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da Rocha VP, Mansano BSDM, Dos Santos CFC, Teixeira ILA, de Oliveira HA, Vieira SS, Antonio EL, Izar MCDO, Fonseca FAH, Serra AJ. How long does the biological effect of a red light-emitting diode last on adipose-derived mesenchymal stem cells? Photochem Photobiol 2025; 101:206-214. [PMID: 38888236 DOI: 10.1111/php.13983] [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: 03/14/2024] [Revised: 05/16/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024]
Abstract
This research investigated the duration of the influence of red light-emitting diodes (LED, 630 nm; output power: 2452.5 mW; laser beam: 163.5 cm2; irradiance: 15 mW/cm2; radiant exposure: 4 J/cm2) on different periods after irradiation (6, 12, 24, 48, and 72 h) on adipose-derived mesenchymal stem cells' (AdMSCs) metabolism and paracrine factors. AdMSCs were irradiated three times every 48 h. Twenty-four hours after the last irradiation, there was a higher MTT absorbance, followed by a decrease after 48 h. The cells' secretome showed increased levels of IL-6 and VEGF after 12 and 24 h, but this was reversed after 48 h. Additionally, LED irradiation resulted in higher levels of nitrite and did not affect oxidative stress markers. LED irradiation had significant effects on AdMSCs after 24 h compared to other groups and its control group.
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Affiliation(s)
- Vitor Pocani da Rocha
- Department of Medicine, Cardiology Division, Federal University of Sao Paulo, São Paulo, SP, Brazil
| | | | | | | | | | - Stella Sousa Vieira
- Department of Medicine, Cardiology Division, Federal University of Sao Paulo, São Paulo, SP, Brazil
| | - Ednei Luiz Antonio
- Department of Medicine, Cardiology Division, Federal University of Sao Paulo, São Paulo, SP, Brazil
| | | | | | - Andrey Jorge Serra
- Department of Medicine, Cardiology Division, Federal University of Sao Paulo, São Paulo, SP, Brazil
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2
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Yang Y, Wu A, Deng AN, Liu H, Lan Q, Mazhar M, Xue JY, Chen MT, Luo G, Liu MN. Macrophages after myocardial infarction: Mechanisms for repairing and potential as therapeutic approaches. Int Immunopharmacol 2024; 143:113562. [PMID: 39536484 DOI: 10.1016/j.intimp.2024.113562] [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: 09/21/2024] [Revised: 10/20/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Macrophages - one of the crucial immune cells, are recruited to the cardiac tissue by chemokines, cytokines and upregulated endothelial adhesion molecules after myocardial infarction (MI). During the course of inflammation in the cardiac tissue, necrotic cells and matrix debris is phagocytosed by M1 macrophages. During the resolution phase of cardiac inflammation, M2 macrophages promote cardiac recovery. Suppression or over expression of both the M1 and M2 macrophage subtypes significantly affect the reparation of infarction. Stem cells therapy, cytokine regulation and immune cells therapy are considered as effective interventions to regulate the phenotypic transformation of cardiac macrophages after MI. Intervention with macrophages in the myocardium has shown unique advantages. In this review, the mechanisms and role of macrophages in the development of MI are elaborated in detail, the promising therapeutic methods for regulating macrophage phenotypes, their limitations and possible future research directions are discussed.
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Affiliation(s)
- You Yang
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Ai Wu
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - An-Ni Deng
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Hao Liu
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Qi Lan
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Maryam Mazhar
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Jin-Yi Xue
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Ming-Tai Chen
- Department of Cardiovascular Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China.
| | - Gang Luo
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
| | - Meng-Nan Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
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Matta A, Ohlmann P, Nader V, Moussallem N, Carrié D, Roncalli J. A review of therapeutic approaches for post-infarction left ventricular remodeling. Curr Probl Cardiol 2024; 49:102562. [PMID: 38599556 DOI: 10.1016/j.cpcardiol.2024.102562] [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: 03/31/2024] [Accepted: 04/07/2024] [Indexed: 04/12/2024]
Abstract
Left ventricular remodeling is an adaptive process initially developed in response to acute myocardial infarction (AMI), but it ends up with negative adverse outcomes such as infarcted wall thinning, ventricular dilation, and cardiac dysfunction. A prolonged excessive inflammatory reaction to cardiomyocytes death and necrosis plays the crucial role in the pathophysiological mechanisms. The pharmacological treatment includes nitroglycerine, β-blockers, ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonists, and some miscellaneous aspects. Stem cells therapy, CD34+ cells transplantation and gene therapy constitute the promissing therapeutic approaches for post AMI cardiac remodeling, thereby enhancing angiogenesis, cardiomyocytes differenciation and left ventricular function on top of inhibiting apoptosis, inflammation, and collagen deposition. All these lead to reduce infarct size, scar formation and myocardial fibrosis.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Civilian Hospitals of Colmar, Colmar, France; School of Medicine and Medical Sciences, Holy Spirit University of Kaslik, P.O.Box 446, Jounieh, Lebanon.
| | - Patrick Ohlmann
- Department of Cardiology, Strasbourg University Hospital, Strasbourg, France
| | - Vanessa Nader
- Department of Cardiology, Civilian Hospitals of Colmar, Colmar, France
| | - Nicolas Moussallem
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik, P.O.Box 446, Jounieh, Lebanon
| | - Didier Carrié
- Department of Cardiology, Toulouse University Hospital, Toulouse, France
| | - Jerome Roncalli
- Department of Cardiology, Toulouse University Hospital, Toulouse, France
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Zhang Y, Zhang Y, Hu A, Meng F, Cui P, Li T, Cui G. Mesenchymal stem cells derived from CHIR99021 and TGF‑β induction remained on the colicomentum and improved cardiac function of a rat model of acute myocardium infarction. Exp Ther Med 2024; 27:182. [PMID: 38515646 PMCID: PMC10952379 DOI: 10.3892/etm.2024.12470] [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: 07/03/2023] [Accepted: 01/17/2024] [Indexed: 03/23/2024] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) have been regarded as a potential stem cell source for cell therapy. However, the production of cells with mesenchymal potential from hiPSCs through spontaneous differentiation is time consuming and laborious. In the present study, the combined use of the GSK-3 inhibitor CHIR99021 and TGF-β was used to obtain mesenchymal stem cell (MSC)-like cells from hiPSCs. During the induction process, the transcription of epithelial-mesenchymal transition (EMT)-related genes N-cadherin and Vimentin in the transformed cells was upregulated, whereas the transcription of E-cadherin and pluripotency-related transcription factors SOX2, OCT4 and NANOG did not change significantly. This indicated that whilst cells were pluripotent, EMT was initiated by the upregulation of transcription of EMT promoting genes. Both SMAD-dependent and independent signalling pathways were significantly activated by the combined induction treatment compared with the single factor induction. The hiPSC-derived MSC-like cells (hiPSC-MSCs) expressed MSC-related markers and acquired osteogenic, chondrogenic and adipogenic differentiation potentials. After being injected into the peritoneal cavity of rats, the hiPSC-MSCs secreted angiogenic and immune-regulatory factors and remained on the colicomentum for 3 weeks. Within an 11-week period, four intraperitoneal hiPSC-MSC injections (1x107 cells/injection) into acute myocardial infarction (AMI) model rats significantly increased the left ventricular ejection fraction, left ventricular fractional shortening and angiogenesis and significantly reduced scar size and the extent of apoptosis in the infarcted area compared with that of the control PBS injection. Symptoms of hiPSC-MSC-induced immune reaction or tumour formation were not observed over the course of the experiment in the hiSPC-MSC treated rats. In conclusion, the CHIR99021 and TGF-β combined induction was a rapid and effective method to obtain MSC-like cells from hiPSCs and multiple high dose intraperitoneal injections of hiPSC-derived MSCs were safe and effective at restoring cardiac function in an AMI rat model.
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Affiliation(s)
- Yusen Zhang
- Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yanmin Zhang
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Azhen Hu
- Shenzhen Key Laboratory of Drug Addiction and Safe Medication, Shenzhen PKU-HKUST Medical Centre, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Fanhua Meng
- Reproductive Medical Centre, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Peng Cui
- Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Tianshi Li
- Department of Plastic Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Guanghui Cui
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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He H, Yuan Y, Wu Y, Lu J, Yang X, Lu K, Liu A, Cao Z, Sun M, Yu M, Wang H. Exoskeleton Partial-Coated Stem Cells for Infarcted Myocardium Restoring. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2307169. [PMID: 37962473 DOI: 10.1002/adma.202307169] [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: 07/20/2023] [Revised: 10/30/2023] [Indexed: 11/15/2023]
Abstract
The integration of abiotic materials with live cells has emerged as an exciting strategy for the control of cellular functions. Exoskeletons consisting ofmetal-organic frameworks are generated to produce partial-coated bone marrow stem cells (BMSCs) to overcome low cell survival leading to disappointing effects for cell-based cardiac therapy. Partially coated exoskeletons can promote the survival of suspended BMSCs by integrating the support of exoskeletons and unimpaired cellular properties. In addition, partial exoskeletons exhibit protective effects against detrimental environmental conditions, including reactive oxygen species, pH changes, and osmotic pressure. The partial-coated cells exhibit increased intercellular adhesion forces to aggregate and adhere, promoting cell survival and preventing cell escape during cell therapy. The exoskeletons interact with cell surface receptors integrin α5β1, leading to augmented biological functions with profitable gene expression alteration, such as Vegfa, Cxcl12, and Adm. The partial-coated BMSCs display enhanced cell retention in infarcted myocardium through non-invasive intravenous injections. The repair of myocardial infarction has been achieved with improved cardiac function, myocardial angiogenesis, proliferation, and inhibition of cell apoptosis. This discovery advances the elucidation of potential molecular and cellular mechanisms for cell-exoskeleton interactions and benefits the rational design and manufacture of next-generation nanobiohybrids.
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Affiliation(s)
- Huihui He
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Yuan Yuan
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, 310058, China
| | - Yunhong Wu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Jingyi Lu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Xiaofu Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Kejie Lu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - An Liu
- Department of Orthopaedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, China
| | - Zelin Cao
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, China
| | - Miao Sun
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Mengfei Yu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Huiming Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
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Liu X, Zhou Z, Zeng WN, Zeng Q, Zhang X. The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology. Front Cell Dev Biol 2023; 11:1277686. [PMID: 37941898 PMCID: PMC10629627 DOI: 10.3389/fcell.2023.1277686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Osteoimmunology is a concept involving molecular and cellular crosstalk between the skeletal and immune systems. Toll-like receptors (TLRs) are widely expressed both on mesenchymal stromal cells (MSCs), the hematopoietic cells, and immune cells in the osteogenic microenvironment for bone development or repair. TLRs can sense both exogenous pathogen-associated molecular patterns (PAMPs) derived from microorganisms, and damage-associated molecular patterns (DAMPs) derived from normal cells subjected to injury, inflammation, or cell apoptosis under physiological or pathological conditions. Emerging studies reported that TLR signaling plays an important role in bone remodeling by directly impacting MSC osteogenic differentiation or osteoimmunology. However, how to regulate TLR signaling is critical and remains to be elucidated to promote the osteogenic differentiation of MSCs and new bone formation for bone tissue repair. This review outlines distinct TLR variants on MSCs from various tissues, detailing the impact of TLR pathway activation or inhibition on MSC osteogenic differentiation. It also elucidates TLR pathways' interplay with osteoclasts, immune cells, and extracellular vesicles (EVs) derived from MSCs. Furthermore, we explore biomaterial-based activation to guide MSCs' osteogenic differentiation. Therefore, understanding TLRs' role in this context has significant implications for advancing bone regeneration and repair strategies.
