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Ochieng BO, Zhao L, Ye Z. Three-Dimensional Bioprinting in Vascular Tissue Engineering and Tissue Vascularization of Cardiovascular Diseases. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:340-358. [PMID: 37885200 DOI: 10.1089/ten.teb.2023.0175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
In the 21st century, significant progress has been made in repairing damaged materials through material engineering. However, the creation of large-scale artificial materials still faces a major challenge in achieving proper vascularization. To address this issue, researchers have turned to biomaterials and three-dimensional (3D) bioprinting techniques, which allow for the combination of multiple biomaterials with improved mechanical and biological properties that mimic natural materials. Hydrogels, known for their ability to support living cells and biological components, have played a crucial role in this research. Among the recent developments, 3D bioprinting has emerged as a promising tool for constructing hybrid scaffolds. However, there are several challenges in the field of bioprinting, including the need for nanoscale biomimicry, the formulation of hydrogel blends, and the ongoing complexity of vascularizing biomaterials, which requires further research. On a positive note, 3D bioprinting offers a solution to the vascularization problem due to its precise spatial control, scalability, and reproducibility compared with traditional fabrication methods. This paper aims at examining the recent advancements in 3D bioprinting technology for creating blood vessels, vasculature, and vascularized materials. It provides a comprehensive overview of the progress made and discusses the limitations and challenges faced in current 3D bioprinting of vascularized tissues. In addition, the paper highlights the future research directions focusing on the development of 3D bioprinting techniques and bioinks for creating functional materials.
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Affiliation(s)
- Ben Omondi Ochieng
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, China
| | - Leqian Zhao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, China
- Department of Biomedical Science and Biochemistry, Research School of Biology, The Australian National University, Canberra, Australia
| | - Zhiyi Ye
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, China
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2
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Wei Q, Xiao Y, Du L, Li Y. Advances in Nanoparticles in the Prevention and Treatment of Myocardial Infarction. Molecules 2024; 29:2415. [PMID: 38893291 PMCID: PMC11173599 DOI: 10.3390/molecules29112415] [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: 03/26/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Myocardial infarction (MI) is one of the most prevalent types of cardiovascular disease. During MI, myocardial cells become ischemic and necrotic due to inadequate blood perfusion, leading to irreversible damage to the heart. Despite the development of therapeutic strategies for the prevention and treatment of MI, their effects are still unsatisfactory. Nanoparticles represent a new strategy for the pre-treatment and treatment of MI, and novel multifunctional nanoparticles with preventive and therapeutic capabilities hold promise for the prevention and treatment of this disease. This review summarizes the common types and properties of nanoparticles, and focuses on the research progress of nanoparticles for the prevention and treatment of MI.
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Affiliation(s)
| | | | | | - Ya Li
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.W.); (Y.X.); (L.D.)
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Yan W, Li Y, Yin J, Liu Q, Shi Y, Tan J, Wang Y, Zhang S, Zhang J, Li J, Yan S. Protective effect of human epicardial adipose-derived stem cells on myocardial injury driven by poly-lactic acid nanopillar array. Biotechnol Appl Biochem 2024; 71:110-122. [PMID: 37904285 DOI: 10.1002/bab.2525] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/07/2023] [Indexed: 11/01/2023]
Abstract
We investigated if poly-lactic acid (PLA) nanopillar array can trigger the differentiation of human epicardial (ADSCs) (heADSCs) into cardiomyocyte-like cells and explored the effects of these cardiomyocyte-like cells on myocardial infarction (MI) in vivo. PLA nanopillar array (200 nm diameter) and plain PLA film (PLA planar) induced heADSCs were marked with carboxyfluorescein. After 7 days, the expressions of myocardiocyte-specific genes were significantly enhanced in cells seeded on PLA nanopillar array compared with that on PLA planar, especially CACNA1C, KCNH2, and MYL2 genes (p < 0.05). However, the expressions of cardiac troponin T (cTNT), KCNQ1, and KCNA5 were lower than those in PLA planar-induced heADSCs (p < 0.05), whereas GATA4 tended to increase with time. The cells with positively stained α-actinin and cTNT were elevated in heADSCs induced by PLA nanopillar array compared with those induced by PLA planar only (p < 0.05). In vivo experiments showed that cardiac function was improved after injecting PLA-nanopillar array-induced heADSCs into the ischemic heart (p < 0.05, compared with PLA planar + MI group). Furthermore, tyrosine hydroxylase density was significantly lower (p < 0.05). PLA nanopillar array directly drives the differentiation of heADSCs into cardiomyocyte-like cells, and the induced heADSCs exhibit a protective effect on ischemic myocardium by improving cardiac function in MI rats.
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Affiliation(s)
- Wenju Yan
- Cheeloo College of Medicine, Shandong University& Shandong Qianfoshan Hospital, Jinan, China
- Department of Vasculocardiology, Taian City Central Hospital, Taian, China
| | - Yan Li
- Department of Cardiology, The First Hospital Affiliated to Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jie Yin
- Department of Cardiology, The First Hospital Affiliated to Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Qian Liu
- Cheeloo College of Medicine, Shandong University& Shandong Qianfoshan Hospital, Jinan, China
| | - Yugen Shi
- Department of Cardiology, The First Hospital Affiliated to Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jiayu Tan
- Department of Cardiology, The First Hospital Affiliated to Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yu Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shan Zhang
- State Key Laboratory of Crystal Materials, Shandong University, Jinan, China
| | - Junyi Zhang
- Cheeloo College of Medicine, Shandong University& Shandong Qianfoshan Hospital, Jinan, China
| | - Jingxin Li
- Cheeloo College of Medicine, Shandong University& Shandong Qianfoshan Hospital, Jinan, China
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Suhua Yan
- Cheeloo College of Medicine, Shandong University& Shandong Qianfoshan Hospital, Jinan, China
- Department of Cardiology, The First Hospital Affiliated to Shandong First Medical University& Shandong Provincial Qianfoshan Hospital, Jinan, China
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Abdel-Reheim MA, Zaafar D, El-Shoura EAM, Abdelaal N, Atwa AM, Bazeed SM, Mahmoud HM. Unlocking the miRNA-34a-5p/TGF-β and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model. Int Immunopharmacol 2024; 127:111369. [PMID: 38101219 DOI: 10.1016/j.intimp.2023.111369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/07/2023] [Accepted: 12/10/2023] [Indexed: 12/17/2023]
Abstract
Liraglutide (LIRA), a drug used to treat type 2 diabetes mellitus that belongs to the glucagon-like peptide-1 class, has recently drawn attention for its potential cardioprotective properties because of its anti-oxidative and anti-inflammatory properties. This current investigation was designed to assess the impact of LIRA on myocardial injury induced by isoproterenol (ISO). The experiment included 24 male Wistar rats in total, and they were divided into four groups: Control, LIRA (200 µg/kg/12 hrs., S.C.), ISO (85 mg/kg, S.C.), and ISO + LIRA. To assess the results, various biochemical and histopathological analyses were carried out. The findings showed elevated serum enzyme levels, a sign of cardiac injury. ISO-treated rats showed an upregulation of oxidative stress and inflammatory biomarkers like MDA, MPO, nitrites, NADPH oxidase, TNF-α, IL-1β, IL-6, 8-Hydroxyguanosine (8-OHdG), and TGF-β, as well as altered gene expressions like TLR-1 and miRNA-34a-5p. According to western blotting analysis, protein levels of AKT, PI3K, and mTOR were obviously enhanced. Additionally, ISO-treated samples showed altered tissue morphology, elevated caspase 3, and decreased Bcl2 concentrations. The levels of these dysregulated parameters were significantly normalized by LIRA therapy, demonstrating its cardioprotective function against ISO-induced myocardial injury in rats. This protective mechanism was linked to anti-inflammatory properties, redox balance restoration, and modulation of the miRNA-34a-5p/TGF-β pathway.
