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Solopov M, Chechekhina E, Kavelina A, Akopian G, Turchin V, Popandopulo A, Filimonov D, Ishchenko R. Comparative Study of Deep Transfer Learning Models for Semantic Segmentation of Human Mesenchymal Stem Cell Micrographs. Int J Mol Sci 2025; 26:2338. [PMID: 40076956 PMCID: PMC11899854 DOI: 10.3390/ijms26052338] [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: 01/28/2025] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
The aim of this study is to conduct a comparative assessment of the effectiveness of neural network models-U-Net, DeepLabV3+, SegNet and Mask R-CNN-for the semantic segmentation of micrographs of human mesenchymal stem cells (MSCs). A dataset of 320 cell micrographs annotated by cell biology experts was created. The models were trained using a transfer learning method based on ImageNet pre-trained weights. As a result, the U-Net model demonstrated the best segmentation accuracy according to the metrics of the Dice coefficient (0.876) and the Jaccard index (0.781). The DeepLabV3+ and Mask R-CNN models also showed high performance, although slightly lower than U-Net, while SegNet exhibited the least accurate results. The obtained data indicate that the U-Net model is the most suitable for automating the segmentation of MSC micrographs and can be recommended for use in biomedical laboratories to streamline the routine analysis of cell cultures.
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Affiliation(s)
- Maksim Solopov
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | | | - Anna Kavelina
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | - Gulnara Akopian
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | - Viktor Turchin
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | - Andrey Popandopulo
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | - Dmitry Filimonov
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
| | - Roman Ishchenko
- V.K. Gusak Institute of Emergency and Reconstructive Surgery, 283045 Donetsk, Russia; (M.S.); (D.F.)
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2
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Chakraborty A, Wang C, Hodgson-Garms M, Broughton BRS, Frith JE, Kelly K, Samuel CS. Induced pluripotent stem cell-derived mesenchymal stem cells reverse bleomycin-induced pulmonary fibrosis and related lung stiffness. Biomed Pharmacother 2024; 178:117259. [PMID: 39116786 DOI: 10.1016/j.biopha.2024.117259] [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: 06/03/2024] [Revised: 07/23/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterised by lung scarring and stiffening, for which there is no effective cure. Based on the immunomodulatory and anti-fibrotic effects of induced pluripotent stem cell (iPSC) and mesenchymoangioblast-derived mesenchymal stem cells (iPSCs-MSCs), this study evaluated the therapeutic effects of iPSCs-MSCs in a bleomycin (BLM)-induced model of pulmonary fibrosis. Adult male C57BL/6 mice received a double administration of BLM (0.15 mg/day) 7-days apart and were then maintained for a further 28-days (until day-35), whilst control mice were administered saline 7-days apart and maintained for the same time-period. Sub-groups of BLM-injured mice were intravenously-injected with 1×106 iPSC-MSCs on day-21 alone or on day-21 and day-28 and left until day-35 post-injury. Measures of lung inflammation, fibrosis and compliance were then evaluated. BLM-injured mice presented with lung inflammation characterised by increased immune cell infiltration and increased pro-inflammatory cytokine expression, epithelial damage, lung transforming growth factor (TGF)-β1 activity, myofibroblast differentiation, interstitial collagen fibre deposition and topology (fibrosis), in conjunction with reduced matrix metalloproteinase (MMP)-to-tissue inhibitor of metalloproteinase (TIMP) ratios and dynamic lung compliance. All these measures were ameliorated by a single or once-weekly intravenous-administration of iPSC-MSCs, with the latter reducing dendritic cell infiltration and lung epithelial damage, whilst promoting anti-inflammatory interleukin (IL)-10 levels to a greater extent. Proteomic profiling of the conditioned media of cultured iPSC-MSCs that were stimulated with TNF-α and IFN-γ, revealed that these stem cells secreted protein levels of immunosuppressive factors that contributed to the anti-fibrotic and therapeutic potential of iPSCs-MSCs as a novel treatment option for IPF.
