functions through varying mechanisms. For the better delivery of nucleic acids, safe and effective viral vectors and non-viral delivery systems (including liposomes, polymers, etc.) have been intensively explored. Herein, after describing a range of nucleic acid categories and vectors, we focus on the application of therapeutic nucleic acid delivery in various IMIDs, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, asthma, ankylosing spondylitis, systemic lupus erythematosus, and uveitis. Molecules implicated in inflammation and immune dysregulation are abnormally expressed in a series of IMIDs, and their meticulous modulation through nucleic acid therapy results in varying degrees of remission and improvement of these diseases. By synthesizing findings centered on specific molecular targets, this review delivers a systematic elucidation and perspective towards advancing and utilization of nucleic acid therapeutics for managing IMIDs.
Collapse
Affiliation(s)
- Lingxiao Xu
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Zhenxuan Shao
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Xia Fang
- Department of Plastic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zengfeng Xin
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Shenzhi Zhao
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Hongbo Zhang
- Pharmaceutical Sciences LaboratoryAbo Akademi UniversityTurkuFinland
| | - Yu Zhang
- Pharmaceutical Sciences LaboratoryAbo Akademi UniversityTurkuFinland
| | - Wenbiao Zheng
- Department of OrthopedicsTaizhou Municipal HospitalTaizhouChina
| | - Xiaohua Yu
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Zengjie Zhang
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| | - Lingling Sun
- Department of Orthopedic SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
- Clinical Research Center of Motor System Disease of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina
| |
Collapse
|
17
|
Didamoony MA, Soubh AA, Ahmed LA. Cutting-edge insights into liver fibrosis: advanced therapeutic strategies and future perspectives using engineered mesenchymal stem cell-derived exosomes. Drug Deliv Transl Res 2025:10.1007/s13346-024-01784-7. [PMID: 39853531 DOI: 10.1007/s13346-024-01784-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2024] [Indexed: 01/26/2025]
Abstract
Liver fibrosis is still a serious health concern worldwide, and there is increasing interest in mesenchymal stem cells (MSCs) with tremendous potential for treating this disease because of their regenerative and paracrine effects. Recently, many researches have focused on using the released exosomes (EXOs) from stem cells to treat liver fibrosis rather than using parent stem cells themselves. MSC-derived EXOs (MSC-EXOs) have demonstrated favourable outcomes similar to cell treatment in terms of regenerative, immunomodulatory, anti-apoptotic, anti-oxidant, anti-necroptotic, anti-inflammatory and anti-fibrotic actions in several models of liver fibrosis. EXOs are superior to their parent cells in several terms, including lower immunogenicity and risk of tumour formation. However, maintaining the stability and efficacy of EXOs after in vivo transplantation remains a major challenge in their clinical applicability. Therefore, several strategies have been applied in EXOs engineering, such as parental cell modification or modifying EXOs directly to achieve optimum performance of EXOs in treating liver fibrosis. Herein, we discuss the underlying mechanisms of liver fibrosis with an overview of the available therapies, among them EXOs. We also summarise the recent developments in improving the effectiveness of EXOs with the advantages and limitations of these approaches in terms of the upcoming clinical applications.
Collapse
Affiliation(s)
- Manar A Didamoony
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo, 11829, Egypt.
| | - Ayman A Soubh
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12451, Egypt
| | - Lamiaa A Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| |
Collapse
|
18
|
Ye X, Lin X, Chen Y, Xu R, Zhou J. The role of ultrasound combined with water bath in the establishment of animal models of rat urethral stricture. Sci Rep 2025; 15:3035. [PMID: 39856358 PMCID: PMC11761433 DOI: 10.1038/s41598-025-87511-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025] Open
Abstract
Urinary tract injuries represent a significant clinical challenge, necessitating precise diagnosis and effective treatment strategies. Rat models are preferred for studying urinary tract injuries due to their size, visibility of external genitalia, and robust reproductive and growth capabilities. However, there is a lack of standardized methodologies for evaluating the endpoints of rat urinary tract injury models. This study aimed to investigate the methodology of model establishment, imaging evaluation techniques, and endpoint effectiveness. Twenty-four male Sprague-Dawley rats were randomly assigned to groups, including a blank control group and surgical groups. The surgical groups underwent urethral injury induced by recombinant transforming growth factor-β1 (TGF-β1) solution, followed by the random selection of one surgical group (n = 6) to receive treatment with mesenchymal stem cell (MSC) exosomes. High-frequency ultrasonography using a GE E10 device combined with a water bath method was employed to evaluate the urethral conditions of all rats. Ultrasonographic characteristics were scored for all surgical group rats, and an intergroup analysis was conducted between the surgical group and the control group rats. Statistical analysis was conducted using SPSS 22.0 software. Ultrasonographic assessment revealed significant differences in urethral echogenicity between the normal group and the surgical group, with noticeable changes in urethral morphology post-injury. Histopathological examination confirmed more severe urethral stenosis in the TGF group compared to the MSC group. High-frequency ultrasound could effectively differentiate between the two groups of rats. Additionally, there were significant differences in the scoring of ultrasonographic characteristics between the two groups. Urethral stricture presents a complex challenge in urology, often requiring invasive treatment modalities. The establishment of animal models plays a crucial role in understanding and addressing this condition. TGF-β1 induced fibrosis and MSC therapy represent promising avenues for urethral stricture management. High-frequency ultrasound combined with the immersion method offers a non-invasive and cost-effective approach for evaluating rat urethral stricture models. This study highlights the practicality of high-frequency ultrasound combined with the water bath method in evaluating rat urethral stricture models, as it can effectively differentiate between rats in the pure TGF-β1 induced group and those in the MSC treatment group based on urethral changes. The results underscore the importance of standardized methodologies for model assessment and the potential of non-invasive imaging techniques in preclinical research. Overall, this study contributes to advancing our understanding of urinary system injuries and holds implications for future therapeutic interventions in urology.
Collapse
Affiliation(s)
- Xiaojian Ye
- Department of Ultrasound, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
- Department of Ultrasound, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China.
| | - Xianjing Lin
- Department of Ultrasound, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Ultrasound, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
| | - Yehui Chen
- Department of Urology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Urology, First Affiliated Hospital, National Regional Medical Center, Binhai Campus, Fujian Medical University, Fuzhou, 350212, China
| | - Rongquan Xu
- Department of Ultrasound, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Ultrasound, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
| | - Jiawei Zhou
- Department of Ultrasound, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
- Department of Ultrasound, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
| |
Collapse
|
19
|
Kheradmand F, Yasaman Rahimzadeh SF, Esmaeili SA, Negah SS, Farkhad NK, Nazari SE, Hajinejad M, Khodadoust MA, Fadaee A, Afshari JT, Khazaei M. Efficacy of umbilical cord-derived mesenchymal stem cells and exosomes in conjunction with standard IBD drug on immune responses in an IBD mouse model. Stem Cell Res Ther 2025; 16:5. [PMID: 39773498 PMCID: PMC11707839 DOI: 10.1186/s13287-024-04062-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 11/11/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a persistent inflammation of the digestive system, and Mesenchymal Stem Cells (MSCs) and their exosomes have demonstrated potential as treatments for this condition. The objective of this research was to examine the possible effectiveness of intraperitoneal injection of umbilical cord-MSCs (UC-MSCs) and their exosomes through a two-time injection regimen in a mouse model. METHOD In this study, an animal model of a specific type of IBD in C57BL/6 mice, induced by dextran sulfate sodium (DSS), was utilized. The mice were treated with MSCs, exosomes, Mesalazine, and a combination of them. Upon sacrificing the mice, colon and spleen tissues were isolated to assess the changes in the mice's weight, colon length, spleen weight, and colitis' pathological symptoms. IL-10 and IL-17 levels were measured, and Treg and Th17 cell percentages were determined as well. Furthermore, colon tissue was stained to investigate histopathological changes. RESULTS In the groups that received MSCs, there was a significant reduction in the disease activity index and their combinations with exosomes and Mesalazine compared to the colitis group. Colon length increased in all groups except the exosome group. Histological measures were notably reduced in the MSC groups and their combinations. Significant increases in the IL-10 level of colon tissue and the proportion of Treg present in the spleen were observed in the groups receiving MSC and combination treatment. Furthermore, these groups showed a notable reduction in the percentage of spleen Th17 cells. However, IL17A decreased non-significantly in all groups. CONCLUSION The results showed that intraperitoneal injection of UC-MSCs and their combination with exosome and Mesalazine in a murine colitis model improved the disease's symptoms. Therefore, MSCs and their combination with exosomes can be a promising therapeutic approach along with other common drugs for IBD, but exosomes alone could not significantly reduce the symptoms of colitis.