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Affiliation(s)
- Xiaoyang Liu
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Zongke Zhou
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Nan Zeng
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
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Song Y, Lu Z, Shu W, Xiang Z, Wang Z, Wei X, Xu X. Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases. CELL INSIGHT 2023; 2:100115. [PMID: 37719773 PMCID: PMC10502372 DOI: 10.1016/j.cellin.2023.100115] [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: 07/08/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023]
Abstract
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
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Affiliation(s)
- Yisu Song
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Zhengyang Lu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Zhejiang Chinese Medical University, Hangzhou, 310053, PR China
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University Shanghai, 200040, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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Mozafari N, Mozafari N, Dehshahri A, Azadi A. Knowledge Gaps in Generating Cell-Based Drug Delivery Systems and a Possible Meeting with Artificial Intelligence. Mol Pharm 2023; 20:3757-3778. [PMID: 37428824 DOI: 10.1021/acs.molpharmaceut.3c00162] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Cell-based drug delivery systems are new strategies in targeted delivery in which cells or cell-membrane-derived systems are used as carriers and release their cargo in a controlled manner. Recently, great attention has been directed to cells as carrier systems for treating several diseases. There are various challenges in the development of cell-based drug delivery systems. The prediction of the properties of these platforms is a prerequisite step in their development to reduce undesirable effects. Integrating nanotechnology and artificial intelligence leads to more innovative technologies. Artificial intelligence quickly mines data and makes decisions more quickly and accurately. Machine learning as a subset of the broader artificial intelligence has been used in nanomedicine to design safer nanomaterials. Here, how challenges of developing cell-based drug delivery systems can be solved with potential predictive models of artificial intelligence and machine learning is portrayed. The most famous cell-based drug delivery systems and their challenges are described. Last but not least, artificial intelligence and most of its types used in nanomedicine are highlighted. The present Review has shown the challenges of developing cells or their derivatives as carriers and how they can be used with potential predictive models of artificial intelligence and machine learning.
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Affiliation(s)
- Negin Mozafari
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, 71468 64685 Shiraz, Iran
| | - Niloofar Mozafari
- Design and System Operations Department, Regional Information Center for Science and Technology, 71946 94171 Shiraz, Iran
| | - Ali Dehshahri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, 71468 64685 Shiraz, Iran
- Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, 71468 64685 Shiraz, Iran
| | - Amir Azadi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, 71468 64685 Shiraz, Iran
- Pharmaceutical Sciences Research Centre, Shiraz University of Medical Sciences, 71468 64685 Shiraz, Iran
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Schary Y, Rotem I, Caller T, Lewis N, Shaihov-Teper O, Brzezinski RY, Lendengolts D, Raanani E, Sternik L, Naftali-Shani N, Leor J. CRISPR-Cas9 editing of TLR4 to improve the outcome of cardiac cell therapy. Sci Rep 2023; 13:4481. [PMID: 36934130 PMCID: PMC10024743 DOI: 10.1038/s41598-023-31286-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/09/2023] [Indexed: 03/20/2023] Open
Abstract
Inflammation and fibrosis limit the reparative properties of human mesenchymal stromal cells (hMSCs). We hypothesized that disrupting the toll-like receptor 4 (TLR4) gene would switch hMSCs toward a reparative phenotype and improve the outcome of cell therapy for infarct repair. We developed and optimized an improved electroporation protocol for CRISPR-Cas9 gene editing. This protocol achieved a 68% success rate when applied to isolated hMSCs from the heart and epicardial fat of patients with ischemic heart disease. While cell editing lowered TLR4 expression in hMSCs, it did not affect classical markers of hMSCs, proliferation, and migration rate. Protein mass spectrometry analysis revealed that edited cells secreted fewer proteins involved in inflammation. Analysis of biological processes revealed that TLR4 editing reduced processes linked to inflammation and extracellular organization. Furthermore, edited cells expressed less NF-ƙB and secreted lower amounts of extracellular vesicles and pro-inflammatory and pro-fibrotic cytokines than unedited hMSCs. Cell therapy with both edited and unedited hMSCs improved survival, left ventricular remodeling, and cardiac function after myocardial infarction (MI) in mice. Postmortem histologic analysis revealed clusters of edited cells that survived in the scar tissue 28 days after MI. Morphometric analysis showed that implantation of edited cells increased the area of myocardial islands in the scar tissue, reduced the occurrence of transmural scar, increased scar thickness, and decreased expansion index. We show, for the first time, that CRISPR-Cas9-based disruption of the TLR4-gene reduces pro-inflammatory polarization of hMSCs and improves infarct healing and remodeling in mice. Our results provide a new approach to improving the outcomes of cell therapy for cardiovascular diseases.
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Affiliation(s)
- Yeshai Schary
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Itai Rotem
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Tal Caller
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Nir Lewis
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Olga Shaihov-Teper
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Rafael Y Brzezinski
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Daria Lendengolts
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Ehud Raanani
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
- Department of Cardiac Surgery, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Leonid Sternik
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
- Department of Cardiac Surgery, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nili Naftali-Shani
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel
| | - Jonathan Leor
- Neufeld and Tamman Cardiovascular Research Institutes, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Heart Center, Sheba Medical Center, 52621, Tel-Hashomer, Israel.
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ElKhatib MAW, Isse FA, El-Kadi AOS. Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy. Drug Metab Rev 2022; 55:50-74. [PMID: 36573379 DOI: 10.1080/03602532.2022.2162075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The incidence of heart failure (HF) is generally preceded by cardiac hypertrophy (CH), which is the enlargement of cardiac myocytes in response to stress. During CH, the metabolism of arachidonic acid (AA), which is present in the cell membrane phospholipids, is modulated. Metabolism of AA gives rise to hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) via cytochrome P450 (CYP) ω-hydroxylases and CYP epoxygenases, respectively. A plethora of studies demonstrated the involvement of CYP-mediated AA metabolites in the pathogenesis of CH. Also, inflammation is known to be a characteristic hallmark of CH. In this review, our aim is to highlight the impact of inflammation on CYP-derived AA metabolites and CH. Inflammation is shown to modulate the expression of various CYP ω-hydroxylases and CYP epoxygenases and their respective metabolites in the heart. In general, HETEs such as 20-HETE and mid-chain HETEs are pro-inflammatory, while EETs are characterized by their anti-inflammatory and cardioprotective properties. Several mechanisms are implicated in inflammation-induced CH, including the modulation of NF-κB and MAPK. This review demonstrated the inflammatory modulation of cardiac CYPs and their metabolites in the context of CH and the anti-inflammatory strategies that can be employed in the treatment of CH and HF.
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Affiliation(s)
| | - Fadumo Ahmed Isse
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada
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Petrosyan A, Montali F, Peloso A, Citro A, Byers LN, La Pointe C, Suleiman M, Marchetti A, Mcneill EP, Speer AL, Ng WH, Ren X, Bussolati B, Perin L, Di Nardo P, Cardinale V, Duisit J, Monetti AR, Savino JR, Asthana A, Orlando G. Regenerative medicine technologies applied to transplant medicine. An update. Front Bioeng Biotechnol 2022; 10:1015628. [PMID: 36263358 PMCID: PMC9576214 DOI: 10.3389/fbioe.2022.1015628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of de novo engineered whole organs for transplantations.
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Affiliation(s)
- Astgik Petrosyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Filippo Montali
- Department of General Surgery, di Vaio Hospital, Fidenza, Italy
| | - Andrea Peloso
- Visceral Surgery Division, University Hospitals of Geneva, Geneva, Switzerland
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Lori N. Byers
- Wake Forest School of Medicine, Winston Salem, NC, United States
| | | | - Mara Suleiman
- Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alice Marchetti
- Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Eoin P. Mcneill
- Department of Pediatric Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, United States
| | - Allison L Speer
- Department of Pediatric Surgery, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, United States
| | - Wai Hoe Ng
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Xi Ren
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Paolo Di Nardo
- Centro Interdipartimentale per la Medicina Rigenerativa (CIMER), Università Degli Studi di Roma Tor Vergata, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Jerome Duisit
- Department of Plastic, Reconstructive and Aesthetic Surgery, CHU Rennes, University of Rennes I, Rennes, France
| | | | | | - Amish Asthana
- Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Giuseppe Orlando
- Wake Forest School of Medicine, Winston Salem, NC, United States
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12
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Bikorimana JP, Saad W, Abusarah J, Lahrichi M, Talbot S, Shammaa R, Rafei M. CD146 Defines a Mesenchymal Stromal Cell Subpopulation with Enhanced Suppressive Properties. Cells 2022; 11:cells11152263. [PMID: 35892560 PMCID: PMC9331786 DOI: 10.3390/cells11152263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are largely known for their immune-suppressive capacity, hence, their common use in the control of unwanted inflammation. However, novel concepts related to their biology, combined with the urgent need to identify MSC subpopulations with enhanced suppressive properties, drive the search for isolation protocols optimized for clinical applications. We show, in this study, that MSCs expressing high CD146 levels exhibit altered surface expression profiles of CD44 and secrete elevated levels of interleukin (IL)-6, amongst other factors. In addition, CD146hi MSCs surpass the polyclonal parental populations in inhibiting alloreactive T cells in vitro, in both a soluble- and cell-contact-dependent manner. Despite the lack of CD146hi MSC-mediated activation of peritoneal macrophages to release the suppressive factor IL-10 in vitro, their administration in animals with graft-versus-host disease alleviates inflammation and leads to 40% survival rate up to 7 weeks post-transplantation. This pronounced inhibitory property is driven by CD146-mediated in situ efferocytosis by myeloid cells. Altogether, this study provides the impetus to adopt an isolation protocol for MSCs based on a CD146 expression profile before their therapeutic use and suggests a major role played by CD146 as a novel “eat-me” signal, capable of enhancing MSC uptake by competent phagocytes.
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Affiliation(s)
- Jean-Pierre Bikorimana
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada;
| | - Wael Saad
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3T 1J4, Canada; (W.S.); (J.A.); (M.L.); (S.T.)
| | - Jamilah Abusarah
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3T 1J4, Canada; (W.S.); (J.A.); (M.L.); (S.T.)
| | - Malak Lahrichi
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3T 1J4, Canada; (W.S.); (J.A.); (M.L.); (S.T.)
| | - Sebastien Talbot
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3T 1J4, Canada; (W.S.); (J.A.); (M.L.); (S.T.)
| | - Riam Shammaa
- Canadian Centers for Regenerative Therapy, Toronto, ON M5R 1A8, Canada
- IntelliStem Technologies Inc., Toronto, ON M5R 3N5, Canada
- Correspondence: (R.S.); (M.R.)
| | - Moutih Rafei
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada;
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3T 1J4, Canada; (W.S.); (J.A.); (M.L.); (S.T.)
- Molecular Biology Program, Université de Montréal, Montréal, QC H3T 1J4, Canada
- Correspondence: (R.S.); (M.R.)