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Affiliation(s)
- Amlan Chakraborty
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Division of Immunology, Immunity to Infection and Respiratory Medicine, The University of Manchester, Manchester, England, UK
| | - Chao Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Margeaux Hodgson-Garms
- Department of Materials Science and Engineering, Monash University, Clayton, Victoria, Australia
| | - Brad R S Broughton
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Clayton, Victoria, Australia
| | - Kilian Kelly
- Cynata Therapeutics Ltd, Cremorne, Victoria, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
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3
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Ye S, Si W, Qin W, Yang L, Luo Z, Li Z, Xie Y, Pan H, Li X, Huang Z, Zhu M, Chen D. Atractylodes lancea volatile oils target ADAR2-miR-181a-5p signaling to mesenchymal stem cell chondrogenic differentiation. Anat Rec (Hoboken) 2023; 306:3006-3020. [PMID: 35446511 DOI: 10.1002/ar.24930] [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: 09/20/2021] [Revised: 02/17/2022] [Accepted: 03/20/2022] [Indexed: 11/07/2022]
Abstract
Atractylodeslancea Rhizoma (Rhizoma atractylodis [RA]) has long been recommended for the treatment of arthritis in traditional Chinese medicine, but its mechanism of action is still unclear. RA contains a large amount of Atractylodes lancea volatile oils (Atr). In this study, we investigated whether Atr can promote mesenchymal stem cells (MSCs) chondrogenic differentiation. The Atr were extracted from RA by steam distillation method, and the effect of Atr on MSCs was detected by the CCK8 assay. The optimal concentration of Atr for MSCs cultivation was 3 μg/ml. The differentially expressed miR-181a-5p was screened by miRNA microarray assay, and its mimics and inhibitors were transfected into MSCs. It was found that the inhibitor of miR-181a-5p could upregulate cartilage-specific genes such as SOX9, COL2A1, and ACAN. Meanwhile, we also found that the expression of gene editing enzyme ADAR2 was significantly increased in the chondrogenic differentiation of MSCs induced by Atr, and the bases of precursor sequence of miR-181a-5p were changed from A to G. After ADAR2 deletion, the expression of cartilage-specific genes was significantly down-regulated and the precursor sequence bases of miR-181a-5p were not changed. Bioinformatics analysis revealed that the predicted target gene of miR-181a-5p was yingyang1 (YY1), and the targeting relationship was verified by dual-luciferase reporter assay. After deleting YY1, the expression of cartilage-specific genes was significantly down-regulated. In conclusion, our study demonstrated that Atr can promote chondrogenic differentiation of MSC through regulation of the ADAR2-miR-181a-5p signaling pathway. This may provide a new insight into the possible mechanism of traditional Chinese medicine (Atr) in treating inflammatory joint diseases.
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Affiliation(s)
- Shanyu Ye
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenwen Si
- Shenzhen BaoAn Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wei Qin
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Yang
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziwei Luo
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhen Li
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yulu Xie
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hao Pan
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinrong Li
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zifeng Huang
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Meiling Zhu
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Dongfeng Chen
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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Yun HH, Kim SG, Park SI, Jo W, Kang KK, Lee EJ, Kim DK, Jung HS, Son JY, Park JM, Park HS, Lee S, Shin HI, Hong IH, Jeong KS. Early Osteogenic-Induced Adipose-Derived Stem Cells and Canine Bone Regeneration Potential Analyzed Using Biodegradable Scaffolds. Bioengineering (Basel) 2023; 10:1311. [PMID: 38002434 PMCID: PMC10669612 DOI: 10.3390/bioengineering10111311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/05/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
The complex process of bone regeneration is influenced by factors such as inflammatory responses, tissue interactions, and progenitor cells. Currently, multiple traumas can interfere with fracture healing, causing the prolonging or failure of healing. In these cases, bone grafting is the most effective treatment. However, there are several drawbacks, such as morbidity at the donor site and availability of suitable materials. Advantages have been provided in this field by a variety of stem cell types. Adipose-derived stem cells (ASCs) show promise. In the radiological examination of this study, it was confirmed that the C/S group showed faster regeneration than the other groups, and Micro-CT also showed that the degree of bone formation in the defect area was highest in the C/S group. Compared to the control group, the change in cortical bone area in the defect area decreased in the sham group (0.874), while it slightly increased in the C/S group (1.027). An increase in relative vascularity indicates a decrease in overall bone density, but a weak depression filled with fibrous tissue was observed outside the compact bone. It was confirmed that newly formed cortical bone showed a slight difference in bone density compared to surrounding normal bone tissue due to increased distribution of cortical bone. In this study, we investigated the effect of bone regeneration by ADMSCs measured by radiation and pathological effects. These data can ultimately be applied to humans with important clinical applications in various bone diseases, regenerative, and early stages of formative differentiation.