Collapse
Affiliation(s)
- Fatemeh Kheradmand
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Fatemeh Yasaman Rahimzadeh
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Islamic Azad University, Garmsar Branch, Faculty of Veterinary Medicine, Tehran, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Najmeh Kaffash Farkhad
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Elnaz Nazari
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Hajinejad
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Qaen Faculty of Medical Science, Birjand University of Medical Science, Birjand, Iran
| | - Mohammad Ali Khodadoust
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsane Fadaee
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jalil Tavakol Afshari
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Khazaei
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
20
|
Wang N, Ma F, Song H, He N, Zhang H, Li J, Liu Q, Xu C. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Regenerative Applications and Radiotherapy. Cell Transplant 2025; 34:9636897241311019. [PMID: 39780320 PMCID: PMC11713979 DOI: 10.1177/09636897241311019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/12/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Tissue repair is an extremely crucial part of clinical treatment. During the course of disease treatment, surgery, chemotherapy, and radiotherapy cause tissue damage. On the other hand, Normal tissue from accidental or therapeutic exposure to high-dose radiation can cause severe tissue damage. There is an urgent need for developing medical countermeasures against radiation injury for tissue repair. Tissue repair involves the regeneration, proliferation, differentiation, and migration of tissue cells; imbalance of local tissue homeostasis, progressive chronic inflammation; decreased cell activity and stem cell function; and wound healing. Although many clinical treatments are currently available for tissue repair, they are expensive. The long recovery time and some unavoidable complications such as cell damage and the inflammatory reaction caused by radiotherapy have led to unsatisfactory results. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have similar tissue repair functions as MSCs. In tissue damage, EVs can be used as an alternative to stem cell therapy, thereby avoiding related complications such as immunological rejection. EVs play a major role in regulating tissue damage, anti-inflammation, pro-proliferation, and immune response, thus providing a diversified and efficient solution for the repair of disease- and radiotherapy-induced tissue damage. This article reviews the research progress of mesenchymal stem cell-derived EVs in promoting the repair of tissue including heart, lung, liver, intestine, skin, blood system, central nervous system, and tissue damage caused by radiotherapy, thereby aiming to offer new directions and ideas for the radiotherapy and regenerative applications.
Collapse
Affiliation(s)
- Ning Wang
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Feifei Ma
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Huijuan Song
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Ningning He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Huanteng Zhang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Jianguo Li
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
| | - Qiang Liu
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Chang Xu
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, China
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, State Key Laboratory of Advanced Medical Materials and Devices, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| |
Collapse
|
21
|
Moratin H, Mache I, Goncalves M, Ehret Kasemo T, Stöth M, Meyer TJ, Hackenberg S, Scherzad A, Herrmann M. Preconditioning with Wound Fluid Enhances Immunosuppressive Properties of Mesenchymal Stromal Cells In Vitro. Int J Mol Sci 2024; 26:293. [PMID: 39796154 PMCID: PMC11719632 DOI: 10.3390/ijms26010293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Immunosuppression is one key feature of mesenchymal stromal cells (MSCs) that has high expectations for therapeutic use. The influence of pro-inflammatory stimuli can modify the characteristics of MSCs and enhance immunosuppressive properties. The local postoperative environment contains cytokines, MSCs, and immune cells in high quantities, and their mutual influence is still unclear. Knowledge of in vivo processes is pivotal for potential therapeutic applications, and therefore, the aim of this study was to investigate the influence of wound fluid (WF) on the immunomodulatory potential of MSCs. CD4+ cells were co-cultured with native or WF-preconditioned MSCs for 5 days. CFSE staining revealed significant suppression of T cell proliferation after co-culture that was even more distinct in co-culture with WF-MSCs. The concentration of IDO-1, TGF-β1 and IFN-γ was higher while TNF-α was reduced in co-culture supernatants, indicating a transition to an anti-inflammatory milieu. In summary, the results provide evidence that the influence of WF alters the immunomodulatory potential of MSCs. These findings should serve as the basis for further investigations with a focus on T cell subpopulations.
Collapse
Affiliation(s)
- Helena Moratin
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Isabel Mache
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Miguel Goncalves
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Totta Ehret Kasemo
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Manuel Stöth
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Till Jasper Meyer
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Stephan Hackenberg
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Agmal Scherzad
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Hospital Würzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany
| | - Marietta Herrmann
- IZKF Research Group Tissue Regeneration in Musculoskeletal Diseases, University Hospital Wuerzburg, D-97070 Wuerzburg, Germany
- Department of Orthopedics, Bernhard-Heine-Center for Locomotion Research, University of Wuerzburg, D-97074 Wuerzburg, Germany
| |
Collapse
|
22
|
Alric H, Mathieu N, Sebbagh A, Peré G, Demarquay C, Cronemberger A, Berger A, Marcel B, Wilhelm C, Gazeau F, Mariani A, Karoui M, Clément O, Araujo-Filho I, Silva AKA, Rahmi G. Thermoresponsive gel embedding extracellular vesicles from adipose stromal cells improves the healing of colonic anastomoses following irradiation in rats. Commun Biol 2024; 7:1673. [PMID: 39702754 DOI: 10.1038/s42003-024-07364-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 12/04/2024] [Indexed: 12/21/2024] Open
Abstract
Anastomotic leak occurrence is a severe complication after colorectal surgery. Considering the difficulty of treating these leaks and their impact on patient care, there is a strong need for an efficient prevention strategy. We evaluated a combination of extracellular vesicles (EVs) from rat adipose-derived stromal cells with a thermoresponsive gel, Pluronic® F127 (PF-127) to prevent anastomotic leaks. The pro-regenerative and immunomodulatory potencies of EVs are assessed in vitro. In vivo efficacy are assessed in rat with a colonic anastomosis model after irradiation. Endoscopic, anatomical and histological data show a consistent effect of EVs + gel on the healing of colonic anastomosis. These results are illustrated by a smaller anastomotic ulcer size, less fibrosis and less inflammatory infiltrations in the EVs + gel group. This multi-modal investigation is the first to point-out the translational potential of EVs combined with PF-127 for the healing of high-risk colorectal anastomosis.
Collapse
Affiliation(s)
- Hadrien Alric
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France.