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13
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Monguió-Tortajada M, Prat-Vidal C, Martínez-Falguera D, Teis A, Soler-Botija C, Courageux Y, Munizaga-Larroudé M, Moron-Font M, Bayes-Genis A, Borràs FE, Roura S, Gálvez-Montón C. Acellular cardiac scaffolds enriched with MSC-derived extracellular vesicles limit ventricular remodelling and exert local and systemic immunomodulation in a myocardial infarction porcine model. Theranostics 2022; 12:4656-4670. [PMID: 35832072 PMCID: PMC9254233 DOI: 10.7150/thno.72289] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/13/2022] [Indexed: 11/05/2022] Open
Abstract
Rationale: Extracellular vesicles (EVs) from mesenchymal stromal cell (MSC) are a potential therapy for cardiac healing after myocardial infarction (MI). Nevertheless, neither their efficient administration nor therapeutic mechanisms are fully elucidated. Here, we evaluate the preclinical efficacy of a tissue engineering approach to locally deliver porcine cardiac adipose tissue MSC-EV (cATMSC-EV) in an acute MI pig model. Methods: After MI by permanent ligation of the coronary artery, pigs (n = 24) were randomized to Untreated or treated groups with a decellularised pericardial scaffold filled with peptide hydrogel and cATMSC-EV purified by size exclusion chromatography (EV-Treated group) or buffer (Control group), placed over the post-infarcted myocardium. Results: After 30 days, cardiac MRI showed an improved cardiac function in EV-Treated animals, with significantly higher right ventricle ejection fraction (+20.8% in EV-Treated; p = 0.026), and less ventricle dilatation, indicating less myocardial remodelling. Scar size was reduced, with less fibrosis in the distal myocardium (-42.6% Col I in EV-Treated vs Untreated; p = 0.03), a 2-fold increase in vascular density (EV-Treated; p = 0.019) and less CCL2 transcription in the infarct core. EV-treated animals had less macrophage infiltration in the infarct core (-31.7% of CD163+ cells/field in EV-Treated; p = 0.026), but 5.8 times more expressing anti-inflammatory CD73 (p = 0.015). Systemically, locally delivered cATMSC-EV also triggered a systemic effect, doubling the circulating IL-1ra (p = 0.01), and reducing the PBMC rush 2d post-MI, the TNFα and GM-CSF levels at 30d post-MI, and modulating the CD73+ and CCR2+ monocyte populations, related to immunomodulation and fibrosis modulation. Conclusions: These results highlight the potential of cATMSC-EV in modulating hallmarks of ischemic injury for cardiac repair after MI.
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Affiliation(s)
- Marta Monguió-Tortajada
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Cristina Prat-Vidal
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Cell Therapy Service, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Daina Martínez-Falguera
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Faculty of Medicine, Universitat de Barcelona (UB), Barcelona, Spain
| | - Albert Teis
- Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Carolina Soler-Botija
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Yvan Courageux
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Department of Biochemistry, Molecular Biology and Biomedicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Micaela Munizaga-Larroudé
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
| | - Miriam Moron-Font
- REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol and Nephrology Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Spain
| | - Antoni Bayes-Genis
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, UAB, Barcelona, Spain
| | - Francesc E. Borràs
- REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol and Nephrology Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Spain
| | - Santiago Roura
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
- Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Barcelona 08500, Spain
- Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L´Hospitalet de Llobregat, Spain
| | - Carolina Gálvez-Montón
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Can Ruti Campus, Badalona, Spain
- Heart Institute (iCor), Cardiology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
- Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L´Hospitalet de Llobregat, Spain
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14
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Hamid T, Xu Y, Ismahil MA, Rokosh G, Jinno M, Zhou G, Wang Q, Prabhu SD. Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure: Role of PDGF Signaling. JACC Basic Transl Sci 2022; 7:465-483. [PMID: 35663630 PMCID: PMC9156441 DOI: 10.1016/j.jacbts.2022.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 11/27/2022]
Abstract
Heart failure (HF) is characterized by progressive fibrosis. Both fibroblasts and mesenchymal stem cells (MSCs) can differentiate into pro-fibrotic myofibroblasts. MSCs secrete and express platelet-derived growth factor (PDGF) and its receptors. We hypothesized that PDGF signaling in cardiac MSCs (cMSCs) promotes their myofibroblast differentiation and aggravates post-myocardial infarction left ventricular remodeling and fibrosis. We show that cMSCs from failing hearts post-myocardial infarction exhibit an altered phenotype. Inhibition of PDGF signaling in vitro inhibited cMSC-myofibroblast differentiation, whereas in vivo inhibition during established ischemic HF alleviated left ventricular remodeling and function, and decreased myocardial fibrosis, hypertrophy, and inflammation. Modulating cMSC PDGF receptor expression may thus represent a novel approach to limit pathologic cardiac fibrosis in HF.
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Key Words
- CCL, C-C motif chemokine ligand
- CCR2, C-C chemokine receptor 2
- DDR2, discoidin domain receptor 2
- DMEM, Dulbecco’s modified Eagle medium
- EDV, end-diastolic volume
- EF, ejection fraction
- ESV, end-systolic volume
- HF, heart failure
- IL, interleukin
- INF, interferon
- LV, left ventricular
- Lin, lineage
- MI, myocardial infarction
- MSC, mesenchymal stem cell
- PBS, phosphate-buffered saline
- PCR, polymerase chain reaction
- PDGF, platelet-derived growth factor
- PDGFR, platelet-derived growth factor receptor
- TGFβ, transforming growth factor beta
- WGA, wheat germ agglutinin
- cDNA, complementary DNA
- cMSC, cardiac mesenchymal stem cell
- cardiac remodeling
- fibrosis
- heart failure
- mRNA, messenger RNA
- mesenchymal stem cells
- myocardial inflammation
- myofibroblasts
- platelet-derived growth factor receptor
- siRNA, small interfering RNA
- α-SMA, alpha smooth muscle actin
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Affiliation(s)
- Tariq Hamid
- Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yuanyuan Xu
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Mohamed Ameen Ismahil
- Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gregg Rokosh
- Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Miki Jinno
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Guihua Zhou
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Qiongxin Wang
- Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sumanth D. Prabhu
- Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Birmingham VAMC, Birmingham, Alabama, USA
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15
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Uberti B, Plaza A, Henríquez C. Pre-conditioning Strategies for Mesenchymal Stromal/Stem Cells in Inflammatory Conditions of Livestock Species. Front Vet Sci 2022; 9:806069. [PMID: 35372550 PMCID: PMC8974404 DOI: 10.3389/fvets.2022.806069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) therapy has been a cornerstone of regenerative medicine in humans and animals since their identification in 1968. MSCs can interact and modulate the activity of practically all cellular components of the immune response, either through cell-cell contact or paracrine secretion of soluble mediators, which makes them an attractive alternative to conventional therapies for the treatment of chronic inflammatory and immune-mediated diseases. Many of the mechanisms described as necessary for MSCs to modulate the immune/inflammatory response appear to be dependent on the animal species and source. Although there is evidence demonstrating an in vitro immunomodulatory effect of MSCs, there are disparate results between the beneficial effect of MSCs in preclinical models and their actual use in clinical diseases. This discordance might be due to cells' limited survival or impaired function in the inflammatory environment after transplantation. This limited efficacy may be due to several factors, including the small amount of MSCs inoculated, MSC administration late in the course of the disease, low MSC survival rates in vivo, cryopreservation and thawing effects, and impaired MSC potency/biological activity. Multiple physical and chemical pre-conditioning strategies can enhance the survival rate and potency of MSCs; this paper focuses on hypoxic conditions, with inflammatory cytokines, or with different pattern recognition receptor ligands. These different pre-conditioning strategies can modify MSCs metabolism, gene expression, proliferation, and survivability after transplantation.
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Affiliation(s)
- Benjamin Uberti
- Instituto de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Anita Plaza
- Instituto de Patología Animal, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Claudio Henríquez
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
- *Correspondence: Claudio Henríquez
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16
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Gokce C, Gurcan C, Delogu LG, Yilmazer A. 2D Materials for Cardiac Tissue Repair and Regeneration. Front Cardiovasc Med 2022; 9:802551. [PMID: 35224044 PMCID: PMC8873146 DOI: 10.3389/fcvm.2022.802551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) have a massive impact on human health. Due to the limited regeneration capacity of adult heart tissue, CVDs are the leading cause of death and disability worldwide. Even though there are surgical and pharmacological treatments for CVDs, regenerative strategies are the most promising approaches and have the potential to benefit millions of people. As in any other tissue engineering approach, the repair and regeneration of damaged cardiac tissues generally involve scaffolds made up of biodegradable and biocompatible materials, cellular components such as stem cells, and growth factors. This review provides an overview of biomaterial-based tissue engineering approaches for CVDs with a specific focus on the potential of 2D materials. It is essential to consider both physicochemical and immunomodulatory properties for evaluating the applicability of 2D materials in cardiac tissue repair and regeneration. As new members of the 2D materials will be explored, they will quickly become part of cardiac tissue engineering technologies.
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Affiliation(s)
- Cemile Gokce
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
| | - Cansu Gurcan
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
| | | | - Acelya Yilmazer
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
- *Correspondence: Acelya Yilmazer
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17
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Kurogi H, Takijiri T, Sakumoto M, Isogai M, Takahashi A, Okubo T, Koike T, Yamada T, Nagamura-Inoue T, Sakaki-Yumoto M. Study on the Umbilical Cord-Mesenchymal Stem Cell Manufacturing Using Clinical-Grade Culture Medium. Tissue Eng Part C Methods 2022; 28:23-33. [PMID: 35018815 DOI: 10.1089/ten.tec.2021.0207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapies have been gaining increasing attention owing to their application in various diseases and conditions. In this study, we aimed to identify the optimal condition for industrial-scale MSC manufacturing. MSCs were isolated from umbilical cord (UC) tissues by implementing the explant method (Exp) or a collagenase based-enzymatic digestion method (Col), using a good manufacturing practice-compatible serum-free medium developed in-house. Microarray analysis demonstrated that the gene expression profiles of Exp-MSCs and Col-MSCs did not significantly differ according to the method of isolation or the culture conditions used. The isolated UC-MSCs were then subjected to expansion using conventional static culture (ST) or microcarrier-based culture in stirred-tank bioreactors (MC). Metabolomic and cytokine array analyses were conducted to evaluate the biochemical status of the MSCs. However, no remarkable differences in the metabolic profile and cytokine secretome between ST-MSCs and MC-MSCs were observed. On the contrary, we observed for the first time that the hydrophobic components of ST-MSCs and MC-MSCs were different, which suggested that the cell membrane distribution of fatty acids and lipids was altered in the process of adaptation to shear stress in MC-MSCs. These results establish the flexibility of the isolation and expansion method for UC-MSCs during the manufacturing processes and provide new insights into the minor differences between expansion methods that may exert remarkable effects on MSCs. In conclusion, we demonstrated the feasibility of both Exp-MSCs and Col-MSCs and MC and ST culture methods for scale-up and scale-out of MSC production, as well as the equivalence of these cells. As for the industrialized mass production of MSCs, enzyme-based methods for isolation and cell expansion in a bioreactor were considered to be more suitable. The methods developed, which underwent comprehensive evaluation in this study, may contribute toward the provision of sufficient MSC sources and the establishment of cost-effective MSC therapies. Impact statement Our in-house-developed good manufacturing practice-grade serum-free medium could be used for both isolation (Exp and Col) and expansion (ST and MC) of umbilical cord (UC)-mesenchymal stem/stromal cells (MSCs). Characteristics of the obtained UC-MSCs were widely assessed with regard to gene expression, metabolome, and secretome. Cellular characteristics and efficacy were observed to be equivalently maintained among whichever technique was applied. In addition, our research presents the first evidence that bioreactor and microcarrier-based MSC cultures alter the fatty acid and phospholipid composition of MSCs. These results provide new insights into the differences between expansion methods that may exert remarkable effects on MSCs.