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Affiliation(s)
- Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62514, Egypt
| | - Dalia Zaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Ehab A M El-Shoura
- Clinical Pharmacy Department, Al-Azhar University, Assiut branch, Assiut 71524, Egypt.
| | - Nashwa Abdelaal
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA
| | - Ahmed M Atwa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Shefaa M Bazeed
- Biochemistry and Chemistry of Nutrition Department, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Cairo, Egypt
| | - Heba M Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62514, Egypt
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Manshori M, Kazemnejad S, Naderi N, Shirazi A, Arabian M, Eghtedar Doost M, Darzi M, Montazeri S, Aboutaleb N, Golshahi H. Higher Improvement of Cardiac Function Following Myocardial Infarction using Menstrual Blood Stromal/Stem Cells (MenSCs) Suspended in Conditioned Medium versus Conditioned Medium Alone in Rat Model. Avicenna J Med Biotechnol 2023; 15:157-166. [PMID: 37538240 PMCID: PMC10395459 DOI: 10.18502/ajmb.v15i3.12924] [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: 12/14/2022] [Accepted: 04/26/2023] [Indexed: 08/05/2023] Open
Abstract
Background To evaluate the efficiency of Menstrual blood Stromal/Stem Cells (MenSCs) administration in Myocardial Infarction (MI), the effects of MenSCs and their derived conditioned Medium (CM) on cardiac function in MI rat model was assessed. Methods Animals were divided into four groups including sham group, MI group, MenSCs derived CM group (CM group), and MenSCs suspended in CM (MenSCs+CM) group. The injection of different groups was carried out 30 min after ligation of left anterior descending coronary artery into the infarct border zone. Results The results showed a significant reduction in scar size after injection of MenSCs+CM compared to MI group. Ejection fraction and fractional shortening of MenSCs+CM group were higher than CM and MI group at day 28. Administration of MenSCs+CM led to much more survival of cardiomyocytes, and prevention of meta-plastic development. Moreover, human mitochondrial transfer from MenSCs to cardiomyocytes was seen in group treated by MenSCs+CM. Indeed, MenSCs+CM treatment evoked nuclear factor-κB (NF-κB) down-regulation more than other treatments. Conclusion MenSCs+CM treatment could significantly ameliorate cardiac function by different mechanisms including inhibition of cartilaginous metaplasia, inhibition of NF-κB and mitochondrial transfer.
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Affiliation(s)
- Mahmood Manshori
- Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Nasim Naderi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Shirazi
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Maedeh Arabian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Darzi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Samaneh Montazeri
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Iran University of Medical Science, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hannaneh Golshahi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Yap L, Chong LY, Tan C, Adusumalli S, Seow M, Guo J, Cai Z, Loo SJ, Lim E, Tan RS, Grishina E, Soong PL, Lath N, Ye L, Petretto E, Tryggvason K. Pluripotent stem cell-derived committed cardiac progenitors remuscularize damaged ischemic hearts and improve their function in pigs. NPJ Regen Med 2023; 8:26. [PMID: 37236990 DOI: 10.1038/s41536-023-00302-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Ischemic heart disease, which is often associated with irreversibly damaged heart muscle, is a major global health burden. Here, we report the potential of stem cell-derived committed cardiac progenitors (CCPs) have in regenerative cardiology. Human pluripotent embryonic stem cells were differentiated to CCPs on a laminin 521 + 221 matrix, characterized with bulk and single-cell RNA sequencing, and transplanted into infarcted pig hearts. CCPs differentiated for eleven days expressed a set of genes showing higher expression than cells differentiated for seven days. Functional heart studies revealed significant improvement in left ventricular ejection fraction at four and twelve weeks following transplantation. We also observed significant improvements in ventricular wall thickness and a reduction in infarction size after CCP transplantation (p-value < 0.05). Immunohistology analyses revealed in vivo maturation of the CCPs into cardiomyocytes (CM). We observed temporary episodes of ventricular tachyarrhythmia (VT) in four pigs and persistent VT in one pig, but the remaining five pigs exhibited normal sinus rhythm. Importantly, all pigs survived without the formation of any tumors or VT-related abnormalities. We conclude that pluripotent stem cell-derived CCPs constitute a promising possibility for myocardial infarction treatment and that they may positively impact regenerative cardiology.
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Affiliation(s)
- Lynn Yap
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Singapore.
| | - Li Yen Chong
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Clarissa Tan
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Swarnaseetha Adusumalli
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Millie Seow
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Jing Guo
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Zuhua Cai
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Sze Jie Loo
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore
| | - Eric Lim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore
| | - Ru San Tan
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore
| | | | - Poh Loong Soong
- Ternion Biosciences, Singapore, 574329, Singapore
- Cardiovascular Disease Translational Research Program, Yong Loo Lin School of Medicine, NUS, Singapore, 169609, Singapore
| | - Narayan Lath
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, 169609, Singapore
| | - Lei Ye
- Department of Biomedical Engineering, University of Alabama, Birmingham, 35233, England
| | - Enrico Petretto
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore
| | - Karl Tryggvason
- Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore, 169857, Singapore.
- Department of Medicine Duke University, Durham, NC, 27710, USA.
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77, Stockholm, Sweden.
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Kim SG, George NP, Hwang JS, Park S, Kim MO, Lee SH, Lee G. Human Bone Marrow-Derived Mesenchymal Stem Cell Applications in Neurodegenerative Disease Treatment and Integrated Omics Analysis for Successful Stem Cell Therapy. Bioengineering (Basel) 2023; 10:bioengineering10050621. [PMID: 37237691 DOI: 10.3390/bioengineering10050621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Neurodegenerative diseases (NDDs), which are chronic and progressive diseases, are a growing health concern. Among the therapeutic methods, stem-cell-based therapy is an attractive approach to NDD treatment owing to stem cells' characteristics such as their angiogenic ability, anti-inflammatory, paracrine, and anti-apoptotic effects, and homing ability to the damaged brain region. Human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) are attractive NDD therapeutic agents owing to their widespread availability, easy attainability and in vitro manipulation and the lack of ethical issues. Ex vivo hBM-MSC expansion before transplantation is essential because of the low cell numbers in bone marrow aspirates. However, hBM-MSC quality decreases over time after detachment from culture dishes, and the ability of hBM-MSCs to differentiate after detachment from culture dishes remains poorly understood. Conventional analysis of hBM-MSCs characteristics before transplantation into the brain has several limitations. However, omics analyses provide more comprehensive molecular profiling of multifactorial biological systems. Omics and machine learning approaches can handle big data and provide more detailed characterization of hBM-MSCs. Here, we provide a brief review on the application of hBM-MSCs in the treatment of NDDs and an overview of integrated omics analysis of the quality and differentiation ability of hBM-MSCs detached from culture dishes for successful stem cell therapy.