- Service d'Hépato-Gastro-Entérologie et Endoscopies Digestives, Hôpital Européen Georges Pompidou, APHP.Centre-Université Paris Cité, Paris, France.
| | - Noëlle Mathieu
- Laboratoire de Radiobiologie des Expositions Médicales, Institut de Radioprotection et de Sureté Nucléaire, Fontenay-Aux-Roses, France
| | - Anna Sebbagh
- Laboratoire Matière et Systèmes Complexes, CNRS, UMR 7057, Université Paris Cité, Paris, France
| | - Guillaume Peré
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service de Chirurgie Digestive, Centre-Hospitalo-Universitaire Toulouse-Rangueil, Toulouse, France
| | - Christelle Demarquay
- Laboratoire de Radiobiologie des Expositions Médicales, Institut de Radioprotection et de Sureté Nucléaire, Fontenay-Aux-Roses, France
| | - André Cronemberger
- Laboratoire Matière et Systèmes Complexes, CNRS, UMR 7057, Université Paris Cité, Paris, France
| | - Arthur Berger
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre-Hospitalo-Universitaire Bordeaux, Bordeaux, France
| | - Benjamin Marcel
- Laboratoire Matière et Systèmes Complexes, CNRS, UMR 7057, Université Paris Cité, Paris, France
| | - Claire Wilhelm
- Laboratoire PhysicoChimie Curie, Institut Curie, PSL Research University-Sorbonne Université-CNRS, Paris, France
| | - Florence Gazeau
- Laboratoire Matière et Systèmes Complexes, CNRS, UMR 7057, Université Paris Cité, Paris, France
| | - Antoine Mariani
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service de Chirurgie Digestive, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Mehdi Karoui
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service de Chirurgie Digestive, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Olivier Clément
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service d'Imagerie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Irami Araujo-Filho
- Department of Surgery, Federal University of Rio Grande do Norte. Institute of Teaching, Research, and Innovation, Liga Contra o Cancer, Natal, Brazil
| | - Amanda K A Silva
- Laboratoire Matière et Systèmes Complexes, CNRS, UMR 7057, Université Paris Cité, Paris, France
| | - Gabriel Rahmi
- Laboratoire de Recherche en Imagerie du Vivant, PARCC, INSERM U970, Université Paris Cité, Paris, France
- Service d'Hépato-Gastro-Entérologie et Endoscopies Digestives, Hôpital Européen Georges Pompidou, APHP.Centre-Université Paris Cité, Paris, France
| |
Collapse
|
23
|
Wu P, Wang M, Jin C, Li L, Tang Y, Wang Z, Wang X, Xu W, Qian H. Highly Efficient Delivery of Novel MiR-13896 by Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Inhibits Gastric Cancer Progression by Targeting ATG2A-Mediated Autophagy. Biomater Res 2024; 28:0119. [PMID: 39697182 PMCID: PMC11654722 DOI: 10.34133/bmr.0119] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/14/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite recent advancements, clinical outcomes for GC remain unsatisfactory. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have shown promise in inhibiting tumor progression, but their role in GC, specifically human umbilical cord MSC-derived small EVs (hucMSC-sEVs), is not well understood. This study investigates the therapeutic potential of hucMSC-sEVs in GC treatment. We found that hucMSC-sEVs are captured by GC cells, substantially inhibiting their proliferation and inducing apoptosis. MiRNA sequencing revealed that hucMSC-sEVs were enriched with miRNAs having anticancer properties. Among these, miR-13896, a new miRNA, was identified as a potent inhibitor of GC cell proliferation and a promoter of apoptosis. Mechanistic studies revealed that miR-13896 targets and down-regulates the ATG2A-mediated autophagy pathway, suppressing GC cell growth and metastasis. Furthermore, we enriched hucMSC-sEVs with miR-13896 through electroporation. These engineered EVs specifically targeted tumor sites and significantly reduced GC cell growth and migration in vitro and in vivo. MiR-13896 emerged as a promising therapeutic target for GC. The delivery of miR-13896 via hucMSC-sEVs represents a novel and effective strategy for GC treatment, highlighting the potential of EV-based therapies to combat this malignancy.
Collapse
Affiliation(s)
- Peipei Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, Anhui 230001, China
| | - Min Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials,
Anhui Medical University, Hefei, Anhui 230032, China
| | - Can Jin
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine,
Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Linli Li
- Department of Clinical Laboratory, Changzhou Second Hospital, Changzhou, Jiangsu 213000, China
| | - Yuting Tang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine,
Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Zhangfei Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, Anhui 230001, China
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials,
Anhui Medical University, Hefei, Anhui 230032, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine,
Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Clinical Laboratory, School of Medicine,
Jiangsu University, Zhenjiang, Jiangsu 212000, China
| |
Collapse
|
24
|
Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
Collapse
Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
| |
Collapse
|
25
|
Hassaan NA, Mansour HA. Exosomal therapy is a luxury area for regenerative medicine. Tissue Cell 2024; 91:102570. [PMID: 39383641 DOI: 10.1016/j.tice.2024.102570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 09/02/2024] [Accepted: 09/17/2024] [Indexed: 10/11/2024]
Abstract
Stem cell-based therapies have made significant advancements in tissue regeneration and medical engineering. However, there are limitations to cell transplantation therapy, such as immune rejection and limited cell viability. These limitations greatly impede the translation of stem cell-based tissue regeneration into clinical practice. In recent years, exosomes, which are packaged vesicles released from cells, have shown promising progress. Specifically, exosomes derived from stem cells have demonstrated remarkable therapeutic benefits. Exosomes are nanoscale extracellular vesicles that act as paracrine mediators. They transfer functional cargos, such as miRNA and mRNA molecules, peptides, proteins, cytokines, and lipids, from MSCs to recipient cells. By participating in intercellular communication events, exosomes contribute to the healing of injured or diseased tissues and organs. Studies have shown that the therapeutic effects of MSCs in various experimental paradigms can be solely attributed to their exosomes. Consequently, MSC-derived exosomes can be modified and utilized to develop a unique cell-free therapeutic approach for treating multiple diseases, including neurological, immunological, heart, and other diseases. This review is divided into several categories, including the current understanding of exosome biogenesis, isolation techniques, and their application as therapeutic tools.
Collapse
Affiliation(s)
- Nahla A Hassaan
- Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt.
| | - Hanaa A Mansour
- Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| |
Collapse
|
26
|
Xiong Z, Li X, Xie M, Guo J, Yin S, Huang D, Jin L, Wang C, Zhang F, Mao C, Chen H, Luo D, Tang H, Chen X, Lian L. Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8. J Gastroenterol 2024; 59:1092-1106. [PMID: 39305336 DOI: 10.1007/s00535-024-02152-5] [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] [Received: 03/06/2024] [Accepted: 09/13/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects. METHODS AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed. RESULTS AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway. CONCLUSIONS MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.
Collapse
Affiliation(s)
- Zhizhong Xiong
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xianzhe Li
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Medical Faculty Heidelberg, Heidelberg University, 69120, Heidelberg, Germany
| | - Minghao Xie
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jianping Guo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shi Yin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dayin Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Longyang Jin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Caiqin Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fengxiang Zhang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chaobin Mao
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huaxian Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dandong Luo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Haijie Tang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xijie Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lei Lian
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| |
Collapse
|
27
|
Yadav S, Maity P, Kapat K. The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine. Cells 2024; 13:1956. [PMID: 39682706 PMCID: PMC11640604 DOI: 10.3390/cells13231956] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.
Collapse
Affiliation(s)
- Sachin Yadav
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
| | - Pritiprasanna Maity
- School of Medicine, University of California Riverside, Riverside, CA 92525, USA
| | - Kausik Kapat
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
| |
Collapse
|
28
|
Tao X, Chen C, Liu M. The Role of Extracellular Vesicles in Liver Fibrosis: Friends or Foes? Biomedicines 2024; 12:2665. [PMID: 39767572 PMCID: PMC11726879 DOI: 10.3390/biomedicines12122665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/15/2024] [Accepted: 11/17/2024] [Indexed: 01/16/2025] Open
Abstract
Liver fibrosis represents a common pathway in the progression of various chronic liver diseases towards cirrhosis and liver failure. Extracellular vesicles (EVs) are membrane-enclosed particles secreted by diverse cell types, including exosomes, microvesicles, apoptotic vesicles, and the recently identified migrasomes. These vesicles can be taken up by recipient cells, thereby modulating their function through the transport of cargo molecules. EVs facilitate intercellular communication and play a significant role in the development of liver fibrosis. Moreover, the detection of EVs in various body fluids offers sensitive diagnostic tools for assessing liver fibrosis. Additionally, EVs may serve as therapeutic targets, potential therapeutic agents, and drug delivery vehicles. This article reviews recent advances in the field of EVs concerning liver fibrosis and related diseases, with a particular focus on the potential role of the newly discovered migrasomes in intracellular crosstalk within the liver.