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Affiliation(s)
- Hikari Kurogi
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan.,Rohto Advanced Research Hong Kong Limited, New Territories, Hong Kong
| | - Takashi Takijiri
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Marimu Sakumoto
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Maya Isogai
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Atsuko Takahashi
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Toru Okubo
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tetsuo Koike
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tetsumasa Yamada
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masayo Sakaki-Yumoto
- Regenerative Medicine Research and Planning Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
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18
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Suksatan W, Chupradit S, Yumashev AV, Ravali S, Shalaby MN, Mustafa YF, Kurochkin A, Siahmansouri H. Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells. Int Immunopharmacol 2021; 101:108217. [PMID: 34627083 PMCID: PMC8487784 DOI: 10.1016/j.intimp.2021.108217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new type of coronavirus causing coronavirus 2019 (COVID-19) that was first observed in Wuhan, China, in Dec. 2019. An inflammatory immune response targeting children appeared during the pandemic, which was associated with COVID-19 named multisystem inflammatory syndrome in children (MIS-C). Characteristics of MIS-C include the classic inflammation findings, multi-organ dysfunction, and fever as the cardinal feature. Up to now, no specific therapy has been identified for MIS-C. Currently, considerable progress has been obtained in the MIS-C treatment by cell therapy, specially Mesenchymal stem cells (MSCs). Unique properties have been reported for MSCs, such as various resources for purification of cell, high proliferation, self-renewal, non-invasive procedure, tissue regenerator, multidirectional differentiation, and immunosuppression. As indicated by a recent clinical research, MSCs have the ability of reducing disease inflammation and severity in children with MIS-C. In the present review study, the benefits and characteristics of MSCs and exosomes are discussed for treating patients with MIS-C.
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Affiliation(s)
- Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | | | - Sahithya Ravali
- Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Chennai, India
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | | | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells. Int Immunopharmacol 2021. [DOI: oi.org/10.1016/j.intimp.2021.108217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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20
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Suksatan W, Chupradit S, Yumashev AV, Ravali S, Shalaby MN, Mustafa YF, Kurochkin A, Siahmansouri H. Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells. Int Immunopharmacol 2021. [DOI: https://doi.org/10.1016/j.intimp.2021.108217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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21
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Kishta MS, Ahmed HH, Ali MAM, Aglan HA, Mohamed MR. Mesenchymal stem cells seeded onto nanofiber scaffold for myocardial regeneration. Biotech Histochem 2021; 97:322-333. [PMID: 34607472 DOI: 10.1080/10520295.2021.1979251] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Cardiac disease is the leading cause of mortality and disability worldwide. We investigated the role of undifferentiated adipose tissue-derived mesenchymal stem cells (ADMSC) alone and ADMSC seeded onto the electro-spun nanofibers (NF) for reconstructing damaged cardiac tissue in isoprenaline-induced myocardial infarction (MI) in rats. ADMSC were sorted by morphological appearance and by detection of cluster of differentiation (CD) surface antigens. The therapeutic potential of ADMSC for treating MI was evaluated by electrocardiogram (ECG), biochemical analysis, molecular genetic analysis and histological examination. Treatment of MI-challenged rats with ADMSC improved ECG findings, which were corroborated by significant decreases in serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) enzyme activities together with reduced serum troponin T (cTnT) and connexin 43 (Cx43) levels. MI model rats treated with ADMSC exhibited a significant increase in serum alpha sarcomeric actin (Actn) and GATA binding protein 4 (GATA4), and NK2 homeobox 5 (NKX2.5) gene expression was decreased following treatment with ADMSC. ADMSC also ameliorated damage to cardiac tissue. The effects of ADMSC seeded onto NF were superior to those of ADMSC alone. ADMSC may be useful for mitigation of MI.
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Affiliation(s)
- Mohamed S Kishta
- Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt.,Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt
| | - Hanaa H Ahmed
- Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt.,Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt
| | - Mohamed A M Ali
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hadeer A Aglan
- Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt.,Stem Cell Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt
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22
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Viola M, de Jager SCA, Sluijter JPG. Targeting Inflammation after Myocardial Infarction: A Therapeutic Opportunity for Extracellular Vesicles? Int J Mol Sci 2021; 22:ijms22157831. [PMID: 34360595 PMCID: PMC8346058 DOI: 10.3390/ijms22157831] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/15/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac remodeling and heart failure post-MI. The present challenge is to find a way to stimulate this process without interfering with the reparative role of the immune system. Extracellular vesicles (EVs) are natural membrane particles that are released by cells and carry different macromolecules, including proteins and non-coding RNAs. In recent years, EVs derived from various stem and progenitor cells have been demonstrated to possess regenerative properties. They can provide cardioprotection via several mechanisms of action, including immunomodulation. In this review, we summarize the role of the innate immune system in post-MI healing. We then discuss the mechanisms by which EVs modulate cardiac inflammation in preclinical models of myocardial injury through regulation of monocyte influx and macrophage function. Finally, we provide suggestions for further optimization of EV-based therapy to improve its potential for the treatment of MI.
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Affiliation(s)
- Margarida Viola
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
- UMC Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, 3584 CS Utrecht, The Netherlands
| | - Saskia C. A. de Jager
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
- UMC Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, 3584 CS Utrecht, The Netherlands
- Correspondence: (S.C.A.d.J.); (J.P.G.S.)
| | - Joost P. G. Sluijter
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
- UMC Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, 3584 CS Utrecht, The Netherlands
- Correspondence: (S.C.A.d.J.); (J.P.G.S.)
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23
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Functions of Mesenchymal Stem Cells in Cardiac Repair. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1312:39-50. [PMID: 33330961 DOI: 10.1007/5584_2020_598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myocardial infarction (MI) and heart failure (HF) are significant contributors of mortality worldwide. Mesenchymal stem cells (MSCs) hold a great potential for cardiac regenerative medicine-based therapies. Their therapeutic potential has been widely investigated in various in-vitro and in-vivo preclinical models. Besides, they have been tested in clinical trials of MI and HF with various outcomes. Differentiation to lineages of cardiac cells, neovascularization, anti-fibrotic, anti-inflammatory, anti-apoptotic and immune modulatory effects are the main drivers of MSC functions during cardiac repair. However, the main mechanisms regulating these functions and cross-talk between cells are not fully known yet. Increasing line of evidence also suggests that secretomes of MSCs and/or their extracellular vesicles play significant roles in a paracrine manner while mediating these functions. This chapter aims to summarize and highlight cardiac repair functions of MSCs during cardiac repair.
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24
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Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging. Int J Mol Sci 2021; 22:ijms22147309. [PMID: 34298927 PMCID: PMC8306573 DOI: 10.3390/ijms22147309] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches.
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25
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Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Outlook for Inflammatory and Degenerative Diseases. Front Immunol 2021; 11:591065. [PMID: 33613514 PMCID: PMC7893976 DOI: 10.3389/fimmu.2020.591065] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.,University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
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26
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Sanchez-Castro EE, Pajuelo-Reyes C, Tejedo R, Soria-Juan B, Tapia-Limonchi R, Andreu E, Hitos AB, Martin F, Cahuana GM, Guerra-Duarte C, de Assis TCS, Bedoya FJ, Soria B, Chávez-Olórtegui C, Tejedo JR. Mesenchymal Stromal Cell-Based Therapies as Promising Treatments for Muscle Regeneration After Snakebite Envenoming. Front Immunol 2021; 11:609961. [PMID: 33633730 PMCID: PMC7902043 DOI: 10.3389/fimmu.2020.609961] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022] Open
Abstract
Snakebite envenoming is a global neglected disease with an incidence of up to 2.7 million new cases every year. Although antivenoms are so-far the most effective treatment to reverse the acute systemic effects induced by snakebite envenoming, they have a limited therapeutic potential, being unable to completely neutralize the local venom effects. Local damage, such as dermonecrosis and myonecrosis, can lead to permanent sequelae with physical, social, and psychological implications. The strong inflammatory process induced by snake venoms is associated with poor tissue regeneration, in particular the lack of or reduced skeletal muscle regeneration. Mesenchymal stromal cells (MSCs)-based therapies have shown both anti-inflammatory and pro-regenerative properties. We postulate that using allogeneic MSCs or their cell-free products can induce skeletal muscle regeneration in snakebite victims, improving all the three steps of the skeletal muscle regeneration process, mainly by anti-inflammatory activity, paracrine effects, neovascularization induction, and inhibition of tissue damage, instrumental for microenvironment remodeling and regeneration. Since snakebite envenoming occurs mainly in areas with poor healthcare, we enlist the principles and potential of MSCs-based therapies and discuss regulatory issues, good manufacturing practices, transportation, storage, and related-procedures that could allow the administration of these therapies, looking forward to a safe and cost-effective treatment for a so far unsolved and neglected health problem.
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Affiliation(s)
| | - Cecilia Pajuelo-Reyes
- Institute of Tropical Diseases, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas, Chachapoyas, Peru
| | - Rebeca Tejedo
- Faculty of Medicine, Universidad Privada San Juan Bautista, Lima, Peru
| | - Bárbara Soria-Juan
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Department of Surgery, Fundación Jiménez Díaz, Unidad de Terapias Avanzadas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Rafael Tapia-Limonchi
- Institute of Tropical Diseases, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas, Chachapoyas, Peru
| | - Etelvina Andreu
- ISABIAL-Hospital General y Universitario de Alicante, Alicante, Spain.,Departmento de Fisica Aplicadas, University Miguel Hernández, Alicante, Spain
| | - Ana B Hitos
- Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC, Seville, Spain.,Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
| | - Franz Martin
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC, Seville, Spain.,Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
| | - Gladys M Cahuana
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC, Seville, Spain
| | - Clara Guerra-Duarte
- Center of Research and Development, Fundação Ezequiel Dias, Belo Horizonte, Brazil
| | - Thamyres C Silva de Assis
- Departament of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Francisco J Bedoya
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC, Seville, Spain.,Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
| | - Bernat Soria
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,ISABIAL-Hospital General y Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.,Institute of Bioengineering, University Miguel Hernandez de Elche, Alicante, Spain
| | - Carlos Chávez-Olórtegui
- Departament of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juan R Tejedo
- Institute of Tropical Diseases, Universidad Nacional Toribio Rodríguez de Mendoza de Amazonas, Chachapoyas, Peru.,Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.,Department of Cell Regeneration and Advanced Therapies, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, University of Pablo de Olavide-University of Sevilla-CSIC, Seville, Spain.,Biomedical Research Network for Diabetes and Related Metabolic Diseases-CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain
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27
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Akita N, Narita Y, Yamawaki-Ogata A, Usui A, Komori K. Therapeutic effect of allogeneic bone marrow-derived mesenchymal stromal cells on aortic aneurysms. Cell Tissue Res 2021; 383:781-793. [PMID: 33146827 DOI: 10.1007/s00441-020-03295-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 09/14/2020] [Indexed: 01/14/2023]
Abstract
We previously reported the effectiveness of autologous mesenchymal stromal cells (MSCs) for the treatment of aortic aneurysm (AA), mediated mainly by these cells' anti-inflammatory properties. In this study, we investigate whether the therapeutic effects of allogeneic MSCs on AA are the same as those of autologous MSCs. To examine the immune response to allogeneic MSCs, C57BL/6 lymphocytes were co-cultured with BALB/c MSCs for 5 days in vitro. Apolipoprotein E-deficient C57BL/6 mice with AA induced by angiotensin II were randomly divided into three groups defined by the following intravenous injections: (i) 0.2 ml of saline (n = 10, group S) as a control, (ii) 1 × 106 autologous MSCs (isolated from C57BL/6, n = 10, group Au) and (iii) 1 × 106 allogeneic MSCs (isolated from BALB/c, n = 10, group Al). Two weeks after injection, aortic diameters were measured, along with enzymatic activities of MMP-2 and MMP-9 and cytokine concentrations in AAs. Neither allogenic (BALB/c) MSCs nor autologous (C57BL/6) MSCs accelerated the proliferation of lymphocytes obtained from C57BL/6. Compared with group S, groups Au and Al had significantly shorter aortic diameters (group S vs Au vs Al; 2.29 vs 1.40 vs 1.36 mm, respectively, p < 0.01), reduced MMP-2 and MMP-9 activities, downregulated IL-6 and MCP-1 and upregulated expression of IGF-1 and TIMP-2. There were no differences in these results between groups Au and Al. Thus, our study suggests that treatment with allogeneic MSCs improves chronic inflammation and reduced aortic dilatation. These effects were equivalent to those of autologous MSCs in established mouse models of AA.