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Affiliation(s)
- Seok Gi Kim
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Nimisha Pradeep George
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Ji Su Hwang
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Seokho Park
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Myeong Ok Kim
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Soo Hwan Lee
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Gwang Lee
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
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Krajnik K, Mietkiewska K, Skowronska A, Kordowitzki P, Skowronski MT. Oogenesis in Women: From Molecular Regulatory Pathways and Maternal Age to Stem Cells. Int J Mol Sci 2023; 24:ijms24076837. [PMID: 37047809 PMCID: PMC10095116 DOI: 10.3390/ijms24076837] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
It is a well-known fact that the reproductive organs in women, especially oocytes, are exposed to numerous regulatory pathways and environmental stimuli. The maternal age is one cornerstone that influences the process of oocyte fertilization. More precisely, the longer a given oocyte is in the waiting-line to be ovulated from menarche to menopause, the longer the duration from oogenesis to fertilization, and therefore, the lower the chances of success to form a viable embryo. The age of menarche in girls ranges from 10 to 16 years, and the age of menopause in women ranges from approximately 45 to 55 years. Researchers are paying attention to the regulatory pathways that are impacting the oocyte at the very beginning during oogenesis in fetal life to discover genes and proteins that could be crucial for the oocyte’s lifespan. Due to the general trend in industrialized countries in the last three decades, women are giving birth to their first child in their thirties. Therefore, maternal age has become an important factor impacting oocytes developmental competence, since the higher a woman’s age, the higher the chances of miscarriage due to several causes, such as aneuploidy. Meiotic failures during oogenesis, such as, for instance, chromosome segregation failures or chromosomal non-disjunction, are influencing the latter-mentioned aging-related phenomenon too. These errors early in life of women can lead to sub- or infertility. It cannot be neglected that oogenesis is a precisely orchestrated process, during which the oogonia and primary oocytes are formed, and RNA synthesis takes place. These RNAs are crucial for oocyte growth and maturation. In this review, we intend to describe the relevance of regulatory pathways during the oogenesis in women. Furthermore, we focus on molecular pathways of oocyte developmental competence with regard to maternal effects during embryogenesis. On the background of transcriptional mechanisms that enable the transition from a silenced oocyte to a transcriptionally active embryo, we will briefly discuss the potential of induced pluripotent stem cells.
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Affiliation(s)
- Kornelia Krajnik
- Department of Basic and Preclinical Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Klaudia Mietkiewska
- Department of Basic and Preclinical Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Agnieszka Skowronska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Pawel Kordowitzki
- Department of Basic and Preclinical Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Mariusz T. Skowronski
- Department of Basic and Preclinical Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
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Ahmed MI, Abdelrazek HMA, Moustafa YM, Alshawwa SZ, Mobasher MA, Abdel-Wahab BA, Abdelgawad FE, Khodeer DM. Cardioprotective Effect of Flibanserin against Isoproterenol-Induced Myocardial Infarction in Female Rats: Role of Cardiac 5-HT2A Receptor Gene/5-HT/Ca2+ Pathway. Pharmaceuticals (Basel) 2023; 16:ph16040502. [PMID: 37111259 PMCID: PMC10143970 DOI: 10.3390/ph16040502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Serotonin (5-HT) release during myocardial ischemia plays an important role in the progression of myocardial cellular injury. This study was conducted to investigate the possible cardioprotective effect of flibanserin (FLP) against isoproterenol (ISO)-induced MI in rats. Rats were randomly divided into five groups and were treated orally (p.o.) with FLP (15, 30, and 45 mg/kg) for 28 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 27th and 28th days to induce MI. ISO-induced myocardial infarcted rats exhibited a significant increase in cardiac markers, oxidative stress markers, cardiac and serum 5-HT levels, and total cardiac calcium (Ca2+) concentration. ISO-induced myocardial infarcted rats also revealed a remarkable alteration of electrocardiogram (ECG) pattern and significantly upregulated expression of the 5-Hydroxytryptamine 2A (5-HT2A) receptors gene. Moreover, ISO-induced myocardial infarcted rats showed significant histopathological findings of MI and hypertrophic signs. However, pretreatment with FLP significantly attenuated the ISO-induced MI in a dose-dependent manner, as the effect of FLP (45 mg/kg) was more pronounced than that of the other two doses, FLP (15 and 30 mg/kg). The present study provides evidence for the cardioprotective efficacy of FLP against ISO-induced MI in rats.
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10
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Azizidoost S, Farzaneh M. MicroRNAs as a Novel Player for Differentiation of Mesenchymal Stem Cells into Cardiomyocytes. Curr Stem Cell Res Ther 2023; 18:27-34. [PMID: 35466882 DOI: 10.2174/1574888x17666220422094150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/14/2022] [Accepted: 03/02/2022] [Indexed: 11/22/2022]
Abstract
Cardiovascular disease (CVD) is defined as a class of disorders affecting the heart and blood vessels. Cardiomyocytes and endothelial cells play important roles in cardiac regeneration and heart repair. However, the proliferating capacity of cardiomyocytes is limited. To overcome this issue, mesenchymal stem cells (MSCs) have emerged as an alternative strategy for CVD therapy. MSCs can proliferate and differentiate (or trans-differentiate) into cardiomyocytes. Several in vitro and in vivo differentiation protocols have been used to obtain MSCs-derived cardiomyocytes. It was recently investigated that microRNAs (miRNAs) by targeting several signaling pathways, including STAT3, Wnt/β-catenin, Notch, and TBX5, play a crucial role in regulating cardiomyocytes' differentiation of MSCs. In this review, we focused on the role of miRNAs in the differentiation of MSCs into cardiomyocytes.
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Affiliation(s)
- Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Manshori M, Kazemnejad S, Naderi N, Darzi M, Aboutaleb N, Golshahi H. Greater angiogenic and immunoregulatory potency of bFGF and 5-aza-2'-deoxycytidine pre-treated menstrual blood stem cells in compare to bone marrow stem cells in rat model of myocardial infarction. BMC Cardiovasc Disord 2022; 22:578. [PMID: 36587199 PMCID: PMC9805241 DOI: 10.1186/s12872-022-03032-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 12/26/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND This study is designed to compare the menstrual blood stem cells (MenSCs) and bone marrow stem cells (BMSCs)-secreted factors with or without pre-treatment regimen using basic fibroblast growth factor (bFGF) and 5-aza-2'-deoxycytidine (5-aza) and also regenerative capacity of pre-treated MenSCs and/or BMSCs in a rat model of myocardial infarction (MI). METHODS BMSCs and MenSCs were pre-treated with bFGF and 5-aza for 48 h and we compared the paracrine activity by western blotting. Furthermore, MI model was created and the animals were divided into sham, MI, pre-treated BMSCs, and pre-treated MenSCs groups. The stem cells were administrated via tail vain. 35 days post-MI, serum and tissue were harvested for further investigations. RESULTS Following pre-treatment, vascular endothelium growth factor, hypoxia-inducible factor-1, stromal cell-derived factor-1, and hepatocyte growth factor were significantly increased in secretome of MenSCs in compared to BMSCs. Moreover, systemic administration of pre-treated MenSCs, leaded to improvement of cardiac function, preservation of myocardium from further subsequent injuries, promotion the angiogenesis, and reduction the level of NF-κB expression in compared to the pre-treated BMSCs. Also, pre-treated MenSCs administration significantly decreased the serum level of Interleukin 1 beta (IL-1β) in compared to the pre-treated BMSCs and MI groups. CONCLUSIONS bFGF and 5-aza pre-treated MenSCs offer superior cardioprotection compare to bFGF and 5-aza pre-treated BMSCs following MI.