Collapse
Affiliation(s)
- Xiang Tao
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Can Chen
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| |
Collapse
|
29
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Extracellular Vesicles in Viral Liver Diseases. Viruses 2024; 16:1785. [PMID: 39599900 PMCID: PMC11598962 DOI: 10.3390/v16111785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
| |
Collapse
|
30
|
Al Saihati HA, Badr OA, Dessouky AA, Mostafa O, Samir Farid A, Aborayah NH, Abdullah Aljasir M, Baioumy B, Mahmoud Taha N, El-Sherbiny M, Hamed Al-Serwi R, Ramadan MM, Salim RF, Shaheen D, E M Ali F, Ebrahim N. Exploring the cytoprotective role of mesenchymal stem Cell-Derived exosomes in chronic liver Fibrosis: Insights into the Nrf2/Keap1/p62 signaling pathway. Int Immunopharmacol 2024; 141:112934. [PMID: 39178516 DOI: 10.1016/j.intimp.2024.112934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
Hepatic fibrosis is a common pathology present in most chronic liver diseases. Autophagy is a lysosome-mediated intracellular catabolic and recycling process that plays an essential role in maintaining normal hepatic functions. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor responsible for the regulation of cellular anti-oxidative stress response. This study was designed to assess the cytoprotective effect of mesenchymal stem cell-derived exosomes (MSC-exos) on endothelial-mesenchymal transition (EMT) in Carbon Tetrachloride (CCL4) induced liver fibrosis. Rats were treated with 0.1 ml of CCL4 twice weekly for 8 weeks, followed by administration of a single dose of MSC-exos. Rats were then sacrificed after 4 weeks, and liver samples were collected for gene expression analyses, Western blot, histological studies, immunohistochemistry, and transmission electron microscopy. Our results showed that MSC-exos administration decreased collagen deposition, apoptosis, and inflammation. Exosomes modulate the Nrf2/Keap1/p62 pathway, restoring autophagy and Nrf2 levels through modulation of the non-canonical pathway of Nrf2/Keap1/p62. Additionally, MSC-exos regulated miR-153-3p, miR-27a, miR-144 and miRNA-34a expression. In conclusion, the present study shed light on MSC-exos as a cytoprotective agent against EMT and tumorigenesis in chronic liver inflammation.
Collapse
Affiliation(s)
- Hajir A Al Saihati
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Saudi Arabia.
| | - Omnia A Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Egypt.
| | - Arigue A Dessouky
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, 44519 Zagazig, Egypt.
| | - Ola Mostafa
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt.
| | - Ayman Samir Farid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Qalyubia, Egypt.
| | - Nashwa H Aborayah
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Egypt, Department of Pharmacology, Mutah University, Mutah 61710, Jordan.
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
| | - Bodour Baioumy
- Department of Anatomy and Embryology, Faculty of Medicine, Benha University, Egypt.
| | | | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Egypt.
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Mahmoud M Ramadan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah City, United Arab Emirates; Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura City, Egypt.
| | - Rabab F Salim
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha Universit, Egypt.
| | - Dalia Shaheen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Nesrine Ebrahim
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Stem Cell Unit, Egypt.
| |
Collapse
|
31
|
Ma H, Jing Y, Zeng J, Ge J, Sun S, Cui R, Qian C, Qu S, Sheng H. Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate muscle atrophy via the miR-132-3p/FoxO3 axis. J Orthop Translat 2024; 49:23-36. [PMID: 39420945 PMCID: PMC11483279 DOI: 10.1016/j.jot.2024.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 08/05/2024] [Accepted: 08/05/2024] [Indexed: 10/19/2024] Open
Abstract
Background Muscle atrophy or sarcopenia is the loss of muscle mass and strength and leads to an increased risk of disability and death including osteoporotic fractures. Currently, there are no available clinical biologic agents for the treatment of sarcopenia. Since exosomes have become increasingly attractive as a novel therapeutic approach due to their ability to facilitate cell-cell transfer of proteins and RNAs, promoting cell repair and function recovery, we hypothesized that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) might benefit muscle atrophy in age-related and dexamethasone-induced sarcopenia animal models. Methods HucMSC-Exos were harvested by ultrafast centrifugation and identified by transmission electron microscopy, particle size analysis, and Western blot analysis. The effects of hucMSC-Exos on muscle atrophy were evaluated using age-related and dexamethasone-induced muscle atrophy mice models. Body weight, grip strength, muscle weight, and muscle histology of these mice were assessed. The expression levels of muscle RING finger 1 (MuRF1) and muscle atrophy F-box (atrogin-1) were measured by Western blot. Dexamethasone-induced C2C12 myotube atrophy was used to establish the cell model of muscle atrophy. Myotube diameter was evaluated by immunofluorescence staining. Bioinformatic analysis, RNA sequencing analysis, and Western blot analysis were performed to explore the underlying mechanisms. Results In vivo experiments, hucMSC-Exos demonstrated a remarkable capacity to improve grip strength, increase muscle mass, and muscle fiber cross-sectional area, while concurrently reducing the expression of MuRF1 and atrogin-1 in age-related and dexamethasone-induced muscle atrophy mice. In vitro experiments, hucMSC-Exos can promote the proliferation of C2C12 cells, and rescue the dexamethasone-induced decline in the viability of C2C12 myotubes. In addition, hucMSC-Exos can increase the diameter of C2C12 myotubes, and reduce dexamethasone-induced upregulation of MuRF1 and atrogin-1. Combined with bioinformatics analysis and RNA sequencing analysis, we further showed that miR-132-3p was one of the essential miRNAs in hucMSC-Exos and played an important role by targeting FoxO3. Conclusion Our findings suggested that hucMSC-Exos can improve age-related and dexamethasone-induced muscle atrophy in mice models. This study first demonstrated that hucMSC-Exos may ameliorate muscle atrophy via the miR-132-3p/FoxO3 axis. These data may provide novel and valuable insights into the clinical transformation of hucMSC-Exos for the treatment of sarcopenia. The translational potential of this article HucMSC-Exos are easily available for clinical application, this study further consolidates the evidence for the clinical transformation potential of hucMSC-Exos for sarcopenia and provides its new target pathway.
Collapse
Affiliation(s)
- Huihui Ma
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Yujie Jing
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Jiangping Zeng
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Jiaying Ge
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Siqi Sun
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Ran Cui
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Chunhua Qian
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Hui Sheng
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
- Department of Endocrinology and Metabolism, Anqing Traditional Chinese Medicine Hospital, Anqing Medical College, Anqing, 246052, China
| |
Collapse
|
32
|
Opretzka LCF, Pinto CD, Santos JRDJ, de Lima AA, Soares MBP, Villarreal CF. Mesenchymal stem cell-derived cell-free technologies: a patent landscape. Biotechnol Lett 2024; 46:907-924. [PMID: 38900338 DOI: 10.1007/s10529-024-03506-y] [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: 01/08/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/21/2024]
Abstract
Mesenchymal stem/stromal cells (MSC) play a pivotal role in regenerative therapies. Recent studies show that factors secreted by MSC can replicate their biological activity, driving the emergence of cell-free therapy, likely to surpass stem cell therapy. Patents are an objective measure of R&D and innovation activities, and patent mapping allows us to verify the state of the art and technology, anticipate trends, and identify emerging lines of research. This review performed a search on Derwent World Patents Index™ and retrieved 269 patent families related to the MSC-derived cell-free products. Analysis reveals an exponential increase in patents from the mid-2010s, primarily focusing on exosomes. The patent's contents offer a great diversity of applications and associated technologies by using the products as medicinal agents or drug delivery systems. Nevertheless, numerous application branches remain unexplored, suggesting vast potential for cell-free technologies alone or combined with other approaches.