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Affiliation(s)
- Hyun-Ho Yun
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Seong-Gon Kim
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Se-Il Park
- Cardiovascular Product Evaluation Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Woori Jo
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Kyung-Ku Kang
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Eun-Joo Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
| | - Dong-Kyu Kim
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Hoe-Su Jung
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea; (S.-G.K.); (W.J.); (D.-K.K.); (H.-S.J.)
| | - Ji-Yoon Son
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
| | - Jae-Min Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
| | - Hyun-Sook Park
- Cell Engineering for Origin Research Center, Seoul 03150, Republic of Korea; (H.-S.P.); (S.L.)
| | - Sunray Lee
- Cell Engineering for Origin Research Center, Seoul 03150, Republic of Korea; (H.-S.P.); (S.L.)
| | - Hong-In Shin
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea;
| | - Il-Hwa Hong
- Department of Veterinary Pathology, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea;
| | - Kyu-Shik Jeong
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea; (H.-H.Y.); (K.-K.K.); (E.-J.L.); (J.-Y.S.); (J.-M.P.)
- Institute for Next Generation Unified Technology, Hoseo University, Asan 31499, Republic of Korea
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5
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Aljefri AM, Brien CO, Tan TJ, Sheikh AM, Ouellette H, Bauones S. Clinical Applications of PRP: Musculoskeletal Applications, Current Practices and Update. Cardiovasc Intervent Radiol 2023; 46:1504-1516. [PMID: 37783774 DOI: 10.1007/s00270-023-03567-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/14/2023] [Indexed: 10/04/2023]
Abstract
Musculoskeletal tissues are often subjected to deleterious effects stemming from traumatic injuries or degenerative pathologies, which can impede the body's natural repair response. The advent of regenerative medicine has emerged as a promising therapeutic approach in modern patient care. Among the interventions in this cutting-edge field, platelet-rich plasma (PRP) and cell-based therapies, such as mesenchymal stem cells, have garnered significant attention. In this article, we endeavor to provide an overview of the current practices and recent developments in PRP therapy, with a particular emphasis on the clinical applications for musculoskeletal pathologies.
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Affiliation(s)
- Ahmad M Aljefri
- Department of Musculoskeletal and Interventional Radiology, King Fahad Medical City, 11525, Riyadh, Saudi Arabia
| | - Cormac O Brien
- Department of Radiology, Vancouver General Hospital/University of British Columbia, Vancouver, BC, Canada
| | - Tien Jin Tan
- Department of Radiology, Changi General Hospital, Singapore, Singapore
| | - Adnan M Sheikh
- Department of Radiology, Vancouver General Hospital/University of British Columbia, Vancouver, BC, Canada
| | - Hugue Ouellette
- Department of Radiology, Vancouver General Hospital/University of British Columbia, Vancouver, BC, Canada
| | - Salem Bauones
- Department of Musculoskeletal and Interventional Radiology, King Fahad Medical City, 11525, Riyadh, Saudi Arabia.
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6
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Gerami MH, Khorram R, Rasoolzadegan S, Mardpour S, Nakhaei P, Hashemi S, Al-Naqeeb BZT, Aminian A, Samimi S. Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier. Eur J Med Res 2023; 28:86. [PMID: 36803566 PMCID: PMC9939872 DOI: 10.1186/s40001-023-01034-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 01/26/2023] [Indexed: 02/22/2023] Open
Abstract
Exosomes are membranous vesicles with a 30 to 150 nm diameter secreted by mesenchymal stem/stromal cells (MSCs) and other cells, such as immune cells and cancer cells. Exosomes convey proteins, bioactive lipids, and genetic components to recipient cells, such as microRNAs (miRNAs). Consequently, they have been implicated in regulating intercellular communication mediators under physiological and pathological circumstances. Exosomes therapy as a cell-free approach bypasses many concerns regarding the therapeutic application of stem/stromal cells, including undesirable proliferation, heterogeneity, and immunogenic effects. Indeed, exosomes have become a promising strategy to treat human diseases, particularly bone- and joint-associated musculoskeletal disorders, because of their characteristics, such as potentiated stability in circulation, biocompatibility, low immunogenicity, and toxicity. In this light, a diversity of studies have indicated that inhibiting inflammation, inducing angiogenesis, provoking osteoblast and chondrocyte proliferation and migration, and negative regulation of matrix-degrading enzymes result in bone and cartilage recovery upon administration of MSCs-derived exosomes. Notwithstanding, insufficient quantity of isolated exosomes, lack of reliable potency test, and exosomes heterogeneity hurdle their application in clinics. Herein, we will deliver an outline respecting the advantages of MSCs-derived exosomes-based therapy in common bone- and joint-associated musculoskeletal disorders. Moreover, we will have a glimpse the underlying mechanism behind the MSCs-elicited therapeutic merits in these conditions.