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Affiliation(s)
- Mahmood Manshori
- grid.417689.5Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somaieh Kazemnejad
- grid.417689.5Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Nasim Naderi
- grid.411746.10000 0004 4911 7066Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Darzi
- grid.417689.5Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Nahid Aboutaleb
- grid.411746.10000 0004 4911 7066Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran ,grid.411746.10000 0004 4911 7066Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hannaneh Golshahi
- grid.417689.5Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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12
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Wang Y, Xue Y, Guo HD. Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction. Front Pharmacol 2022; 13:1013740. [PMID: 36330092 PMCID: PMC9622800 DOI: 10.3389/fphar.2022.1013740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular diseases are the leading cause of global mortality, in which myocardial infarction accounts for 46% of total deaths. Although good progress has been achieved in medication and interventional techniques, a proven method to repair the damaged myocardium has not yet been determined. Stem cell therapy for damaged myocardial repair has evolved into a promising treatment for ischemic heart disease. However, low retention and poor survival of the injected stem cells are the major obstacles to achieving the intended therapeutic effects. Chinese botanical and other natural drug substances are a rich source of effective treatment for various diseases. As such, numerous studies have revealed the role of Chinese medicine in stem cell therapy for myocardial infarction treatment, including promoting proliferation, survival, migration, angiogenesis, and differentiation of stem cells. Here, we discuss the potential and limitations of stem cell therapy, as well as the regulatory mechanism of Chinese medicines underlying stem cell therapy. We focus on the evidence from pre-clinical trials and clinical practices, and based on traditional Chinese medicine theories, we further summarize the mechanisms of Chinese medicine treatment in stem cell therapy by the commonly used prescriptions. Despite the pre-clinical evidence showing that traditional Chinese medicine is helpful in stem cell therapy, there are still some limitations of traditional Chinese medicine therapy. We also systematically assess the detailed experimental design and reliability of included pharmacological research in our review. Strictly controlled animal models with multi-perspective pharmacokinetic profiles and high-grade clinical evidence with multi-disciplinary efforts are highly demanded in the future.
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Affiliation(s)
- Yu Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuezhen Xue
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Hai-dong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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13
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Yang F, Xue J, Wang G, Diao Q. Nanoparticle-based drug delivery systems for the treatment of cardiovascular diseases. Front Pharmacol 2022; 13:999404. [PMID: 36172197 PMCID: PMC9512262 DOI: 10.3389/fphar.2022.999404] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular disease is the most common health problem worldwide and remains the leading cause of morbidity and mortality. Despite recent advances in the management of cardiovascular diseases, pharmaceutical treatment remains suboptimal because of poor pharmacokinetics and high toxicity. However, since being harnessed in the cancer field for the delivery of safer and more effective chemotherapeutics, nanoparticle-based drug delivery systems have offered multiple significant therapeutic effects in treating cardiovascular diseases. Nanoparticle-based drug delivery systems alter the biodistribution of therapeutic agents through site-specific, target-oriented delivery and controlled drug release of precise medicines. Metal-, lipid-, and polymer-based nanoparticles represent ideal materials for use in cardiovascular therapeutics. New developments in the therapeutic potential of drug delivery using nanoparticles and the application of nanomedicine to cardiovascular diseases are described in this review. Furthermore, this review discusses our current understanding of the potential role of nanoparticles in metabolism and toxicity after therapeutic action, with a view to providing a safer and more effective strategy for the treatment of cardiovascular disease.
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Affiliation(s)
- Fangyu Yang
- Department of Clinical Laboratory Medicine, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Jianjiang Xue
- Department of Clinical Laboratory Medicine, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Guixue Wang
- Key Laboratory for Bio-Rheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China
| | - Qizhi Diao
- Department of Clinical Laboratory Medicine, Sanya Women and Children’s Hospital Managed by Shanghai Children’s Medical Center, Hainan, China
- *Correspondence: Qizhi Diao,
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14
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Effectiveness of exosome mediated miR-126 and miR-146a delivery on cardiac tissue regeneration. Cell Tissue Res 2022; 390:71-92. [PMID: 35788900 DOI: 10.1007/s00441-022-03663-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 06/22/2022] [Indexed: 11/02/2022]
Abstract
Despite advances in the treatment of acute myocardial infarction, due to the non-proliferative nature of adult cardiomyocytes, the injured myocardium is mainly replaced by fibrotic tissue, which ultimately causes heart failure. To prevent heart failure, particularly after myocardial infarction, exosome-based therapy has emerged as one of the most promising strategies to regenerate cardiac function. Exosomes can carry microRNAs in support of neovascularization, anti-inflammatory, and endogenous cardiac regeneration. This study demonstrated that animal rat models' combination treatment with microRNA-126 and microRNA-146a mimics in exosomes is desirable for cardiac regeneration after myocardial infarction. The exosomes isolated from stem cells and loaded with microRNAs were characterized their impacts in cell migration, tube formation, and vascular endothelial growth factor degree. In the following, the usefulness of loaded microRNAs in exosomes and their encapsulation within alginate derivative hydrogel was analyzed in myocardial infarction for an animal model. Exosomes isolated and loaded with microRNAs showed the synergetic impact on cell migration, tube formation, and promoted vascular endothelial growth factor folding. Moreover, microRNAs loaded exosomes and encapsulated them in alginate hydrogel could help in reducing infarct size and improving angiogenesis in myocardial infarction. The angiogenesis markers including CD31 and connexion 43 upregulated for myocardial infarction models treated with alginate-based hydrogels loaded with exosomes and microRNAs-exosomes. Histological analysis indicated that myocardial infarction model rats treated with alginate hydrogel loaded with microRNAs-exosomes possessed lower and higher degrees of fibrosis and collagen fiber, respectively. These findings have important therapeutic implications for a myocardial infarction model through angiogenesis and vascular integrity regulation.
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15
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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16
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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17
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Mathur A, Sim DS, Choudry F, Veerapen J, Colicchia M, Turlejski T, Hussain M, Hamshere S, Locca D, Rakhit R, Crake T, Kastrup J, Agrawal S, Jones DA, Martin J. Five‐year follow‐up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE‐AMI trial. ESC Heart Fail 2022; 9:1152-1159. [PMID: 35043578 PMCID: PMC8934988 DOI: 10.1002/ehf2.13786] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/18/2021] [Accepted: 12/13/2021] [Indexed: 12/22/2022] Open
Abstract
Aims The long‐term outcomes of the intracoronary delivery of autologous bone marrow‐derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE‐AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo. Methods and results A 5 year follow‐up of major adverse cardiac events (defined as the composite of all‐cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC‐treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non‐cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group. Conclusion This 5 year follow‐up analysis of the REGENERATE‐AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.