Collapse
Affiliation(s)
| | - Cláudio Damasceno Pinto
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil
| | | | - Alyne Almeida de Lima
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil
- Institute of Advanced Systems in Health, SENAI CIMATEC, Salvador, Bahia, 41650-010, Brazil
| | - Cristiane Flora Villarreal
- Faculty of Pharmacy, Federal University of Bahia, Salvador, Bahia, 40170-115, Brazil.
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, 40296-710, Brazil.
| |
Collapse
|
33
|
Sani F, Shafiei F, Dehghani F, Mohammadi Y, Khorraminejad‐Shirazi M, Anvari‐Yazdi AF, Moayedfard Z, Azarpira N, Sani M. Unveiling exosomes: Cutting-edge isolation techniques and their therapeutic potential. J Cell Mol Med 2024; 28:e70139. [PMID: 39431552 PMCID: PMC11492151 DOI: 10.1111/jcmm.70139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 09/12/2024] [Accepted: 10/01/2024] [Indexed: 10/22/2024] Open
Abstract
Exosomes are one type of nanosized membrane vesicles with an endocytic origin. They are secreted by almost all cell types and play diverse functional roles. It is essential for research purposes to differentiate exosomes from microvesicles and isolate them from other components in a fluid sample or cell culture medium. Exosomes are important mediators in cell-cell communication. They deliver their cargos, such as mRNA transcripts, microRNA, lipids, cytosolic and membrane proteins and enzymes, to target cells with or without physical connections between cells. They are highly heterogeneous in size, and their biological functions can vary depending on the cell type, their ability to interact with recipient cells and transport their contents, and the environment in which they are produced. This review summarized the recent progress in exosome isolation and characterization techniques. Moreover, we review the therapeutic approaches, biological functions of exosomes in disease progression, tumour metastasis regulation, immune regulation and some ongoing clinical trials.
Collapse
Affiliation(s)
- Farnaz Sani
- Shiraz Institute for Stem Cell & Regenerative MedicineShiraz University of Medical SciencesShirazIran
| | - Faezeh Shafiei
- Shiraz Institute for Stem Cell & Regenerative MedicineShiraz University of Medical SciencesShirazIran
| | - Farshad Dehghani
- Shiraz Institute for Stem Cell & Regenerative MedicineShiraz University of Medical SciencesShirazIran
| | - Yasaman Mohammadi
- Pharmaceutical Sciences Research CenterShiraz University of Medical ScienceShirazIran
| | - Mohammadhossein Khorraminejad‐Shirazi
- Department of Pathology, School of MedicineShiraz University of Medical SciencesShirazIran
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
- Department of Pathology, School of MedicineJahrom University of Medical SciencesJahromIran
| | | | - Zahra Moayedfard
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
| | - Negar Azarpira
- Shiraz Institute for Stem Cell & Regenerative MedicineShiraz University of Medical SciencesShirazIran
- Transplant Research CenterShiraz University of Medical SciencesShirazIran
| | - Mahsa Sani
- Shiraz Institute for Stem Cell & Regenerative MedicineShiraz University of Medical SciencesShirazIran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
| |
Collapse
|
34
|
Choi YJ, Kim JH, Lee Y, Pyeon HJ, Yoo IK, Yoo JH. Anti-fibrogenic effect of umbilical cord-derived mesenchymal stem cell-conditioned media in human esophageal fibroblasts. Sci Rep 2024; 14:22233. [PMID: 39333200 PMCID: PMC11437107 DOI: 10.1038/s41598-024-73091-7] [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: 03/18/2024] [Accepted: 09/13/2024] [Indexed: 09/29/2024] Open
Abstract
Esophageal fibrosis can develop due to caustic or radiation injuries. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are known to mitigate fibrosis in various organs. However, the potential effects of UC-MSCs on human esophageal fibrosis remain underexplored. This study investigated the anti-fibrogenic properties and mechanisms of UC-MSC-derived conditioned media (UC-MSC-CM) on human esophageal fibroblasts (HEFs). HEFs were treated with TGF-β1 and then cultured with UC-MSC-CM, and the expression levels of extracellular matrix (ECM) components, RhoA, myocardin related transcription factor A (MRTF-A), serum response factor (SRF), Yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ) were measured. UC-MSC-CM suppressed TGF-β1-induced fibrogenic activation in HEFs, as evidenced by the downregulation of ECM. UC-MSC-CM diminished the expression of RhoA, MRTF-A, and SRF triggered by TGF-β1. In TGF-β1-stimulated HEFs, UC-MSC-CM decreased the nuclear localization of MRTF-A and YAP. Additionally, UC-MSC-CM diminished the TGF-β1-induced nuclear expressions of YAP and TAZ, while concurrently enhancing the cytoplasmic presence of phosphorylated YAP. Furthermore, UC-MSC-CM reduced TGF-β1-induced phosphorylation of Smad2. These findings suggest that UC-MSC-CM may inhibit TGF-β1-induced fibrogenic activation in HEFs by targeting the Rho-mediated MRTF/SRF and YAP/TAZ pathways, as well as the Smad2 pathway. This indicates its potential as a stem cell therapy for esophageal fibrosis.
Collapse
Affiliation(s)
- Yoon Jeong Choi
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea
- Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam, 13496, South Korea
| | - Jee Hyun Kim
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea
| | - Yeonju Lee
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea
| | - Hee Jang Pyeon
- R&D Division, CHA Biotech Co., Ltd, Seongnam, 13488, South Korea
| | - In Kyung Yoo
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
| | - Jun Hwan Yoo
- Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
- Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam, 13496, South Korea.
| |
Collapse
|
35
|
Puspita R, Jusuf AA, Antarianto RD, Sianipar IR. A systematic review of the anti-inflammatory and anti-fibrotic potential of human umbilical cord mesenchymal stem cells-derived exosomes in experimental models of liver regeneration. Mol Biol Rep 2024; 51:999. [PMID: 39302506 DOI: 10.1007/s11033-024-09929-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024]
Abstract
Chronic liver injuries and their complications are leading causes of death, especially in developing countries (Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023). The available and effective treatment plans are limited, implicating the need for innovative treatment approaches (Tsuchiya et al. in Inflamm Regener, 2019;Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023;Younossi et al. in Clin Gastroenterol Hepatol 21:1978-1991, 2023;). This paper aims to summarize the effects and mechanisms of hUC-MSC-exo on liver injuries and its complications; it also suggests future directions for future research. The outcomes of interest are the morphology and histology of the liver, pathology score, liver function enzyme, glucose and lipid metabolism, and the effect hUC-MSC-exo had on gene regulation regarding liver diseases. A comprehensive review of nineteen studies was conducted to assess the effectiveness of the implementation of the hUC-MSC-Exo, instilling confidence in the validity of the findings. Regarding the morphology and histology of the liver and pathology score, hUC-MSC-exo treatment resulted in improved liver morphology post-treatment, as indicated by the reduction in pathology scores. However, these observed improvements in the liver surface are not directly attributed to the hUC-MSC-Exo itself but to the overall healing processes stimulated by the treatment. In physiological outcomes, hUC-MSC-exo also improves glucose and lipid metabolism, especially in diet-induced liver injury and its complications. In gene regulation, one interesting gene in this intervention is the fat mass and obesity-associated (FTO), in which hUC-MSC-exo combined with miRNAs can suppress FTO. HUC-MSC-Exo can improve by utilizing several possible pathways, targeting pinpoints in the pathogenesis of liver disease or glucose and lipid metabolism. This study presents hUC-MSC-exo better in all outcomes of interest compared to the control or sham group. Further specification of indications of the hUC-MSC-exo method may be beneficial and essential to be analyzed in future reviews to better understand the effectiveness of each hUC-MSC-exo dose, duration, and medium.