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Affiliation(s)
- Mohammad Hadi Gerami
- grid.412571.40000 0000 8819 4698Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roya Khorram
- grid.412571.40000 0000 8819 4698Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheil Rasoolzadegan
- grid.411600.2Department of Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Mardpour
- grid.411705.60000 0001 0166 0922Department of Radiology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Pooria Nakhaei
- grid.411705.60000 0001 0166 0922Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheyla Hashemi
- grid.411036.10000 0001 1498 685XObstetrician, Gynaecology & Infertility Department, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Amir Aminian
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Sahar Samimi
- Tehran University of Medical Sciences, Tehran, Iran.
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7
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Asian Pigeonwing Plants (Clitoria ternatea) Synergized Mesenchymal Stem Cells by Modulating the Inflammatory Response in Rats with Cisplatin-Induced Acute Kidney Injury. Pharmaceuticals (Basel) 2022; 15:ph15111396. [DOI: 10.3390/ph15111396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/27/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Acute kidney injury is a heterogeneous set of disorders distinguished by a sudden decrease in the glomerular filtration rate, which is evidenced by an increase in the serum creatinine concentration or oliguria and categorized by stage and cause. It is an ever-growing health problem worldwide, with no reliable treatment. In the present study, we evaluated the role of Clitoria ternatea combined with mesenchymal stem cells in treating cisplatin-induced acute kidney injury in rats. Animals were challenged with cisplatin, followed by 400 mg/kg of Asian pigeonwing extract and/or mesenchymal stem cells (106 cells/150 g body weight). Kidney functions and enzymes were recorded, and histopathological sectioning was also performed. The expression profile of IL-1β, IL-6, and caspase-3 was assessed using the quantitative polymerase chain reaction. The obtained data indicated that mesenchymal stem cells combined with the botanical extract modulated the creatinine uric acid and urea levels. Cisplatin increased the level of malondialdehyde and decreased the levels of both superoxide dismutase and glutathione; however, the dual treatment was capable of restoring the normal levels. Furthermore, all treatments modulated the IL-6, IL-1β, and caspase-3 gene expression profiles. The obtained data shed some light on adjuvant therapy using C. ternatea and mesenchymal stem cells in treating acute kidney injury; however, further investigations are required to understand these agents’ synergistic mechanisms fully. The total RNA was extracted from the control, the positive control, and all of the therapeutically treated animals. The expression profiles of the IL-6, IL-1β, and caspase-3 genes were evaluated using the real-time polymerase chain reaction. Cisplatin treatment caused a significant upregulation in IL-6. All treatments could mitigate the IL-6-upregulating effect of cisplatin, with the mesenchymal stem cell treatment being the most effective. The same profile was observed in the IL-1β and caspase-3 genes, except that the dual treatment (mesenchymal stem cells and the botanical extract) was the most effective in ameliorating the adverse effect of cisplatin; it downregulated caspase-3 expression better than the positive control.