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Affiliation(s)
- Anthony Mathur
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Doo Sun Sim
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiovascular Medicine Chonnam National University Hospital, Chonnam National University School of Medicine Gwangju Korea
| | - Fizzah Choudry
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Jessry Veerapen
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Martina Colicchia
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Tymoteusz Turlejski
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Mohsin Hussain
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Stephen Hamshere
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Didier Locca
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- École Polytechnique Fédérale de Lausanne Lausanne Switzerland
| | - Roby Rakhit
- Department of Cardiology The Royal Free Hospital, Royal Free London Foundation Trust London UK
| | - Tom Crake
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
| | - Jens Kastrup
- Rigshospitalet and University of Copenhagen Copenhagen Denmark
| | - Samir Agrawal
- Haemato‐Oncology, Barts Health NHS Trust & Immunobiology, Blizard Institute Queen Mary University of London London UK
| | - Daniel A. Jones
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute Queen Mary University of London London UK
- Department of Cardiology Barts Heart Centre, Barts Health NHS Trust London UK
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18
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Genome-wide methylome pattern predictive network analysis reveal mesenchymal stem cell's propensity to undergo cardiovascular lineage. 3 Biotech 2022; 12:12. [PMID: 34966635 PMCID: PMC8660944 DOI: 10.1007/s13205-021-03058-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 11/07/2021] [Indexed: 01/03/2023] Open
Abstract
Mesenchymal stem cells (MSCs) differentiation toward cardiovascular lineage prediction using the global methylome profile will highlight its prospective utility in regenerative medicine. We examined the propensity prediction to cardiovascular lineage using 5-Aza, a well-known cardiac lineage inducer. The customized 180 K microarray was performed and further analysis of global differentially methylated regions by Ingenuity pathway analysis (IPA) in both MSCs and 5-AC-treated MSCs. The cluster enrichment tools sorted differentially enriched genes and further annotated to construct the interactive networks. Prediction analysis revealed pathways pertaining to the cardiovascular lineage found active in the native MSCs, suggesting its higher propensity to undergo cardiac, smooth muscle cell, and endothelial lineages in vitro. Interestingly, gene interaction network also proposed majorly stemness gene network NANOG and KLF6, cardiac-specific transcription factors GATA4, NKX2.5, and TBX5 were upregulated in the native MSCs. Furthermore, the expression of cardiovascular lineage specific markers such as Brachury, CD105, CD90, CD31, KDR and various forms of ACTIN (cardiac, sarcomeric, smooth muscle) were validated in native MSCs using real time PCR and immunostaining and blotting analysis. In 5-AC-treated MSCs, mosaic interactive networks were observed to persuade towards osteogenesis and cardiac lineage, indicating that 5-AC treatment resulted in nonspecific lineage induction in MSCs, while MSCs by default have a higher propensity to undergo cardiovascular lineage. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s13205-021-03058-2.
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19
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Hobby ARH, Berretta RM, Eaton DM, Kubo H, Feldsott E, Yang Y, Headrick AL, Koch KA, Rubino M, Kurian J, Khan M, Tan Y, Mohsin S, Gallucci S, McKinsey TA, Houser SR. Cortical bone stem cells modify cardiac inflammation after myocardial infarction by inducing a novel macrophage phenotype. Am J Physiol Heart Circ Physiol 2021; 321:H684-H701. [PMID: 34415185 PMCID: PMC8794230 DOI: 10.1152/ajpheart.00304.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/30/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound-healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably macrophage colony-stimulating factor (M-CSF) and transforming growth factor-β, but not IL-4. CBSC therapy increased the number of galectin-3+ macrophages, CD4+ T cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a proreparative phenotype are characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-β, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased α-smooth muscle actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function.NEW & NOTEWORTHY Cortical bone stem cell (CBSC) therapy after myocardial infarction alters the inflammatory response to cardiac injury. We found that cortical bone stem cell therapy induces a unique macrophage phenotype in vitro and can modulate macrophage/fibroblast cross talk.
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Affiliation(s)
- Alexander R H Hobby
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Remus M Berretta
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Deborah M Eaton
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Hajime Kubo
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Eric Feldsott
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Yijun Yang
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Alaina L Headrick
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Keith A Koch
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Marcello Rubino
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Justin Kurian
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Mohsin Khan
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Yinfei Tan
- Genomic Facility, Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Sadia Mohsin
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Department of Pharmacology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Stefania Gallucci
- Department of Microbiology & Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Timothy A McKinsey
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Steven R Houser
- Department of Physiology, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
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20
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Mulvany E, McMahan S, Xu J, Yazdani N, Willits R, Liao J, Zhang G, Hong Y. In vitro comparison of harvesting site effects on cardiac extracellular matrix hydrogels. J Biomed Mater Res A 2021; 109:1922-1930. [PMID: 33822464 PMCID: PMC9789793 DOI: 10.1002/jbm.a.37184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/04/2021] [Accepted: 03/24/2021] [Indexed: 12/26/2022]
Abstract
Cardiac extracellular matrix (cECM) derived hydrogel has been investigated to treat myocardial infarction through animal studies and clinical trials. The tissue harvesting site commonly selects porcine left ventricle (LV) because heart attack majorly takes place in LV. However, little is known about whether the region of cardiac tissue harvesting is critical for downstream applications. In this work, in vitro studies to compare cECM hydrogels derived from adult porcine whole heart (WH), LV, and right ventricle (RV) were performed. The cECM from WH has similar chemical composition compared with cECM from LV and RV. All three types of cECM hydrogels share many similarities in terms of their microstructure, gelation time, and mechanical properties. WH-derived cECM hydrogels have larger variations in storage modulus (G') and complex modulus (G*) compared with the other two types of cECM hydrogels. Both human cardiomyocytes and mesenchymal stem cells could maintain high cell viability on all hydrogels without significant difference. In terms of above results, the cECM hydrogels from WH, LV and RV exhibited similarity in material properties and cell response in vitro. Thus, future fabrication of cECM hydrogels from WH would increase the yield, which would decrease processing time and production cost.