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Affiliation(s)
- Naohiro Akita
- Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuji Narita
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Aika Yamawaki-Ogata
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Akihiko Usui
- Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Kimihiro Komori
- Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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28
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Lin HJ, Ramesh S, Chang YM, Tsai CT, Tsai CC, Shibu MA, Tamilselvi S, Mahalakshmi B, Kuo WW, Huang CY. D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:86-94. [PMID: 32889782 DOI: 10.1002/tox.23014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/17/2020] [Accepted: 08/02/2020] [Indexed: 06/11/2023]
Abstract
This study addresses the effect of D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus (AOF; Alpinia oxyphylla Miq) extracts fortified with adipose-derived mesenchymal stem cells (ADMSCs) in rats. Male 18 week-old Wistar Kyoto (WKY) rats were used in this study. We analyzed cardiac fibrosis by Masson's trichrome staining. The tissue sections were dyed using hematoxylin and eosin (H&E). Tissue sections were stained for the restoration of Nrf2 expression in treatment groups by immunohistochemistry. Immunohistochemistry and western blotting analysis showed that AOF with ADMSCs could significantly reduce aging-induced oxidative stress in D-galactose-induced aging rat hearts by inducing Nrf2 pathway. Reduction in ROS resulted in the suppression of inflammatory signals (p-NF-κB and IL-6). Histopathological studies were showed an increased interstitium and collagen accumulation in aging-induced heart sections. However, AOF and ADMSCs treated hearts were recovered from cardiac remodeling. Furthermore, hypertrophy and fibrosis associated markers were also significantly reduced (P < .05) in treatment groups. We speculate that ADMSCs might activate certain paracrine factors, which could target the upstream activator of aging associated cardiac complications and AOF might provide homing for these stem cells.
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Affiliation(s)
- Hung-Jen Lin
- School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Samiraj Ramesh
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Microbiology, PRIST Deemed to be University, Thanjavur, Tamil Nadu, India
| | - Yung-Ming Chang
- The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
- Chinese Medicine Department, E-DA Hospital, Kaohsiung, Taiwan
- 1PT Biotechnology Co., Ltd., Taichung, Taiwan
| | | | - Chin-Chuan Tsai
- The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
- Chinese Medicine Department, E-DA Hospital, Kaohsiung, Taiwan
| | - Marthandam Asokan Shibu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Shanmugam Tamilselvi
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - B Mahalakshmi
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
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29
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Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2863501. [PMID: 33381545 PMCID: PMC7759411 DOI: 10.1155/2020/2863501] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 11/22/2022]
Abstract
Mounting evidence indicates that the mesenchymal stem cell (MSC) injection is safe and efficacious for treating cardiomyopathy; however, there is limited information relating to multiple intravenous injections of human-induced pluripotent stem cell-derived mesenchymal stem cell (hiPSC-MSC) and long-term evaluation of the cardiac function. In the current study, MSC-like cells were derived from human-induced pluripotent stem cells through valproic acid (VPA) induction and continuous cell passages. The derived spindle-like cells expressed MSC-related markers, secreted angiogenic and immune-regulatory factors, and could be induced to experience chondrogenic and adipogenic differentiation. During the induction process, expression of epithelial-to-mesenchymal transition- (EMT-) related gene N-cadherin and vimentin was upregulated to a very high level, and the expression of pluripotency-related genes Sox2 and Oct4 was downregulated or remained unchanged, indicating that VPA initiated EMT by upregulating the expression of EMT promoting genes and downregulating that of pluripotency-related genes. Two and four intravenous hiPSC-MSC injections (106 cells/per injections) were provided, respectively, to model rats one week after acute myocardial infarction (AMI). Cardiac function parameters were dynamically monitored during a 12-week period. Two and four cell injections significantly the improved left ventricular ejection fraction and left ventricular fractional shortening; four-injection markedly stimulated angiogenesis reduced the scar size and cell apoptosis number in the scar area in comparison with that of the untreated control model rats. Although the difference was insignificant, the hiPSC-MSC administration delayed the increase of left ventricular end-diastolic dimension to different extents compared with that of the PBS-injection control. No perceptible immune reaction symptom or hiPSC-MSC-induced tumour formation was found over 12 weeks. Compared with the PBS-injection control, four injections produced better outcome than two injections; as a result, at least four rounds of MSC injections were suggested for AMI treatment.
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30
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Xin L, Gao J, Lin H, Qu Y, Shang C, Wang Y, Lu Y, Cui X. Regulatory Mechanisms of Baicalin in Cardiovascular Diseases: A Review. Front Pharmacol 2020; 11:583200. [PMID: 33224035 PMCID: PMC7667240 DOI: 10.3389/fphar.2020.583200] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular diseases (CVDs) is the leading cause of high morbidity and mortality worldwide, which emphasizes the urgent necessity to develop new pharmacotherapies. In eastern countries, traditional Chinese medicine Scutellaria baicalensis Georgi has been used clinically for thousands of years. Baicalin is one of the main active ingredients extracted from Chinese herbal medicine S. baicalensis. Emerging evidence has established that baicalin improves chronic inflammation, immune imbalance, disturbances in lipid metabolism, apoptosis and oxidative stress. Thereby it offers beneficial roles against the initiation and progression of CVDs such as atherosclerosis, hypertension, myocardial infarction and reperfusion, and heart failure. In this review, we summarize the pharmacological features and relevant mechanisms by which baicalin regulates CVDs in the hope to reveal its application for CVDs prevention and/or therapy.
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Affiliation(s)
- Laiyun Xin
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jialiang Gao
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongchen Lin
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Qu
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chang Shang
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuling Wang
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingdong Lu
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Cui
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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31
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Roy S, Spinali K, Schmuck EG, Kink JA, Hematti P, Raval AN. Cardiac fibroblast derived matrix-educated macrophages express VEGF and IL-6, and recruit mesenchymal stromal cells. ACTA ACUST UNITED AC 2020; 10. [PMID: 33564732 DOI: 10.1016/j.regen.2020.100033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The polarization of monocytes into macrophages that possess anti-inflammatory and pro-angiogenic properties could provide a novel therapeutic strategy for patients who are at a high risk for developing heart failure following myocardial infarction (MI). Here in, we describe a novel method of "educating" monocytes into a distinct population of macrophages that exhibit anti-inflammatory and pro-angiogenic features through a 3-day culture on fibronectin-rich cardiac matrix (CX) manufactured using cultured human cardiac fibroblasts. Our data suggest that CX can educate monocytes into a unique macrophage population termed CX educated macrophages (CXMq) that secrete high levels of VEGF and IL-6. In vitro, CXMq also demonstrate the ability to recruit mesenchymal stromal cells (MSC) with known anti-inflammatory properties. Selective inhibition of fibronectin binding to αVβ3 surface integrins on CXMq prevented MSC recruitment. This suggests that insoluble fibronectin within CX is, at least in part, responsible for CXMq conversion.
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Affiliation(s)
- Sushmita Roy
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Keith Spinali
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Eric G Schmuck
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - John A Kink
- Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.,University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Peiman Hematti
- Division of Hematology/Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.,University of Wisconsin Carbone Cancer Center, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
| | - Amish N Raval
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA
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Jan RL, Yang SC, Liu YC, Yang RC, Tsai SP, Huang SE, Yeh JL, Hsu JH. Extracellular heat shock protein HSC70 protects against lipopolysaccharide-induced hypertrophic responses in rat cardiomyocytes. Biomed Pharmacother 2020; 128:110370. [PMID: 32521457 DOI: 10.1016/j.biopha.2020.110370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/28/2020] [Accepted: 06/02/2020] [Indexed: 02/08/2023] Open
Abstract
We have recently shown that exogenous administration of extracellular heat shock protein HSC70, a previously recognized intracellular chaperone protein, can protect against LPS-induced cardiac dysfunction through anti-inflammatory actions. However, whether it can also exert anti-hypertrophic effect is unknown. The present study was aimed to investigate the efficacy of HSC70 against cardiac hypertrophy and its underlying molecular mechanisms. Cardiomyocytes were isolated from the cardiac ventricles of neonatal Wistar rats and LPS (1 μg/mL) was used to induce the hypertrophic responses. We found that HSC70 (0.1, 1 and 5 μg/mL) pretreatment attenuated LPS-induced cardiomyocyte hypertrophy dose-dependently. In addition, HSC70 mitigated LPS-induced inflammatory mediators including TNF-α, IL-6, NO, iNOS and COX-2, with down-regulated protein expression of MMP-2 and MMP-9. Moreover, HSC70 repressed LPS-induced signaling of MAPK and Akt. Finally, HSC70 inhibited NF-κB subunit p65, and the DNA binding activity of NF-κB. Taken together, these findings suggest that in vitro HSC70 can exert anti-hypertrophic effects through inhibition of pro-inflammatory mediators, which are potential mediated by the down-regulation of MAPK, Akt and NF-κB signaling pathways. In conclusion, extracellular HSC70 may be a novel pharmacologic strategy in the management of cardiac hypertrophy.
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Affiliation(s)
- Ren-Long Jan
- Department of Pediatrics, Chi Mei Medical Center, Liouying, Tainan, 73657, Taiwan; Graduate Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan, 71101, Taiwan
| | - Shun-Cheng Yang
- Department of Pediatric Infection, Changhua Christian Children Hospital, Changhua, 50050, Taiwan
| | - Yi-Ching Liu
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Rei-Cheng Yang
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Siao-Ping Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shang-En Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Jwu-Lai Yeh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
| | - Jong-Hau Hsu
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
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Wang J, Chen Z, Dai Q, Zhao J, Wei Z, Hu J, Sun X, Xie J, Xu B. Intravenously delivered mesenchymal stem cells prevent microvascular obstruction formation after myocardial ischemia/reperfusion injury. Basic Res Cardiol 2020; 115:40. [PMID: 32451935 DOI: 10.1007/s00395-020-0800-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/15/2020] [Indexed: 12/11/2022]
Abstract
Microvascular obstruction (MVO) after primary percutaneous coronary intervention (pPCI) is identified as an independent risk factor for poor prognosis in patients with acute myocardial infarction (AMI). The inflammatory response induced by ischemia and reperfusion (I/R) injury is considered one of the main mechanisms of MVO. Mesenchymal stem cells (MSCs) are a unique stromal cell type that confers an immunomodulatory effect in cardiac disease. The present study aimed to investigate whether immediate intravenous delivery of MSCs could be used as a potential therapeutic method to attenuate MVO formation. A cardiac catheterization-induced porcine model of myocardial I/R injury was established, and allograft MSCs were immediately delivered intravenously. Cardiac magnetic resonance (CMR) imaging was performed on days 2 and 7 after the operation to determine the infarct area, MVO, and cardiac function. The pigs with allograft MSCs showed decreased MVO and infarct size, as well as an improved left ventricular ejection fraction (LVEF). Histological analysis revealed decreased myocyte area, fibrosis, and inflammatory cell infiltration in the peri-infarct zone of pigs with allograft MSCs. Moreover, the concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6) and C-reactive protein (CRP) in the serum were reduced in the allograft MSC group compared to the control group. Flow cytometry indicated decreased natural killer (NK) cells in the peripheral blood and ischemic heart tissue in the pigs with allograft MSCs. In summary, allograft MSCs delivered intravenously and immediately after myocardial I/R injury can attenuate MVO formation in a porcine model through a decline in the number of NK cells in the myocardium.