Collapse
Affiliation(s)
- Ratna Puspita
- Doctoral Program in Biomedical Science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Department of Biochemistry, Faculty of Medicine, Universitas Pembangunan Nasional Veteran Jakarta, Jakarta, Indonesia
| | - Ahmad Aulia Jusuf
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | | | | |
Collapse
|
36
|
Zhong Z, Cui XL, Tan KJ, Wu XY, Zhu XJ, Zhang JY, Zhang WJ, Wang HY, Zhang PL. Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis. J Nanobiotechnology 2024; 22:541. [PMID: 39238002 PMCID: PMC11375929 DOI: 10.1186/s12951-024-02824-7] [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: 06/24/2024] [Accepted: 08/31/2024] [Indexed: 09/07/2024] Open
Abstract
Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.
Collapse
Affiliation(s)
- Zhi Zhong
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xiu-Liang Cui
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Naval Medical University, Shanghai, 200438, China
| | - Kun-Jiang Tan
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Naval Medical University, Shanghai, 200438, China
| | - Xiang-Yu Wu
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
| | - Xiang-Jie Zhu
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
- Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Jiu-Yu Zhang
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
- Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, 200438, China
| | - Wei-Jia Zhang
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China
| | - Hong-Yang Wang
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China.
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Naval Medical University, Shanghai, 200438, China.
| | - Pei-Lin Zhang
- National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China.
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Naval Medical University, Shanghai, 200438, China.
| |
Collapse
|
37
|
Soltanmohammadi F, Gharehbaba AM, Zangi AR, Adibkia K, Javadzadeh Y. Current knowledge of hybrid nanoplatforms composed of exosomes and organic/inorganic nanoparticles for disease treatment and cell/tissue imaging. Biomed Pharmacother 2024; 178:117248. [PMID: 39098179 DOI: 10.1016/j.biopha.2024.117248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024] Open
Abstract
Exosome-nanoparticle hybrid nanoplatforms, can be prepared by combining exosomes with different types of nanoparticles. The main purpose of combining exosomes with nanoparticles is to overcome the limitations of using each of them as drug delivery systems. Using nanoparticles for drug delivery has some limitations, such as high immunogenicity, poor cellular uptake, low biocompatibility, cytotoxicity, low stability, and rapid clearance by immune cells. However, using exosomes as drug delivery systems also has its own drawbacks, such as poor encapsulation efficiency, low production yield, and the inability to load large molecules. These limitations can be addressed by utilizing hybrid nanoplatforms. Additionally, the use of exosomes allows for targeted delivery within the hybrid system. Exosome-inorganic/organic hybrid nanoparticles may be used for both therapy and diagnosis in the future. This may lead to the development of personalized medicine using hybrid nanoparticles. However, there are a few challenges associated with this. Surface modifications, adding functional groups, surface charge adjustments, and preparing nanoparticles with the desired size are crucial to the possibility of preparing exosome-nanoparticle hybrids. Additional challenges for the successful implementation of hybrid platforms in medical treatments and diagnostics include scaling up the manufacturing process and ensuring consistent quality and reproducibility across various batches. This review focuses on various types of exosome-nanoparticle hybrid systems and also discusses the preparation and loading methods for these hybrid nanoplatforms. Furthermore, the potential applications of these hybrid nanocarriers in drug/gene delivery, disease treatment and diagnosis, and cell/tissue imaging are explained.
Collapse
Affiliation(s)
- Fatemeh Soltanmohammadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Adel Mahmoudi Gharehbaba
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rajabi Zangi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khosro Adibkia
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Javadzadeh
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
38
|
Ji G, Zhang Z, Wang X, Guo Q, Zhang E, Li C. Comprehensive evaluation of the mechanism of human adipose mesenchymal stem cells ameliorating liver fibrosis by transcriptomics and metabolomics analysis. Sci Rep 2024; 14:20035. [PMID: 39198546 PMCID: PMC11358327 DOI: 10.1038/s41598-024-70281-1] [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: 05/04/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Liver fibrosis is a chronic liver disease with progressive wound healing reaction caused by liver injury. Currently, there is no FDA approved drugs for liver fibrosis. Human adipose mesenchymal stem cells (hADSCs) have shown remarkable therapeutic effects in liver diseases. However, few studies have evaluated the therapeutic role of hADSCs in liver fibrosis, and the detailed mechanism of action is unknown. Here, we investigated the in vitro and in vivo anti-fibrosis efficacy of hADSCs and identified important metabolic changes and detailed mechanisms through transcriptomic and metabolomic analyses. We found that hADSCs could inhibit the proliferation of activated hepatic stellate cells (HSCs), promote their apoptosis, and effectively inhibit the expression of pro-fibrotic protein. It can significantly reduce collagen deposition and liver injury, improve liver function and alleviate liver inflammation in cirrhotic mouse models. In addition, transcriptome analysis revealed that the key mechanism of hADSCs against liver fibrosis is the regulation of AGE-RAGE signaling pathway. Metabolic analysis showed that hADSCs influenced changes of metabolites in lipid metabolism. Therefore, our study shows that hADSCs could reduce the activation of hepatic stellate cells and inhibit the progression of liver fibrosis, which has important potential in the treatment of liver fibrosis as well as other refractory chronic liver diseases.
Collapse
Affiliation(s)
- Guibao Ji
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Hepatobiliary-Pancreatic and Hernia Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Zilong Zhang
- Department of Hepatobiliary-Pancreatic and Hernia Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Xinze Wang
- Department of Trauma and Orthopedics, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Qiuxia Guo
- Department of Gastroenterology Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, People's Republic of China
| | - Erlei Zhang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
| | - Chuanjiang Li
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
| |
Collapse
|
39
|
Chiabotto G, Semnani A, Ceccotti E, Guenza M, Camussi G, Bruno S. Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Reversing Hepatic Fibrosis in 3D Liver Spheroids. Biomedicines 2024; 12:1849. [PMID: 39200313 PMCID: PMC11351945 DOI: 10.3390/biomedicines12081849] [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: 07/02/2024] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 09/02/2024] Open
Abstract
Hepatic fibrosis, arising from prolonged liver injury, entails the activation of hepatic stellate cells (HSCs) into myofibroblast-like cells expressing alpha-smooth muscle actin (α-SMA), thereby driving extracellular matrix deposition and fibrosis progression. Strategies targeting activated HSC reversal and hepatocyte regeneration show promise for fibrosis management. Previous studies suggest that extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) can suppress HSC activation, but ensuring EV purity is essential for clinical use. This study investigated the effects of MSC-derived EVs cultured in chemically defined conditions on liver spheroids and activated HSCs. Umbilical cord- and bone marrow-derived MSCs were expanded in chemically defined media, and EVs were isolated using filtration and differential ultracentrifugation. The impact of MSC-EVs was evaluated on liver spheroids generated in Sphericalplate 5D™ and on human HSCs, both activated by transforming growth factor beta 1 (TGF-β1). MSC-EVs effectively reduced the expression of profibrotic markers in liver spheroids and activated HSCs induced by TGF-β1 stimulation. These results highlight the potential of MSC-EVs collected under chemically defined conditions to mitigate the activated phenotype of HSCs and liver spheroids, suggesting MSC-EVs as a promising treatment for hepatic fibrosis.