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Affiliation(s)
- Emily Mulvany
- Department of Biomedical Engineering, The University of Akron, Ohio, OH 44325
| | - Sara McMahan
- Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019
| | - Jiazhu Xu
- Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019
| | - Narges Yazdani
- Department of Biomedical Engineering, The University of Akron, Ohio, OH 44325
| | - Rebecca Willits
- Department of Biomedical Engineering, The University of Akron, Ohio, OH 44325
| | - Jun Liao
- Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019
| | - Ge Zhang
- Department of Biomedical Engineering, The University of Akron, Ohio, OH 44325,Corresponding authors: Yi Hong, , Phone: 01-817-272-0562; Ge Zhang, , phone: 01-330-972-5237
| | - Yi Hong
- Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019,Corresponding authors: Yi Hong, , Phone: 01-817-272-0562; Ge Zhang, , phone: 01-330-972-5237
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21
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Uribe-Juárez O, Godínez R, Morales-Corona J, Velasco M, Olayo-Valles R, Acosta-García MC, Alvarado EJ, Miguel-Alavez L, Carrillo-González OJ, Flores-Sánchez MG, Olayo R. Application of plasma polymerized pyrrole nanoparticles to prevent or reduce de-differentiation of adult rat ventricular cardiomyocytes. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2021; 32:121. [PMID: 34499229 PMCID: PMC8429391 DOI: 10.1007/s10856-021-06595-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/16/2021] [Indexed: 06/13/2023]
Abstract
Cardiovascular diseases are the leading cause of death in the world, cell therapies have been shown to recover cardiac function in animal models. Biomaterials used as scaffolds can solve some of the problems that cell therapies currently have, plasma polymerized pyrrole (PPPy) is a biomaterial that has been shown to promote cell adhesion and survival. The present research aimed to study PPPy nanoparticles (PPPyN) interaction with adult rat ventricular cardiomyocytes (ARVC), to explore whether PPPyN could be employed as a nanoscaffold and develop cardiac microtissues. PPPyN with a mean diameter of 330 nm were obtained, the infrared spectrum showed that some pyrrole rings are fragmented and that some fragments of the ring can be dehydrogenated during plasma synthesis, it also showed the presence of amino groups in the structure of PPPyN. PPPyN had a significant impact on the ARVC´s shape, delaying dedifferentiation, necrosis, and apoptosis processes, moreover, the cardiomyocytes formed cell aggregates up to 1.12 mm2 with some aligned cardiomyocytes and generated fibers on its surface similar to cardiac extracellular matrix. PPPyN served as a scaffold for adult ARVC. Our results indicate that PPPyN-scaffold is a biomaterial that could have potential application in cardiac cell therapy (CCT).
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Affiliation(s)
- Omar Uribe-Juárez
- Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México.
| | - Rafael Godínez
- Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - Juan Morales-Corona
- Departamento de Física, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - Myrian Velasco
- Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Av. Universidad 3000, Col Ciudad Universitaria, Del. Coyoacán, C. P. 04510, Ciudad de México, México
| | - Roberto Olayo-Valles
- Departamento de Física, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - M C Acosta-García
- Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - E J Alvarado
- Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - Luis Miguel-Alavez
- Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - Oscar-J Carrillo-González
- Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
| | - María G Flores-Sánchez
- Facultad de Ingeniería, Vicerrectoría de Investigación, Universidad La Salle México, Benjamín Franklin 45, Col. Condesa, Del. Cuauhtémoc, C. P. 06140, Ciudad de México, México
| | - Roberto Olayo
- Departamento de Física, Universidad Autónoma Metropolitana, Av. San Rafael Atlixco 186, Col. Leyes de Reforma 1ra Secc., Del. Iztapalapa, C. P. 09340, Ciudad de México, México
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22
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Affiliation(s)
- Mircea Cinteza
- Department of Cardiology, Emergency University Hospital, Bucharest, Romania
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23
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Ivankovic I, Déan-Ben XL, Haas H, Kimm MA, Wildgruber M, Razansky D. Volumetric Optoacoustic Tomography Differentiates Myocardial Remodelling. Mol Imaging Biol 2021; 22:1235-1243. [PMID: 32394284 DOI: 10.1007/s11307-020-01498-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Myocardial healing following myocardial infarction (MI) is a complex process that is yet to be fully understood. Clinical attempts in regeneration of the injured myocardium using cardiac stem cells faced major challenges, calling for a better understanding of the processes involved at a more basic level in order to foster translation. PROCEDURES We examined the feasibility of volumetric optoacoustic tomography (VOT) in studying healing of the myocardium in different models of MI, including permanent occlusion (PO) of the left coronary artery, temporary occlusion (ischemia-reperfusion-I/R) and infarcted c-kit mutants, a genetic mouse model with impaired cardiac healing. Murine hearts were imaged at 100 Hz frame rate using 800 nm excitation wavelength, corresponding to the peak absorption of indocyanine green (ICG) in plasma and the isosbestic point of haemoglobin. RESULTS The non-invasive real-time volumetric imaging capabilities of VOT have allowed the detection of significant variations in the pulmonary transit time (PTT), a parameter affected by MI, across different murine models. Upon intravenous injection of ICG, we were able to track alterations in cardiac perfusion in I/R models, which were absent in wild-type (wt) PO or kitW/kitW-v PO mice. The wt-PO and I/R models further exhibited irregularities in their cardiac cycles. CONCLUSIONS Clear differences in the PTT, ICG perfusion and cardiac cycle patterns were identified between the different models and days post MI. Overall, the results highlight the unique capacity of VOT for multi-parametric characterization of morphological and functional changes in murine models of MI.
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Affiliation(s)
- Ivana Ivankovic
- Faculty of Medicine and Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Institute for Biomedical Engineering and Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland
| | - Xosé Luís Déan-Ben
- Faculty of Medicine and Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Institute for Biomedical Engineering and Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland
| | - Helena Haas
- Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar Technical University of Munich, Munich, Germany
| | - Melanie A Kimm
- Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar Technical University of Munich, Munich, Germany
| | - Moritz Wildgruber
- Department of Diagnostic and Interventional Radiology, Klinikum Rechts der Isar Technical University of Munich, Munich, Germany
- Translational Research Imaging Center, Department of Clinical Radiology, Universitätsklinikum Münster, Munster, Germany
| | - Daniel Razansky
- Faculty of Medicine and Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
- Institute for Biomedical Engineering and Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland.
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Abstract
Cardiovascular diseases top the list of fatal illnesses worldwide. Cardiac tissues is known to be one of te least proliferative in the human body, with very limited regenraive capacity. Stem cell therapy has shown great potential for treatment of cardiovascular diseases in the experimental setting, but success in human trials has been limited. Applications of stem cell therapy for cardiovascular regeneration necessitate understamding of the complex and unique structure of the heart unit, and the embryologic development of the heart muscles and vessels. This chapter aims to provide an insight into cardiac progenitor cells and their potential applications in regenerative medicine. It also provides an overview of the embryological development of cardiac tissue, and the major findings on the development of cardiac stem cells, their characterization, and differentiation, and their regenerative potential. It concludes with clinical applications in treating cardiac disease using different approaches, and concludes with areas for future research.