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Affiliation(s)
- Junzhuo Wang
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Ziwei Chen
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Qing Dai
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Jinxuan Zhao
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Zilun Wei
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Jiaxin Hu
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Xuan Sun
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Jun Xie
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China.
| | - Biao Xu
- Department of Cardiology, Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, China. .,Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
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Zhang Z, Tian H, Yang C, Liu J, Zhang H, Wang J, Hu S, Sun Z, He K, Chen G. Mesenchymal Stem Cells Promote the Resolution of Cardiac Inflammation After Ischemia Reperfusion Via Enhancing Efferocytosis of Neutrophils. J Am Heart Assoc 2020; 9:e014397. [PMID: 32079474 PMCID: PMC7335576 DOI: 10.1161/jaha.119.014397] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Neutrophils play a major role in inflammation after myocardial ischemia‐reperfusion (I/R) injury. The effects of mesenchymal stem cells (MSCs) on neutrophils in I/R are complex and not fully understood. This study was designed to investigate the effects and mechanism of MSCs on alleviating myocardial I/R injury in rats. Methods and Results MSCs induced M2 macrophages polarization in vitro and enhanced macrophage efferocytosis of apoptotic neutrophils, measured by fluorescence‐activated cell sorting analysis and immunofluorescence staining. Rats myocardial I/R were induced by transient ligation of left anterior descending coronary. Adipose‐derived MSCs or vehicle were infused at initiation (immediate after reperfusion) or peak of inflammation (24 hours after I/R). Hematoxylin and eosin, 2,3,5‐triphenyltetrazolium chloride/Evans Blue staining and immunofluorescence staining were applied within 72 hours after cell infusion. Cardiac function was assessed by echocardiography and left cardiac catheterization analysis at 28 days post‐operation. MSCs infused immediately and 24 hours later both markedly ameliorated myocardial I/R injury, and immediate infusion had more significant outcome. These improvements were associated with neutrophils infiltration, measured by fluorescence‐activated cell sorting analysis and immunofluorescence staining. When infused immediately, MSCs did not significantly change neutrophil number at 24 hours but CD11b expression was significantly higher. When infused at 24 hours, MSCs markedly decreased neutrophil number by enhanced M2 macrophage infiltration and macrophage efferocytosis of neutrophils within 72 hours. Conclusions Efferocytosis is pivotal to relieve neutrophil‐mediated I/R injury and initial the immune response for healing. MSCs infusion improves cardiac function in rats after myocardial I/R via the possible mechanism of enhancing M2 macrophages‐induced efferocytosis of apoptotic neutrophils.
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Affiliation(s)
- Zeyu Zhang
- Department of Cardiology Chinese PLA General Hospital Beijing China.,Beijing Key Laboratory of Chronic Heart Failure Precision Medicine Chinese PLA General Hospital Beijing China
| | - Hongzhen Tian
- Department of Cardiology Chinese PLA General Hospital Beijing China.,Department of Cardiology 969 Hospital of Joint Logistic Support Force of PLA Huhehaote China
| | - Chen Yang
- Department of Cardiology Chinese PLA General Hospital Beijing China
| | - Jixuan Liu
- Department of Cardiology Chinese PLA General Hospital Beijing China.,Beijing Key Laboratory of Chronic Heart Failure Precision Medicine Chinese PLA General Hospital Beijing China
| | - Huawei Zhang
- Department of Cardiology Chinese PLA General Hospital Beijing China
| | - Jinda Wang
- Department of Cardiology Chinese PLA General Hospital Beijing China
| | - Shunying Hu
- Department of Cardiology Chinese PLA General Hospital Beijing China
| | - Zhijun Sun
- Department of Cardiology Chinese PLA General Hospital Beijing China
| | - Kunlun He
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine Chinese PLA General Hospital Beijing China
| | - Guanghui Chen
- Department of Cardiology Chinese PLA General Hospital Beijing China
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van den Hoogen P, de Jager SCA, Mol EA, Schoneveld AS, Huibers MMH, Vink A, Doevendans PA, Laman JD, Sluijter JPG. Potential of mesenchymal- and cardiac progenitor cells for therapeutic targeting of B-cells and antibody responses in end-stage heart failure. PLoS One 2019; 14:e0227283. [PMID: 31891633 PMCID: PMC6938331 DOI: 10.1371/journal.pone.0227283] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/16/2019] [Indexed: 01/21/2023] Open
Abstract
Upon myocardial damage, the release of cardiac proteins induces a strong antibody-mediated immune response, which can lead to adverse cardiac remodeling and eventually heart failure (HF). Stem cell therapy using mesenchymal stromal cells (MSCs) or cardiomyocyte progenitor cells (CPCs) previously showed beneficial effects on cardiac function despite low engraftment in the heart. Paracrine mediators are likely of great importance, where, for example, MSC-derived extracellular vesicles (EVs) also show immunosuppressive properties in vitro. However, the limited capacity of MSCs to differentiate into cardiac cells and the sufficient scaling of MSC-derived EVs remain a challenge to clinical translation. Therefore, we investigated the immunosuppressive actions of endogenous CPCs and CPC-derived EVs on antibody production in vitro, using both healthy controls and end-stage HF patients. Both MSCs and CPCs strongly inhibit lymphocyte proliferation and antibody production in vitro. Furthermore, CPC-derived EVs significantly lowered the levels of IgG1, IgG4, and IgM, especially when administered for longer duration. In line with previous findings, plasma cells of end-stage HF patients showed high production of IgG3, which can be inhibited by MSCs in vitro. MSCs and CPCs inhibit in vitro antibody production of both healthy and end-stage HF-derived immune cells. CPC-derived paracrine factors, such as EVs, show similar effects, but do not provide the complete immunosuppressive capacity of CPCs. The strongest immunosuppressive effects were observed using MSCs, suggesting that MSCs might be the best candidates for therapeutic targeting of B-cell responses in HF.
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Affiliation(s)
- Patricia van den Hoogen
- Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Saskia C. A. de Jager
- Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Emma A. Mol
- Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
- Laboratory of Cardiovascular Cell Biology, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Arjan S. Schoneveld
- Laboratory of Clinical Chemistry & Haematology, ARCADIA, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Manon M. H. Huibers
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Aryan Vink
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Pieter A. Doevendans
- Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
- Netherlands Heart Institute, Utrecht, the Netherlands
- Central Military Hospital, Utrecht, the Netherlands
| | - Jon D. Laman
- Department of Biomedical Sciences of Cells and Systems (BSCS), University Medical Center Groningen, Groningen, the Netherlands
| | - Joost P. G. Sluijter
- Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
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Yang C, Chen Y, Zhong L, You M, Yan Z, Luo M, Zhang B, Yang B, Chen Q. Homogeneity and heterogeneity of biological characteristics in mesenchymal stem cells from human umbilical cords and exfoliated deciduous teeth. Biochem Cell Biol 2019; 98:415-425. [PMID: 31794246 DOI: 10.1139/bcb-2019-0253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have proven powerful potential for cell-based therapy both in regenerative medicine and disease treatment. Human umbilical cords and exfoliated deciduous teeth are the main sources of MSCs with no donor injury or ethical issues. The goal of this study was to investigate the differences in the biological characteristics of human umbilical cord mesenchymal stem cells (UCMSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). UCMSCs and SHEDs were identified by flow cytometry. The proliferation, differentiation, migration, chemotaxis, paracrine, immunomodulatory, neurite growth-promoting capabilities, and acetaldehyde dehydrogenase (ALDH) activity were comparatively studied between these two MSCs in vitro. The results showed that both SHEDs and UCMSCs expressed cell surface markers characteristic of MSCs. Furthermore, SHEDs exhibited better capacity for proliferation, migration, promotion of neurite growth, and chondrogenic differentiation. Meanwhile, UCMSCs showed more outstanding adipogenic differentiation and chemotaxy. Additionally, there were no significant differences in osteogenic differentiation, immunomodulatory capacity, and the proportion of ALDHBright compartment. Our findings indicate that although both UCMSCs and SHEDs are mesenchymal stem cells and presented some similar biological characteristics, they also have differences in many aspects, which might be helpful for developing future clinical cellular therapies.
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Affiliation(s)
- Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Yu Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Liwu Zhong
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Min You
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Zhiling Yan
- Department of Stomatology, Chengdu Women's and Children's Central Hospital, Chengdu, China
| | - Maowen Luo
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Bo Zhang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Benyanzi Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China.,Center for Stem Cell Research & Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
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Immune Regulatory Cells in Inflammation, Infection, Tumor, Metabolism, and Other Diseases 2019. Mediators Inflamm 2019; 2019:3182198. [PMID: 31772501 PMCID: PMC6854187 DOI: 10.1155/2019/3182198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 09/12/2019] [Indexed: 12/02/2022] Open
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Kot M, Baj-Krzyworzeka M, Szatanek R, Musiał-Wysocka A, Suda-Szczurek M, Majka M. The Importance of HLA Assessment in "Off-the-Shelf" Allogeneic Mesenchymal Stem Cells Based-Therapies. Int J Mol Sci 2019; 20:E5680. [PMID: 31766164 PMCID: PMC6888380 DOI: 10.3390/ijms20225680] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/31/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023] Open
Abstract
The need for more effective therapies of chronic and acute diseases has led to the attempts of developing more adequate and less invasive treatment methods. Regenerative medicine relies mainly on the therapeutic potential of stem cells. Mesenchymal stem cells (MSCs), due to their immunosuppressive properties and tissue repair abilities, seem to be an ideal tool for cell-based therapies. Taking into account all available sources of MSCs, perinatal tissues become an attractive source of allogeneic MSCs. The allogeneic MSCs provide "off-the-shelf" cellular therapy, however, their allogenicity may be viewed as a limitation for their use. Moreover, some evidence suggests that MSCs are not as immune-privileged as it was previously reported. Therefore, understanding their interactions with the recipient's immune system is crucial for their successful clinical application. In this review, we discuss both autologous and allogeneic application of MSCs, focusing on current approaches to allogeneic MSCs therapies, with a particular interest in the role of human leukocyte antigens (HLA) and HLA-matching in allogeneic MSCs transplantation. Importantly, the evidence from the currently completed and ongoing clinical trials demonstrates that allogeneic MSCs transplantation is safe and seems to cause no major side-effects to the patient. These findings strongly support the case for MSCs efficacy in treatment of a variety of diseases and their use as an "off-the-shelf" medical product.