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Arshinchi Bonab R, Asfa S, Kontou P, Karakülah G, Pavlopoulou A. Identification of neoplasm-specific signatures of miRNA interactions by employing a systems biology approach. PeerJ 2022; 10:e14149. [PMID: 36213495 PMCID: PMC9536303 DOI: 10.7717/peerj.14149] [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: 04/28/2022] [Accepted: 09/07/2022] [Indexed: 01/21/2023] Open
Abstract
MicroRNAs represent major regulatory components of the disease epigenome and they constitute powerful biomarkers for the accurate diagnosis and prognosis of various diseases, including cancers. The advent of high-throughput technologies facilitated the generation of a vast amount of miRNA-cancer association data. Computational approaches have been utilized widely to effectively analyze and interpret these data towards the identification of miRNA signatures for diverse types of cancers. Herein, a novel computational workflow was applied to discover core sets of miRNA interactions for the major groups of neoplastic diseases by employing network-based methods. To this end, miRNA-cancer association data from four comprehensive publicly available resources were utilized for constructing miRNA-centered networks for each major group of neoplasms. The corresponding miRNA-miRNA interactions were inferred based on shared functionally related target genes. The topological attributes of the generated networks were investigated in order to detect clusters of highly interconnected miRNAs that form core modules in each network. Those modules that exhibited the highest degree of mutual exclusivity were selected from each graph. In this way, neoplasm-specific miRNA modules were identified that could represent potential signatures for the corresponding diseases.
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Affiliation(s)
- Reza Arshinchi Bonab
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey,Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Seyedehsadaf Asfa
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey,Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Panagiota Kontou
- Department of Mathematics, University of Thessaly, Lamia, Greece
| | - Gökhan Karakülah
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey,Izmir Biomedicine and Genome Center, Izmir, Turkey
| | - Athanasia Pavlopoulou
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey,Izmir Biomedicine and Genome Center, Izmir, Turkey
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9
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Ko KR, Lee H, Han SH, Ahn W, Kim DK, Kim IS, Jung BS, Lee S. Substance P, A Promising Therapeutic Target in Musculoskeletal Disorders. Int J Mol Sci 2022; 23:ijms23052583. [PMID: 35269726 PMCID: PMC8910130 DOI: 10.3390/ijms23052583] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 02/04/2023] Open
Abstract
A large number of studies have focused on the role of substance P (SP) and the neurokinin-1 receptor (NK1R) in the pathogenesis of a variety of medical conditions. This review provides an overview of the role of the SP-NK1R pathway in the pathogenesis of musculoskeletal disorders and the evidence for its role as a therapeutic target for these disorders, which are major public health problems in most countries. To summarize, the brief involvement of SP may affect tendon healing in an acute injury setting. SP combined with an adequate conjugate can be a regenerative therapeutic option in osteoarthritis. The NK1R antagonist is a promising agent for tendinopathy, rheumatoid arthritis, and osteoarthritis. Research on the SP-NK1R pathway will be helpful for developing novel drugs for osteoporosis.
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Affiliation(s)
- Kyung Rae Ko
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; (K.R.K.); (I.-S.K.)
| | - Hyunil Lee
- Department of Orthopedic Surgery, Ilsan Paik Hospital, Inje University, 170 Juhwa-ro, Ilsanseo-gu, Goyang-si 10380, Gyeonggi-do, Korea;
| | - Soo-Hong Han
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea; (S.-H.H.); (W.A.); (D.K.K.)
| | - Wooyeol Ahn
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea; (S.-H.H.); (W.A.); (D.K.K.)
| | - Do Kyung Kim
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea; (S.-H.H.); (W.A.); (D.K.K.)
| | - Il-Su Kim
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; (K.R.K.); (I.-S.K.)
| | - Bo Sung Jung
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea; (S.-H.H.); (W.A.); (D.K.K.)
- Correspondence: (B.S.J.); (S.L.); Tel.: +82-31-780-5289 (B.S.J. & S.L.); Fax: +82-31-881-7114 (B.S.J. & S.L.)
| | - Soonchul Lee
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Korea; (S.-H.H.); (W.A.); (D.K.K.)
- Correspondence: (B.S.J.); (S.L.); Tel.: +82-31-780-5289 (B.S.J. & S.L.); Fax: +82-31-881-7114 (B.S.J. & S.L.)