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Intramyocardial delivery of human cardiac stem cell spheroids with enhanced cell engraftment ability and cardiomyogenic potential for myocardial infarct repair. J Control Release 2021; 336:499-509. [PMID: 34224774 DOI: 10.1016/j.jconrel.2021.06.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 06/18/2021] [Accepted: 06/25/2021] [Indexed: 12/13/2022]
Abstract
Strategies for stem cell-based cardiac regeneration and repair are key issues for the ischemic heart disease (IHD) patients with chronic complications related to ischemic necrosis. Cardiac stem cells (CSCs) have demonstrated high therapeutic efficacy for IHD treatment owing to their specific cardiac-lineage commitment. The therapeutic potential of CSCs could be further enhanced by designing a cellular spheroid formulation. The spheroid culture condition of CSCs was optimized to ensure regulated size and minimal core necrosis in the spheroids. The CSC spheroids revealed mRNA profiles of the factors related to cardiac regeneration, angiogenesis, anti-inflammatory, and cardiomyocyte differentiation with a higher expression level than the CSCs. Intramyocardially delivered CSC spheroids in the rat IHD model resulted in a significant increase in retention rate by 1.82-fold (day 3) and 1.98-fold (day 14) compared to CSCs. Endothelial cell differentiation and neovascularization of the engrafted CSC spheroids were noted in the infarcted myocardium. CSC spheroids significantly promoted cardiac regeneration: i.e., decreased infarction and fibrotic area (11.22% and 4.18%) and increased left ventricle thickness (0.62 mm) compared to the untreated group. Cardiac performance was also improved by 2.04-fold and 1.44-fold increase in the ejection fraction and fractional shortening, respectively. Intramyocardial administration of CSC spheroids might serve as an advanced therapeutic modality with enhanced cell engraftment and regenerative abilities for cardiac repair after myocardial infarction.
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Khalifa AA, Rashad RM, El-Hadidy WF. Thymoquinone protects against cardiac mitochondrial DNA loss, oxidative stress, inflammation and apoptosis in isoproterenol-induced myocardial infarction in rats. Heliyon 2021; 7:e07561. [PMID: 34355083 PMCID: PMC8322274 DOI: 10.1016/j.heliyon.2021.e07561] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 03/28/2021] [Accepted: 07/09/2021] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Myocardial infarction (MI) is an ischemic life-threatening disease with exaggerated oxidative stress state that vigorously damages the cardiomyocyte membrane and subcellular structures, including the vital mitochondrial DNA (mtDNA). The mtDNA is responsible for the proper functionality of the mitochondria, which are abundant in cardiomyocytes due to their dynamic nature and energy production requirements. Furthermore, oxidative stress triggers an inflammatory cascade and eventual apoptosis, which exacerbates cardiac injuries and dysfunction. AIM The present study used an isoproterenol (ISP)-induced MI rat model to investigate the role of the main active constituent of Nigella Sativa seeds, thymoquinone (TQ), in preserving the cardiac mtDNA content and ameliorating oxidative stress, inflammation, and apoptosis. METHODS Rats in the (TQ + ISP) group were pre-treated with TQ (20 mg/kg/day) for 21 days before the MI induction using ISP (85 mg/kg/day). In addition, negative control and ISP groups were included in the study for comparison. A histopathological examination was performed and serum cardiac parameters (cTnI and LDH) were assessed. In addition, mtDNA content, oxidative stress parameters (MDA, GSH, SOD, GPx, and CAT), inflammatory mediators (IL-6, IL-1β, and TNF-α), and apoptosis markers (BAX, Bcl2, and caspase-3) were detected. RESULTS The results showed that pre- and co-treatment with TQ in the (TQ + ISP) group reversed the histoarchitecture changes, caused a significant decrease in serum cardiac markers, oxidative stress markers, inflammatory cytokines, the apoptosis process, and preserved the cardiac mtDNA content. CONCLUSION TQ is a cardioprotective agent with an extended effect on preserving the cardiac mtDNA content, in addition to its powerful antioxidant, anti-inflammatory, and anti-apoptotic action.
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Affiliation(s)
- Asmaa A. Khalifa
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Egypt
| | - Radwa M. Rashad
- Department of Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Wessam F. El-Hadidy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Egypt
- Department of Pharmacology and Experimental Therapeutics, Medical Research Institute, Alexandria University, Alexandria, Egypt
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27
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Zhang Q, Wang C, Cheema ZM, Kutryk MJB. An optimal non-viral gene transfer method for genetically modifying porcine bone marrow-derived endothelial progenitor cells for experimental therapeutics. Sci Prog 2021; 104:368504211024113. [PMID: 34283683 PMCID: PMC10358567 DOI: 10.1177/00368504211024113] [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] [Indexed: 11/15/2022]
Abstract
No currently available treatment is able to generate new contractile tissue or significantly improve cardiac function after myocardial infarction (MI), a leading cause of morbidity and mortality worldwide. Although gene transfer-enhanced endothelial progenitor cells (GTE-EPCs) show effectiveness in MI treatment in small animal models, no clinical trials using GTE-EPCs have been documented. Before the introduction of GTE-EPCs into human trials, gene-transfer-mediated augmentation of EPC function in animal models that reflect the human MI scenario should be tested. In this regard, a porcine model is the best choice since pigs have cardiac size, hemodynamics and coronary anatomy similar to that of humans. To examine GTE-EPC therapeutic efficacy in pig MI models, an efficient method for gene transfer into pig EPCs is required, which however, has been poorly documented. Pig bone marrow mononuclear cells were isolated and cultured in EGM-2 medium to obtain bone marrow-derived EPCs (BM-EPCs) that were characterized by immunostaining and the tube formation assay. Gene transfer was optimized in 6-well plates using a GFP and a VEGF plasmid, and scaled up in T75 flasks. Gene transfer efficiency was determined by fluorescence microscopy and flow cytometry. VEGF levels were measured by ELISA. Cell proliferation was assayed by the CCK-8 kit. (1) BM-EPCs expressed VEGFR2 and eNOS but not CD45 protein, and formed tube structures on Matrigel; (2) several chemical compounds were explored with the highest transfection efficiency of 41.4% ± 5.8% achieved using Lipofectamine 3000; (3) the VEGF level in culture medium after VEGF transfection was 378 ± 48 ng/106 cells; and (4) BM-EPCs overexpressing VEGF had significantly enhanced proliferation than GFP-transfected EPCs. A simple, easy and cheap method that can be applied to produce a large number of genetically-modified BM-EPCs was established, which will facilitate the study of GTE-EPC therapeutic efficacy in pig MI model.
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Affiliation(s)
- Qiuwang Zhang
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Chenxi Wang
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Zayed M Cheema
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Michael JB Kutryk
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
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28
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Increased Myocardial Retention of Mesenchymal Stem Cells Post-MI by Pre-Conditioning Exercise Training. Stem Cell Rev Rep 2021; 16:730-741. [PMID: 32306279 DOI: 10.1007/s12015-020-09970-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Stem cell (SC) therapy is a promising approach to improve post-myocardial infarction (MI) cardiac remodeling, but the proinflammatory microenvironment may lead to SC loss and, therefore, may have a negative impact on therapy. It appears that exercise training (ET) improves myocardial microenvironment for SC transplantation. Therefore, we tested the effect of ET on post-infarction retention of adipose-derived SCs (ADSCs) and its combined effects on the inflammatory microenvironment. Fischer-344 female rats were randomized to one of the following groups: Sham; sedentary coronary occlusion who did not receive ADSCs (sMI); sedentary coronary occlusion who received ADSCs; exercise coronary occlusion who received ADSCs. Rats were trained nine weeks prior to MI, followed by ADSCs transplantation. The MI led to left ventricle (LV) dilation and dysfunction, myocardial hypertrophy and fibrosis, and increased proinflammatory profile compared to Sham rats. Conversely, ADSCs transplanted rats exhibited, better morphological and functional LV parameters; inhibition of myocardial hypertrophy and fibrosis; and attenuation of proinflammatory cytokines (interleukins 1β and 10, tumor necrosis factor α, and transforming growth factor β) in the myocardium compared to sMI rats. Interestingly, ET enhanced the effect of ADSCs on interleukin 10 expression. There was a correlation between cytokine expression and myocardial ADSCs retention. The. ET enhanced the beneficial effects of ADSCs in infarcted myocardium, which was associated with higher ADSCs retention. These findings highlight the importance of ET in myocardial retention of ADSCs and attenuation of cardiac remodeling post-infarction. Cytokine analysis suggests improvement in ET-linked myocardial microenvironment based on its anti-inflammatory action.