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Affiliation(s)
- Marta Kot
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.B.-K.); (R.S.)
| | - Rafał Szatanek
- Department of Clinical Immunology, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.B.-K.); (R.S.)
| | - Aleksandra Musiał-Wysocka
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Magdalena Suda-Szczurek
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
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Dabrowska S, Andrzejewska A, Strzemecki D, Muraca M, Janowski M, Lukomska B. Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats. J Neuroinflammation 2019; 16:216. [PMID: 31722731 PMCID: PMC6852925 DOI: 10.1186/s12974-019-1602-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022] Open
Abstract
Background Ischemic stroke is the major cause of long-term severe disability and death in aged population. Cell death in the infarcted region of the brain induces immune reaction leading to further progression of tissue damage. Immunomodulatory function of mesenchymal stem cells (MSCs) has been shown in multiple preclinical studies; however, it has not been successfully translated to a routine clinical practice due to logistical, economical, regulatory, and intellectual property obstacles. It has been recently demonstrated that therapeutic effect of intravenously administered MSCs can be recapitulated by extracellular vesicles (EVs) derived from them. However, in contrast to MSCs, EVs were not capable to decrease stroke-induced neuroinflammation. Therefore, the aim of the study was to investigate if intra-arterial delivery of MSC-derived EVs will have stronger impact on focal brain injury-induced neuroinflammation, which mimics ischemic stroke, and how it compares to MSCs. Methods The studies were performed in adult male Wistar rats with focal brain injury induced by injection of 1 μl of 50 nmol ouabain into the right hemisphere. Two days after brain insult, 5 × 105 human bone marrow MSCs (hBM-MSCs) labeled with Molday ION or 1.3 × 109 EVs stained with PKH26 were intra-arterially injected into the right hemisphere under real-time MRI guidance. At days 1, 3, and 7 post-transplantation, the rats were decapitated, the brains were removed, and the presence of donor cells or EVs was analyzed. The cellular immune response in host brain was evaluated immunohistochemically, and humoral factors were measured by multiplex immunoassay. Results hBM-MSCs and EVs transplanted intra-arterially were observed in the rat ipsilateral hemisphere, near the ischemic region. Immunohistochemical analysis of brain tissue showed that injection of hBM-MSCs or EVs leads to the decrease of cell activation by ischemic injury, i.e., astrocytes, microglia, and infiltrating leucocytes, including T cytotoxic cells. Furthermore, we observed significant decrease of pro-inflammatory cytokines and chemokines after hBM-MSC or EV infusion comparing with non-treated rats with focal brain injury. Conclusions Intra-arterially injected EVs attenuated neuroinflammation evoked by focal brain injury, which mimics ischemic stroke, and this effect was comparable to intra-arterial hBM-MSC transplantation. Thus, intra-arterial injection of EVs might be an attractive therapeutic approach, which obviates MSC-related obstacles.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Damian Strzemecki
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Maurizio Muraca
- Department of Women's and Children's Health, University of Padua, Via Giustiniani 3, 35128, Padua, Italy
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, 5 Pawinskiego Street, 02-106, Warsaw, Poland.
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Carotenuto F, Teodori L, Maccari AM, Delbono L, Orlando G, Di Nardo P. Turning regenerative technologies into treatment to repair myocardial injuries. J Cell Mol Med 2019; 24:2704-2716. [PMID: 31568640 PMCID: PMC7077550 DOI: 10.1111/jcmm.14630] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/28/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Regenerative therapies including stem cell treatments hold promise to allow curing patients affected by severe cardiac muscle diseases. However, the clinical efficacy of stem cell therapy remains elusive, so far. The two key roadblocks that still need to be overcome are the poor cell engraftment into the injured myocardium and the limited knowledge of the ideal mixture of bioactive factors to be locally delivered for restoring heart function. Thus, therapeutic strategies for cardiac repair are directed to increase the retention and functional integration of transplanted cells in the damaged myocardium or to enhance the endogenous repair mechanisms through cell‐free therapies. In this context, biomaterial‐based technologies and tissue engineering approaches have the potential to dramatically impact cardiac translational medicine. This review intends to offer some consideration on the cell‐based and cell‐free cardiac therapies, their limitations and the possible future developments.
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Affiliation(s)
- Felicia Carotenuto
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy.,Diagnostics and Metrology (FSN-TECFIS-DIM), ENEA, C.R. Frascati, Rome, Italy
| | - Laura Teodori
- Diagnostics and Metrology (FSN-TECFIS-DIM), ENEA, C.R. Frascati, Rome, Italy
| | - Anna Maria Maccari
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy
| | - Luciano Delbono
- Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Giuseppe Orlando
- Wake Forest University School of Medicine, Winston Salem, NC, USA.,Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Paolo Di Nardo
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy.,I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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Ueda M, Jo JI, Gao JQ, Tabata Y. Effect of lipopolysaccharide addition on the gene transfection of spermine-introduced pullulan-plasmid DNA complexes for human mesenchymal stem cells. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2019; 30:1542-1558. [PMID: 31354063 DOI: 10.1080/09205063.2019.1650240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The objective of this study is to investigate the effect of lipopolysaccharide (LPS) addition on the gene transfection of human mesenchymal stem cells (hMSC). hMSC were treated with the LPS at different concentrations and the complex of spermine-introduced pullulan and luciferase plasmid DNA for 3 h. The maximum level of gene expression was observed for hMSC treated with a certain concentration range of LPS. In addition, the cytotoxicity, cellular internalization of complexes, and cell cycle after LPS treatment were investigated. The cytotoxicity increased with an increase in the LPS concentration treated. On the other hand, the cellular internalization of complexes increased with the increased LPS concentration, although the internalization was sharply reduced at the high concentration. The LPS treatment increased the actin polymerization of cells to allow to spread more. The enhanced cells spreading would enhance the cellular internalization of complexes. In addition, the LPS treatment increased the rate of cell cycle. It is possible that the balance of cytotoxicity, cellular internalization, and cell cycle caused by the LPS addition results in the enhanced gene transfection at a certain LPS concentration. It is concluded that LPS treatment positively modified the cellular internalization and the cell cycle, resulting in the enhanced gene transfection.
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Affiliation(s)
- Masumi Ueda
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University , Japan
| | - Jun-Ichiro Jo
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University , Japan
| | - Jian-Qing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University , P. R. China
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University , Japan
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Diedrichs F, Stolk M, Jürchott K, Haag M, Sittinger M, Seifert M. Enhanced Immunomodulation in Inflammatory Environments Favors Human Cardiac Mesenchymal Stromal-Like Cells for Allogeneic Cell Therapies. Front Immunol 2019; 10:1716. [PMID: 31396228 PMCID: PMC6665953 DOI: 10.3389/fimmu.2019.01716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 07/09/2019] [Indexed: 12/29/2022] Open
Abstract
Rising numbers of patients with cardiovascular diseases and limited availability of donor hearts require new and improved therapy strategies. Human atrial appendage-derived cells (hAACs) are promising candidates for an allogeneic cell-based treatment. In this study, we evaluated their inductive and modulatory capacity regarding immune responses and underlying key mechanisms in vitro. For this, cryopreserved hAACs were either cultured in the presence of interferon-gamma (IFNγ) or left unstimulated. The expression of characteristic mesenchymal stromal cell markers (CD29, CD44, CD73, CD105, CD166) was revealed by flow cytometry that also highlighted a predominant negativity for CD90. A low immunogeneic phenotype in an inflammatory milieu was shown by lacking expression of co-stimulatory molecules and upregulation of the inhibitory ligands PD-L1 and PD-L2, despite de novo expression of HLA-DR. Co-cultures of hAACs with allogeneic peripheral blood mononuclear cells, proved their low immunogeneic state by absence of induced T cell proliferation and activation. Additionally, elevated levels of IL-1β, IL-33, and IL-10 were detectable in those cell culture supernatants. Furthermore, the immunomodulatory potential of hAACs was assessed in co-cultures with αCD3/αCD28-activated peripheral blood mononuclear cells. Here, a strong inhibition of T cell proliferation and reduction of pro-inflammatory cytokines (IFNγ, TNFα, TNFβ, IL-17A, IL-2) were observable after pre-stimulation of hAACs with IFNγ. Transwell experiments confirmed that mostly soluble factors are responsible for these suppressive effects. We were able to identify indolamin-2,3-dioxygenase (IDO) as a potential key player through a genome-wide gene expression analysis and could demonstrate its involvement in the observed immunological responses. While the application of blocking antibodies against both PD-1 ligands did not affect the immunomodulation by hAACs, 1-methyl-L-tryptophan as specific inhibitor of IDO was able to restore proliferation and to lower apoptosis of T cells. In conclusion, hAACs represent a cardiac-derived mesenchymal stromal-like cell type with a high potential for the application in an allogeneic setting, since they do not trigger T cell responses and even increase their immunomodulatory potential in inflammatory environments.
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Affiliation(s)
- Falk Diedrichs
- Berlin Institute of Health (BIH), Berlin, Germany.,BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Meaghan Stolk
- BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Karsten Jürchott
- BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Marion Haag
- BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Tissue Engineering Laboratory, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Michael Sittinger
- BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Tissue Engineering Laboratory, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Martina Seifert
- BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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43
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García Gómez-Heras S, Largo C, Larrea JL, Vega-Clemente L, Calderón Flores M, Ruiz-Pérez D, García-Olmo D, García-Arranz M. Main histological parameters to be evaluated in an experimental model of myocardial infarct treated by stem cells on pigs. PeerJ 2019; 7:e7160. [PMID: 31367480 PMCID: PMC6657680 DOI: 10.7717/peerj.7160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/22/2019] [Indexed: 12/22/2022] Open
Abstract
Myocardial infarction has been carefully studied in numerous experimental models. Most of these models are based on electrophysiological and functional data, and pay less attention to histological discoveries. During the last decade, treatment using advanced therapies, mainly cell therapy, has prevailed from among all the options to be studied for treating myocardial infarction. In our study we wanted to show the fundamental histological parameters to be evaluated during the development of an infarction on an experimental model as well as treatment with mesenchymal stem cells derived from adipose tissue applied intra-lesionally. The fundamental parameters to study in infarcted tissue at the histological level are the cells involved in the inflammatory process (lymphocytes, macrophages and M2, neutrophils, mast cells and plasma cells), neovascularization processes (capillaries and arterioles) and cardiac cells (cardiomyocytes and Purkinje fibers). In our study, we used intramyocardial injection of mesenchymal stem cells into the myocardial infarction area 1 hour after arterial occlusion and allowed 1 month of evolution before analyzing the modifications on the normal tissue inflammatory infiltrate. Acute inflammation was shortened, leading to chronic inflammation with abundant plasma cells and mast cells and complete disappearance of neutrophils. Another benefit was an increase in the number of vessels formed. Cardiomyocytes and Purkinje fibers were better conserved, both from a structural and metabolic point of view, possibly leading to reduced morbidity in the long term. With this study we present the main histological aspects to be evaluated in future assays, complementing or explaining the electrophysiological and functional findings.
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Affiliation(s)
| | - Carlota Largo
- Experimental Surgery, La Paz University Hospital, IdiPaz, Madrid, Spain
| | - Jose Luis Larrea
- Surgical Cardiology Department, La Paz University Hospital, Madrid, Spain
| | - Luz Vega-Clemente
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
| | | | - Daniel Ruiz-Pérez
- Experimental Surgery, La Paz University Hospital, IdiPaz, Madrid, Spain
| | - Damián García-Olmo
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
| | - Mariano García-Arranz
- Cell Therapy laboratory, Health Research Institute, Fundación Jiménez Diaz, Madrid, Spain
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Hussain MA, Colicchia M, Veerapen J, Weeraman D, Podaru MN, Jones D, Suzuki K, Mathur A. Circulatory support and stem cell therapy in the management of advanced heart failure: a concise review of available evidence. Regen Med 2019; 14:585-593. [PMID: 31115248 DOI: 10.2217/rme-2018-0121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Stem cell therapy utilizing bone marrow mononuclear cells (BMC's) is a potential strategy to treat heart failure patients with improvement in symptom profile and cardiac function. We describe a rationale for concurrent BMC and left ventricular assist device therapy in selected heart failure patients. This combination therapy has demonstrated improved myocardial perfusion and cardiac function in patients with advanced ischemic cardiomyopathy. Moreover, preclinical data support improved cell retention with left ventricular unloading. The beneficial effects of BMC's are likely through a paracrine mechanism initiating a 'cardiac-repair' process. Combination therapy of BMC's and a left ventricular assist device may exhibit a synergistic effect with improved engraftment of BMC's through left ventricular unloading.