Collapse
Affiliation(s)
| | | | | | | | | | - Stefania Bruno
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy; (G.C.); (A.S.); (E.C.); (G.C.)
| |
Collapse
|
40
|
Zhou X, Xu Y, Wang X, Lu W, Tang X, Jin Y, Ye J. Single and combined strategies for mesenchymal stem cell exosomes alleviate liver fibrosis: a systematic review and meta-analysis of preclinical animal models. Front Pharmacol 2024; 15:1432683. [PMID: 39144628 PMCID: PMC11322148 DOI: 10.3389/fphar.2024.1432683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/09/2024] [Indexed: 08/16/2024] Open
Abstract
Background: The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been supported by various clinical studies. However, stem cell transplantation is limited in clinical application due to its low survival rate, low liver implantation rate, and possible carcinogenicity. Recently, there has been increasing interest in the use of MSC-exos due to their widespread availability, low immunogenicity, and non-carcinogenic properties. Numerous studies have demonstrated the potential of MSC-exos in treating liver fibrosis and preventing progression to end-stage liver disease. Objective: This study aimed to systematically investigate the efficacy of MSC-exos single administration in the treatment of hepatic fibrosis and the combined advantages of MSC-exos in combination with drug therapy (MSC-exos-drugs). Methods: Data sources included PubMed, Web of Science, Embase, and the Cochrane Library, which were built up to January 2024. The population, intervention, comparison, outcomes, and study design (PICOS) principle was used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Results: After screening, a total of 18 papers (19 studies) were included, of which 12 involved MSC-exos single administration for the treatment of liver fibrosis and 6 involved MSC-exos-drugs for the treatment of liver fibrosis. Pooled analysis revealed that MSC-exos significantly improved liver function, promoted the repair of damaged liver tissue, and slowed the progression of hepatic fibrosis and that MSC-exos-drugs were more efficacious than MSC-exos single administration. Subgroup analyses revealed that the use of AD-MSC-exos resulted in more consistent and significant efficacy when MSC-exos was used to treat hepatic fibrosis. For MSC-exos-drugs, a more stable end result is obtained by kit extraction. Similarly, infusion through the abdominal cavity is more effective. Conclusion: The results suggest that MSC-exos can effectively treat liver fibrosis and that MSC-exos-drugs are more effective than MSC-exos single administration. Although the results of the subgroup analyses provide recommendations for clinical treatment, a large number of high-quality experimental validations are still needed. Systematic Review Registration: CRD42024516199.
Collapse
Affiliation(s)
- Xiaolei Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yan Xu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Wenming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xingkun Tang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yu Jin
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, Jiangxi, China
- Jiangxi Provincal Key Laboratory of Tissue Engineering (2024SSY06291), Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China
| |
Collapse
|
41
|
Zheng L, Chen W, Yao K, Xie Y, Liao C, Zhou T. Clinical and preclinical studies of mesenchymal stem cells to alleviate peritoneal fibrosis. Stem Cell Res Ther 2024; 15:237. [PMID: 39080683 PMCID: PMC11290310 DOI: 10.1186/s13287-024-03849-3] [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: 04/20/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024] Open
Abstract
Peritoneal dialysis is an important part of end-stage kidney disease replacement therapy. However, prolonged peritoneal dialysis can result in peritoneal fibrosis and ultrafiltration failure, forcing patients to withdraw from peritoneal dialysis treatment. Therefore, there is an urgent need for some effective measures to alleviate the occurrence and progression of peritoneal fibrosis. Mesenchymal stem cells play a crucial role in immunomodulation and antifibrosis. Numerous studies have investigated the fact that mesenchymal stem cells can ameliorate peritoneal fibrosis mainly through the paracrine pathway. It has been discovered that mesenchymal stem cells participate in the improvement of peritoneal fibrosis involving the following signaling pathways: TGF-β/Smad signaling pathway, AKT/FOXO signaling pathway, Wnt/β-catenin signaling pathway, TLR/NF-κB signaling pathway. Additionally, in vitro experiments, mesenchymal stem cells have been shown to decrease mesothelial cell death and promote proliferation. In animal models, mesenchymal stem cells can enhance peritoneal function by reducing inflammation, neovascularization, and peritoneal thickness. Mesenchymal stem cell therapy has been demonstrated in clinical trials to improve peritoneal function and reduce peritoneal fibrosis, thus improving the life quality of peritoneal dialysis patients.
Collapse
Affiliation(s)
- Lingqian Zheng
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Wenmin Chen
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Kaijin Yao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Yina Xie
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
| |
Collapse
|
42
|
Mahmoudi A, Meidany P, Almahmeed W, Jamialahmadi T, Sahebkar A. Stem Cell Therapy as a Potential Treatment of Non-Alcoholic Steatohepatitis-Related End-Stage Liver Disease: A Narrative Review. CURRENT STEM CELL REPORTS 2024; 10:85-107. [DOI: 10.1007/s40778-024-00241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 01/04/2025]
|
43
|
Mladenović D, Vesković M, Šutulović N, Hrnčić D, Stanojlović O, Radić L, Macut JB, Macut D. Adipose-derived extracellular vesicles - a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Endocrine 2024; 85:18-34. [PMID: 38285412 DOI: 10.1007/s12020-024-03702-w] [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: 11/17/2023] [Accepted: 01/14/2024] [Indexed: 01/30/2024]
Abstract
Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.
Collapse
Affiliation(s)
- Dušan Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
| | - Milena Vesković
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nikola Šutulović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Hrnčić
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Stanojlović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Lena Radić
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Jelica Bjekić Macut
- University of Belgrade Faculty of Medicine, Department of Endocrinology, UMC Bežanijska kosa, Belgrade, Serbia
| | - Djuro Macut
- University of Belgrade Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
| |
Collapse
|
44
|
Margiana R, Pilehvar Y, Amalia FL, Lestari SW, Supardi S, I'tishom R. Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction? Asian J Urol 2024; 11:391-405. [PMID: 39139521 PMCID: PMC11318444 DOI: 10.1016/j.ajur.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 12/06/2023] [Indexed: 08/15/2024] Open
Abstract
Objective The secretome, comprising bioactive chemicals released by mesenchymal stem cells (MSCs), holds therapeutic promise in regenerative medicine. This review aimed to explore the therapeutic potential of the MSC secretome in regenerative urology, particularly for treating erectile dysfunction (ED), and to provide an overview of preclinical and clinical research on MSCs in ED treatment and subsequently to highlight the rationales, mechanisms, preclinical investigations, and therapeutic potential of the MSC secretome in this context. Methods The review incorporated an analysis of preclinical and clinical research involving MSCs in the treatment of ED. Subsequently, it delved into the existing knowledge regarding the MSC secretome, exploring its therapeutic potential. The methods included a comprehensive examination of relevant literature to discern the processes underlying the therapeutic efficacy of the MSC secretome. Results Preclinical research indicated the effectiveness of the MSC secretome in treating various models of ED. However, the precise mechanisms of its therapeutic efficacy remain unknown. The review provided insights into the anti-inflammatory, pro-angiogenic, and trophic properties of the MSC secretome. It also discussed potential advantages, such as avoiding issues related to cellular therapy, including immunogenicity, neoplastic transformation, and cost. Conclusion This review underscores the significant therapeutic potential of the MSC secretome in regenerative urology, particularly for ED treatment. While preclinical studies demonstrate promising outcomes, further research is essential to elucidate the specific mechanisms underlying the therapeutic efficacy before clinical application. The review concludes by discussing future perspectives and highlighting the challenges associated with the clinical translation of the MSC secretome in regenerative urology.
Collapse
Affiliation(s)
- Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Indonesia General Academic Hospital, Depok, Indonesia
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia
| | - Younes Pilehvar
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Science, Urmia, Iran
| | - Fatkhurrohmah L. Amalia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Dr. Kariadi Hospital, Semarang, Indonesia
| | - Silvia W. Lestari
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Indonesia General Academic Hospital, Depok, Indonesia
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Supardi Supardi
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Reny I'tishom
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Biomedical Science, Faculty of Medicine, Universitas Airlangga Surabaya, Indonesia
| |
Collapse
|
45
|
Ellakany AR, El Baz H, Shoheib ZS, Elzallat M, Ashour DS, Yassen NA. Stem cell-derived exosomes as a potential therapy for schistosomal hepatic fibrosis in experimental animals. Pathog Glob Health 2024; 118:429-449. [PMID: 37519008 PMCID: PMC11338202 DOI: 10.1080/20477724.2023.2240085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
Schistosomiasis is a neglected tropical disease. Egg-induced granuloma formation and tissue fibrosis are the main causes of the high morbidity and mortality of schistosomiasis. Mesenchymal stem cells (MSCs)-derived exosomes play an important role with a superior safety profile than MSCs in the treatment of liver fibrosis. Therefore, the aim of this study was to investigate the potential therapeutic effect of MSCs-derived exosomes on schistosomal hepatic fibrosis. Exosomes were isolated from bone marrow MSCs and characterized. A total of 85 mice were divided into four groups: group I (control group), group II (PZQ group) infected and treated with PZQ, group III (EXO group) infected and treated with MSCs-derived exosomes and group IV (PZQ+EXO group) infected and treated with both PZQ and MSCs-derived exosomes. Assessment of treatment efficacy was evaluated by histopathological and immunohistochemical examination of liver sections by proliferating cell nuclear antigen (PCNA) and nuclear factor-κB (NF-κB). The results showed significant reduction of the number and diameter of hepatic granulomas, hepatic fibrosis, upregulation of PCNA expression and reduction of NF-κB expression in EXO and PZQ+EXO groups as compared to other groups at all durations post infection. Additionally, more improvement was observed in PZQ+EXO group. In conclusion, MSCs-derived exosomes are a promising agent for the treatment of schistosomal hepatic fibrosis, and their combination with PZQ shows a synergistic action including antifibrotic and anti-inflammatory effects. However, further studies are required to establish their functional components and their mechanisms of action.