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Protein Expression of AEBP1, MCM4, and FABP4 Differentiate Osteogenic, Adipogenic, and Mesenchymal Stromal Stem Cells. Int J Mol Sci 2022; 23:ijms23052568. [PMID: 35269711 PMCID: PMC8910760 DOI: 10.3390/ijms23052568] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stem cells (MSCs) gain an increasing focus in the field of regenerative medicine due to their differentiation abilities into chondrocytes, adipocytes, and osteoblastic cells. However, it is apparent that the transformation processes are extremely complex and cause cellular heterogeneity. The study aimed to characterize differences between MSCs and cells after adipogenic (AD) or osteoblastic (OB) differentiation at the proteome level. Comparative proteomic profiling was performed using tandem mass spectrometry in data-independent acquisition mode. Proteins were quantified by deep neural networks in library-free mode and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. We analyzed 4108 proteins across all samples, which revealed a distinct clustering between MSCs and cell differentiation states. Protein expression profiling identified activation of the Peroxisome proliferator-activated receptors (PPARs) signaling pathway after AD. In addition, two distinct protein marker panels could be defined for osteoblastic and adipocytic cell lineages. Hereby, overexpression of AEBP1 and MCM4 for OB as well as of FABP4 for AD was detected as the most promising molecular markers. Combination of deep neural network and machine-learning algorithms with data-independent mass spectrometry distinguish MSCs and cell lineages after adipogenic or osteoblastic differentiation. We identified specific proteins as the molecular basis for bone formation, which could be used for regenerative medicine in the future.
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Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther 2022; 29:1105-1116. [PMID: 35082400 DOI: 10.1038/s41417-022-00427-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/11/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are known as promising sources for cancer therapy and can be utilized as vehicles in cancer gene therapy. MSC-derived exosomes are central mediators in the therapeutic functions of MSCs, known as the novel cell-free alternatives to MSC-based cell therapy. MSC-derived exosomes show advantages including higher safety as well as more stability and convenience for storage, transport and administration compared to MSCs transplant therapy. Unmodified MSC-derived exosomes can promote or inhibit tumors while modified MSC-derived exosomes are involved in the suppression of cancer development and progression via the delivery of several therapeutics molecules including chemotherapeutic drugs, miRNAs, anti-miRNAs, specific siRNAs, and suicide gene mRNAs. In most malignancies, dysregulation of miRNAs not only occurs as a consequence of cancer progression but also is directly involved during tumor initiation and development due to their roles as oncogenes (oncomiRs) or tumor suppressors (TS-miRNAs). MiRNA restoration is usually achieved by overexpression of TS-miRNAs using synthetic miRNA mimics and viral vectors or even downregulation of oncomiRs using anti-miRNAs. Similar to other therapeutic molecules, the efficacy of miRNAs restoration in cancer therapy depends on the effectiveness of the delivery system. In the present review, we first provided an overview of the properties and potentials of MSCs in cancer therapy as well as the application of MSC-derived exosomes in cancer therapy. Finally, we specifically focused on harnessing the MSC-derived exosomes for the aim of miRNA delivery in cancer therapy.
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Canine Mesenchymal Cell Lyosecretome Production and Safety Evaluation after Allogenic Intraarticular Injection in Osteoarthritic Dogs. Animals (Basel) 2021; 11:ani11113271. [PMID: 34828003 PMCID: PMC8614457 DOI: 10.3390/ani11113271] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/21/2022] Open
Abstract
In recent years, mesenchymal stromal cells (MSCs) have shown promise as a therapy in treating musculoskeletal diseases, and it is currently believed that their therapeutic effect is mainly related to the release of proteins and extracellular vesicles (EVs), known as secretome. In this work, three batches of canine MSC-secretome were prepared by standardized processes according to the current standard ISO9001 and formulated as a freeze-dried powder named Lyosecretome. The final products were characterized in protein and lipid content, EV size distribution and tested to ensure the microbiological safety required for intraarticular injection. Lyosecretome induced the proliferation of adipose tissue-derived canine MSCs, tenocytes, and chondrocytes in a dose-dependent manner and showed anti-elastase activity, reaching 85% of inhibitory activity at a 20 mg/mL concentration. Finally, to evaluate the safety of the preparation, three patients affected by bilateral knee or elbow osteoarthritis were treated with two intra-articular injections (t = 0 and t = 40 days) of the allogeneic Lyosecretome (20 mg corresponding 2 × 106 cell equivalents) resuspended in hyaluronic acid in one joint and placebo (mannitol resuspended in hyaluronic acid) in the other joint. To establish the safety of the treatment, the follow-up included a questionnaire addressed to the owner and orthopaedic examinations to assess lameness grade, pain score, functional disability score and range of motion up to day 80 post-treatment. Overall, the collected data suggest that intra-articular injection of allogeneic Lyosecretome is safe and does not induce a clinically significant local or systemic adverse response.
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