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Affiliation(s)
- Mohsin A Hussain
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Martina Colicchia
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Jessry Veerapen
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Deshan Weeraman
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Mihai-Nicolae Podaru
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Daniel Jones
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Ken Suzuki
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
| | - Anthony Mathur
- William Harvey Research Institute, Queen Mary University of London, St Bartholomew's Hospital NHS Foundation Trust, London, UK
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45
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Affiliation(s)
- Tariq Hamid
- From the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Medical Service, Birmingham VAMC
| | - Sumanth D Prabhu
- From the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, and Medical Service, Birmingham VAMC.
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46
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Chu X, Xu B, Gao H, Li BY, Liu Y, Reiter JL, Wang Y. Lipopolysaccharides Improve Mesenchymal Stem Cell-Mediated Cardioprotection by MyD88 and stat3 Signaling in a Mouse Model of Cardiac Ischemia/Reperfusion Injury. Stem Cells Dev 2019; 28:620-631. [PMID: 30808255 DOI: 10.1089/scd.2018.0213] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) improve cardiac function after ischemia/reperfusion injury, in part, due to the release of cytoprotective paracrine factors. Toll-like receptor 4 (TLR4) is expressed in MSCs and regulates the expression of cytoprotective factors, cytokines, and chemokines. Lipopolysaccharide (LPS) stimulation of TLR4 activates two distinct signaling pathways that are either MyD88 dependent or MyD88 independent/TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent. While it was reported previously that LPS treatment improved MSC-mediated cardioprotection, the mechanism underlying such improved effect remains unknown. To study the role of MyD88 signaling in MSC cardioprotective activity, wild type (WT) and MyD88-/- MSCs were treated with LPS (200 ng/mL) for 24 h. WT and MyD88-/- MSCs with or without LPS pretreatment were infused into the coronary circulation of isolated mouse hearts (Langendorff model) and then subjected to ischemia (25 min) and reperfusion (50 min). Saline served as a negative control. Both untreated and LPS-pretreated WT MSCs significantly improved postischemic recovery of myocardial function of isolated mouse hearts, as evidenced by improved left ventricular developed pressure and ventricular contractility assessment (ie, the rate of left ventricle pressure change over time, ± dp/dt). LPS-pretreated WT MSCs conferred better cardiac function recovery than untreated MSCs; however, such effect of LPS was abolished when using MyD88-/- MSCs. In addition, LPS stimulated stat3 activity in WT MSCs, but not MyD88-/- MSCs. stat3 small interfering RNA abolished the effect of LPS in improving the cardioprotection of WT MSCs. In conclusion, this study demonstrates that LPS improves MSC-mediated cardioprotection by MyD88-dependent activation of stat3.
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Affiliation(s)
- Xiaona Chu
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Bing Xu
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,2 Department of Pharmacology, Harbin Medical University, Harbin, China
| | - Hongyu Gao
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Bai-Yan Li
- 2 Department of Pharmacology, Harbin Medical University, Harbin, China
| | - Yunlong Liu
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,3 Centers for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jill L Reiter
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,3 Centers for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Yue Wang
- 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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47
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de Souza Vieira S, Antonio EL, de Melo BL, Portes LA, Montemor J, Oliveira HA, Martins FL, Zogbi C, Girardi AC, Silva JA, Camillo de Carvalho PDT, Tucci PJF, Serra AJ. Exercise Training Potentiates The Cardioprotective Effects of Stem Cells Post-infarction. Heart Lung Circ 2019; 28:263-271. [PMID: 29503239 DOI: 10.1016/j.hlc.2017.11.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 11/06/2017] [Accepted: 11/10/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Preconditioning of cell recipients may exert a significant role in attenuating the hostility of the infarction milieu, thereby enhancing the efficacy of cell therapy. This study was conducted to examine whether exercise training potentiates the cardioprotective effects of adipose-derived stem cell (ADSC) transplantation following myocardial infarction (MI) in rats. METHODS Four groups of female Fisher-344 rats were studied: Sham; non-trained rats with MI (sMI); non-trained rats with MI submitted to ADSCs transplantation (sADSC); trained rats with MI submitted to ADSCs (tADSC). Rats were trained 9 weeks prior to MI and ADSCs transplantation. Echocardiography was applied to assess cardiac function. Myocardial performance was evaluated in vitro. Protein expression analyses were carried out by immunoblotting. Periodic acid-Schiff staining was used to analyse capillary density and apoptosis was evaluated with terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. RESULTS Echocardiography performed 4 weeks after the infarction revealed attenuated scar size in the both sADSC and tADSC groups compared to the sMI group. However, fractional shortening was improved only in the tADSC group. In vitro myocardial performance was similar between the tADSC and Sham groups. The expression of phosphoSer473Akt1 and VEGF were found to be higher in the hearts of the tADSC group compared to both the sADSC and sMI groups. Histologic analysis demonstrated that tADSC rats had higher capillary density in the remote and border zones of the infarcted sites compared to the sMI rats. CONCLUSIONS Preconditioning with exercise induces a pro-angiogenic milieu that may potentiate the therapeutic effects of ADSCs on cardiac remodelling following MI.
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Affiliation(s)
| | | | | | - Leslie Andrews Portes
- Cardiology Division, Federal University of São Paulo, São Paulo, Brazil; Adventist Center University of São Paulo, São Paulo, Brazil
| | - Jairo Montemor
- Cardiology Division, Federal University of São Paulo, São Paulo, Brazil
| | | | - Flavia Leticia Martins
- Laboratory of Genetic and Molecular Cardiology, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil
| | - Camila Zogbi
- Laboratory of Genetic and Molecular Cardiology, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil
| | - Adriana Costa Girardi
- Laboratory of Genetic and Molecular Cardiology, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil
| | - José Antônio Silva
- Laboratory of Biophotonic, Universidade Nove de Julho, São Paulo, Brazil
| | | | | | - Andrey Jorge Serra
- Cardiology Division, Federal University of São Paulo, São Paulo, Brazil; Laboratory of Biophotonic, Universidade Nove de Julho, São Paulo, Brazil.
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48
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Roura S, Rudilla F, Gastelurrutia P, Enrich E, Campos E, Lupón J, Santiago-Vacas E, Querol S, Bayés-Genís A. Determination of HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in heart failure patients. ESC Heart Fail 2019; 6:388-395. [PMID: 30672659 PMCID: PMC6437550 DOI: 10.1002/ehf2.12406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 12/12/2018] [Indexed: 12/19/2022] Open
Abstract
Aims Cell therapy can be used to repair functionally impaired organs and tissues in humans. Although autologous cells have an immunological advantage, it is difficult to obtain high cell numbers for therapy. Well‐characterized banks of cells with human leukocyte antigens (HLA) that are representative of a given population are thus needed. The present study investigates the HLA allele and haplotype frequencies in a cohort of heart failure (HF) patients. Methods and results We carried out the HLA typing and the allele and haplotype frequency analysis in 247 ambulatory HF patients. We determined HLA class I (A, B, and C) and class II (DRB1 and DQB1) using next‐generation sequencing technology. The allele frequencies were obtained using Python for Population Genomics (PyPop) software, and HLA haplotypes were estimated using HaploStats. A total of 30 HLA‐A, 56 HLA‐B, 23 HLA‐C, 36 HLA‐DRB1, and 15 HLA‐DQB1 distinct alleles were identified within the studied cohort. The genotype frequencies of all five HLA loci were in Hardy–Weinberg equilibrium. We detected differences in HLA allele frequencies among patients when the etiological cause of HF was considered. There were a total of 494 five‐loci haplotypes, five of which were present six or more times. Moreover, the most common estimated HLA haplotype was HLA‐A*01:01, HLA‐B*08:01, HLA‐C*07:01, HLA‐DRB1*03:01, and HLA‐DQB1*02:01 (6.07% haplotype frequency per patient). Remarkably, the 11 most frequent haplotypes would cover 31.17% of the patients of the cohort in need of allogeneic cell therapy. Conclusions Our findings could be useful for improving allogeneic cell administration outcomes without concomitant immunosuppression.
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Affiliation(s)
- Santiago Roura
- ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Badalona, Spain.,CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Francesc Rudilla
- Histocompatibility and Immunogenetics Laboratory, Blood and Tissue Bank, Barcelona, Spain.,Transfusional Medicine Group, Vall d'Hebron Research Institute, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Paloma Gastelurrutia
- ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Badalona, Spain.,CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Enrich
- Histocompatibility and Immunogenetics Laboratory, Blood and Tissue Bank, Barcelona, Spain.,Transfusional Medicine Group, Vall d'Hebron Research Institute, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Eva Campos
- Histocompatibility and Immunogenetics Laboratory, Blood and Tissue Bank, Barcelona, Spain
| | - Josep Lupón
- CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain.,Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain.,Department of Medicine, UAB, Barcelona, Spain
| | | | - Sergi Querol
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Autonomous University of Barcelona (UAB), Barcelona, Spain.,Cell Therapy Unit, Blood and Tissue Bank, Barcelona, Spain
| | - Antoni Bayés-Genís
- ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Badalona, Spain.,CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain.,Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain.,Department of Medicine, UAB, Barcelona, Spain
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49
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Jargin SV. Scientific Papers and Patents on Substances with Unproven Effects. Part 2. RECENT PATENTS ON DRUG DELIVERY & FORMULATION 2019; 13:160-173. [PMID: 31424374 PMCID: PMC7011683 DOI: 10.2174/1872211313666190819124752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/19/2019] [Accepted: 08/01/2019] [Indexed: 12/03/2022]
Abstract
Several examples are discussed in this review, where substances without proven effects were proposed for practical use within the scope of evidence-based medicines. The following is discussed here: generalizations of the hormesis concept and its use in support of homeopathy; phytoestrogens and soy products potentially having feminizing effects; glycosaminoglycans for the treatment of osteoarthritis and possibilities of their replacement by diet modifications; flavonoids recommended for the treatment of chronic venous insufficiency and varicose veins; acetylcysteine as a mucolytic agent and its questionable efficiency especially by an oral intake; stem cells and cell therapies. In conclusion, placebo therapies can be beneficial and ethically justifiable but it is not a sufficient reason to publish biased information. Importantly, placebo must be devoid of adverse effects, otherwise, it is named pseudo-placebo. Therapeutic methods with unproven effects should be tested in high-quality research shielded from the funding bias. Some issues discussed in this review are not entirely clear, and the arguments provided here can initiate a constructive discussion.
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Affiliation(s)
- Sergei V. Jargin
- Peoples’ Friendship University of Russia, Clementovski per 6-82, Moscow115184, Russia
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50
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Zeglinski MR, Moghadam AR, Ande SR, Sheikholeslami K, Mokarram P, Sepehri Z, Rokni H, Mohtaram NK, Poorebrahim M, Masoom A, Toback M, Sareen N, Saravanan S, Jassal DS, Hashemi M, Marzban H, Schaafsma D, Singal P, Wigle JT, Czubryt MP, Akbari M, Dixon IM, Ghavami S, Gordon JW, Dhingra S. Myocardial Cell Signaling During the Transition to Heart Failure. Compr Physiol 2018; 9:75-125. [DOI: 10.1002/cphy.c170053] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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