Collapse
Affiliation(s)
- Asmaa R. Ellakany
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanan El Baz
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Zeinab S. Shoheib
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elzallat
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Dalia S. Ashour
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Nabila A. Yassen
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| |
Collapse
|
46
|
Bahar R, Darabi S, Norouzian M, Roustaei S, Torkamani-Dordshaikh S, Hasanzadeh M, Vakili K, Fathi M, Khodagholi F, Kaveh N, Jahanbaz S, Moghaddam MH, Abbaszadeh HA, Aliaghaei A. Neuroprotective effect of human cord blood-derived extracellular vesicles by improved neuromuscular function and reduced gliosis in a rat model of Huntington's disease. J Chem Neuroanat 2024; 138:102419. [PMID: 38609056 DOI: 10.1016/j.jchemneu.2024.102419] [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: 12/15/2023] [Revised: 04/09/2024] [Accepted: 04/09/2024] [Indexed: 04/14/2024]
Abstract
Huntington's disease (HD) is a hereditary condition characterized by the gradual deterioration of nerve cells in the striatum. Recent scientific investigations have revealed the promising potential of Extracellular vesicles (EVs) as a therapy to mitigate inflammation and enhance motor function. This study aimed to examine the impact of administering EVs derived from human umbilical cord blood (HUCB) on the motor abilities and inflammation levels in a rat model of HD. After ultracentrifugation to prepare EVs from HUCB to determine the nature of the obtained contents, the expression of CD markers 81 and 9, the average size and also the morphology of its particles were investigated by DLS and Transmission electron microscopy (TEM). Then, in order to induce the HD model, 3-nitropropionic acid (3-NP) neurotoxin was injected intraperitoneal into the rats, after treatment by HUCB-EVs, rotarod, electromyogram (EMG) and the open field tests were performed on the rats. Finally, after rat sacrifice and the striatum was removed, Hematoxylin and eosin staining (H&E), stereology, immunohistochemistry, antioxidant tests, and western blot were performed. Our results showed that the contents of the HUCB-EVs express the CD9 and CD81 markers and have spherical shapes. In addition, the injection of HUCB-EVs improved motor and neuromuscular function, reduced gliosis, increased antioxidant activity and inflammatory factor, and partially prevented the decrease of neurons. The findings generally show that HUCB-EVs have neuroprotective effects and reduce neuroinflammation from the toxic effects of 3-NP, which can be beneficial for the recovery of HD.
Collapse
Affiliation(s)
- Reza Bahar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Norouzian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Roustaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shayesteh Torkamani-Dordshaikh
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maral Hasanzadeh
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Kaveh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shima Jahanbaz
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Hassani Moghaddam
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Hojjat-Allah Abbaszadeh
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
47
|
Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [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: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
Collapse
Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
48
|
Huang D, Shen H, Xie F, Hu D, Jin Q, Hu Y, Zhong T. Role of mesenchymal stem cell-derived exosomes in the regeneration of different tissues. J Biol Eng 2024; 18:36. [PMID: 38845032 PMCID: PMC11155050 DOI: 10.1186/s13036-024-00431-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/10/2024] [Indexed: 06/10/2024] Open
Abstract
Exosomes are nanovesicles with multiple components used in several applications. Mesenchymal stem cells (MSCs) are well known for their great potential in clinical applications. MSC-derived exosomes (MSC-Exos) have been shown to mediate tissue regeneration in various diseases, including neurological, autoimmune, and inflammatory diseases, cancer, ischemic heart disease, lung injury, and liver fibrosis. They can modulate the immune response by interacting with immune effector cells in the presence of anti-inflammatory compounds and are involved in intercellular communication through various types of cargo. This review summarizes the MSC-Exos-mediated tissue regeneration in various diseases, including neurological, cardiovascular, liver, kidney, articular cartilage, and oral tissue applications. In addition, we discuss the challenges and prospects of MSC-Exos in tissue regeneration.
Collapse
Affiliation(s)
- Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Fangfang Xie
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yuexin Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
| |
Collapse
|
49
|
Gopal A, Gangadaran P, Rajendran RL, Oh JM, Lee HW, Hong CM, Kalimuthu S, Han MH, Lee J, Ahn BC. Extracellular vesicle mimetics engineered from mesenchymal stem cells and curcumin promote fibrosis regression in a mouse model of thioacetamide-induced liver fibrosis. Regen Ther 2024; 26:911-921. [PMID: 39502438 PMCID: PMC11535984 DOI: 10.1016/j.reth.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Recent research suggests that advanced liver fibrosis could be reversed, but the therapeutic agents needed for the prevention of liver fibrosis remain to be elucidated. The beneficial effects of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) on liver fibrosis have been reported. However, the large-scale production of MSC-EVs remains challenging. The present study investigated the therapeutic effects of mouse MSC-derived EV mimetics (MEVMs) in combination with curcumin (antifibrotic compound) using a mouse model of thioacetamide-induced liver fibrosis. MEVMs were prepared through the serial extrusion of MSCs. These MEVMs were similar in size and morphology to the EVs. The biodistribution study showed that fluorescently labeled MEVMs predominantly accumulated in the liver. The establishment of liver fibrosis was confirmed via increased collagen (histology), liver fibrosis score, α-smooth muscle actin (α-SMA), and vimentin proteins levels. Treatment with MEVMs, curcumin, or their combination decreased the amount of collagen in liver tissues, with the antifibrotic effects of MEVMs being further confirmed by the liver fibrosis score. All treatments decreased the expression of collagen 1α, α-SMA, and vimentin. MEVMs showed superior effects than curcumin. Thus, MSC-derived EVMs could be a potential alternative for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Arunnehru Gopal
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ho Won Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Senthilkumar Kalimuthu
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Pathology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Jaetae Lee
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| |
Collapse
|
50
|
Liam-Or R, Faruqu FN, Walters A, Han S, Xu L, Wang JTW, Oberlaender J, Sanchez-Fueyo A, Lombardi G, Dazzi F, Mailaender V, Al-Jamal KT. Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent. NATURE NANOTECHNOLOGY 2024; 19:846-855. [PMID: 38366223 PMCID: PMC11186763 DOI: 10.1038/s41565-023-01585-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/27/2023] [Indexed: 02/18/2024]
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.
Collapse
Affiliation(s)
- Revadee Liam-Or
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Farid N Faruqu
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
- Pharmacology Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Adam Walters
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Shunping Han
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Lizhou Xu
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Julie Tzu-Wen Wang
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Jennifer Oberlaender
- Max Planck Institute for Polymer Research, Mainz, Germany
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, UK
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Francesco Dazzi
- Comprehensive Cancer Centre, King's College London, London, UK
| | - Volker Mailaender
- Max Planck Institute for Polymer Research, Mainz, Germany
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Khuloud T Al-Jamal
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.
| |
Collapse
|