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29
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Hassanpour M, Fathi Karkan S, Rahbarghazi R, Nouri M, Amini H, Saghati S, Baradar Khoshfetrat A. Culture of rabbit bone marrow mesenchymal stem cells on polyurethane/pyrrole surface promoted differentiation into endothelial lineage. Artif Organs 2021; 45:E324-E334. [PMID: 33908072 DOI: 10.1111/aor.13971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/19/2021] [Accepted: 03/24/2021] [Indexed: 12/22/2022]
Abstract
Due to the electrical conductivity, pyrrole-based scaffolds are one of the attractive biomaterials in the regeneration of electrically active tissues like the heart and brain. Here, we investigated the impact of polyurethane/pyrrole scaffold on the angiogenesis differentiation of rabbit mesenchymal stem cells toward endothelial lineage in vitro. Nanoelectrospun polyurethane/pyrrole fibers were synthesized and characterized using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrum analysis, scanning electron microscope (SEM) imaging. Mechanical properties, electroconductivity, and hydrophobicity were also measured. The viability of cells was monitored 72 hours after being plated on the polyurethane/pyrrole surface. The endothelial differentiation of stem cells was explored using western blotting. ATR-FTIR revealed that the pyrrole was successfully polymerized to polypyrrole and blend with polyurethane fibers. The addition of pyrrole to polyurethane increased the tensile strength compared to the polyurethane group. These features coincided with the reduction of the hydrophilic properties of polyurethane. Based on our data, the electro-conductivity of polyurethane/pyrrole was superior compared to the polyurethane group. SEM imaging showed an appropriate cell attachment to the surface of polyurethane/pyrrole and polyurethane groups synthesized membranes. MTT assay revealed a significantly increased survival rate in the polyurethane/pyrrole group compared to the polyurethane group (P < .05). We noted a statistically significant increase of endothelial-associated proteins, CD31, von Willebrand factor, and CD34, in cells expanded on polyurethane/pyrrole compared to the polyurethane group (P < .05). As a more general note, it could be hypothesized that the polyurethane/pyrrole blend could improve the angiogenesis potency of rabbit bone marrow mesenchymal stem cells for regenerative purposes.
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Affiliation(s)
- Mehdi Hassanpour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sonia Fathi Karkan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Amini
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Saghati
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Wang Q, Wang K, Zhao X. Monocytes recruitment blocking synergizes with mesenchymal stem cell transplantation for treating myocardial infarction. Regen Med 2021; 16:9-17. [PMID: 33560157 DOI: 10.2217/rme-2020-0047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background: Mesenchymal stem cell (MSC) transplantation is a promising therapeutic approach for acute myocardial infarction (AMI), however, research to date has demonstrated unsatisfactory results. Materials & methods: An AMI mouse model was established via left coronary artery ligation. AMI mice were treated with MSCs, anti-CCR2 or MSCs + anti-CCR2 and the effects of each treatment group were compared. Macrophage infiltration was analyzed by immunofluorescence staining and flow cytometry. Results: Implantation of MSCs + anti-CCR2 yielded a greater improvement in cardiac function and significantly reduced macrophage accumulation in the infarct site of AMI mice compared with the injection of MSCs or anti-CCR2 alone. Moreover, reduced macrophage infiltration was accompanied by reduced pro-inflammatory cytokine secretion in the injury sites and the low inflammatory response favored tissue regeneration. Conclusion: Treatment with MSCs and anti-CCR2 in combination may be a promising therapeutic strategy for AMI.
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Affiliation(s)
- Qian Wang
- Department of Cardiology, Changhai Hospital, Naval Medical University, No.168 Changhai Road, Shanghai 200433, China
| | - Ke Wang
- Department of Cardiology, Changhai Hospital, Naval Medical University, No.168 Changhai Road, Shanghai 200433, China
| | - Xianxian Zhao
- Department of Cardiology, Changhai Hospital, Naval Medical University, No.168 Changhai Road, Shanghai 200433, China
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31
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Laundos TL, Vasques-Nóvoa F, Gomes RN, Sampaio-Pinto V, Cruz P, Cruz H, Santos JM, Barcia RN, Pinto-do-Ó P, Nascimento DS. Consistent Long-Term Therapeutic Efficacy of Human Umbilical Cord Matrix-Derived Mesenchymal Stromal Cells After Myocardial Infarction Despite Individual Differences and Transient Engraftment. Front Cell Dev Biol 2021; 9:624601. [PMID: 33614654 PMCID: PMC7890004 DOI: 10.3389/fcell.2021.624601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/11/2021] [Indexed: 11/24/2022] Open
Abstract
Human mesenchymal stem cells gather special interest as a universal and feasible add-on therapy for myocardial infarction (MI). In particular, human umbilical cord matrix-derived mesenchymal stromal cells (UCM-MSC) are advantageous since can be easily obtained and display high expansion potential. Using isolation protocols compliant with cell therapy, we previously showed UCM-MSC preserved cardiac function and attenuated remodeling 2 weeks after MI. In this study, UCM-MSC from two umbilical cords, UC-A and UC-B, were transplanted in a murine MI model to investigate consistency and durability of the therapeutic benefits. Both cellular products improved cardiac function and limited adverse cardiac remodeling 12 weeks post-ischemic injury, supporting sustained and long-term beneficial therapeutic effect. Donor associated variability was found in the modulation of cardiac remodeling and activation of the Akt-mTOR-GSK3β survival pathway. In vitro, the two cell products displayed similar ability to induce the formation of vessel-like structures and comparable transcriptome in normoxia and hypoxia, apart from UCM-MSCs proliferation and expression differences in a small subset of genes associated with MHC Class I. These findings support that UCM-MSC are strong candidates to assist the treatment of MI whilst calling for the discussion on methodologies to characterize and select best performing UCM-MSC before clinical application.
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Affiliation(s)
- Tiago L. Laundos
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Francisco Vasques-Nóvoa
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Cardiovascular RandD Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Internal Medicine, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Rita N. Gomes
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Vasco Sampaio-Pinto
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | | | | | | | | | - Perpétua Pinto-do-Ó
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Diana S. Nascimento
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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Hassanpour M, Aghamohamadzade N, Cheraghi O, Heidarzadeh M, Nouri M. Current status of cardiac regenerative medicine; An update on point of view to cell therapy application. J Cardiovasc Thorac Res 2021; 12:256-268. [PMID: 33510874 PMCID: PMC7828760 DOI: 10.34172/jcvtr.2020.44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 09/19/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death globally. Because of the economic and social burden of acute myocardial infarction and its chronic consequences in surviving patients, understanding the pathophysiology of myocardial infarction injury is a major priority for cardiovascular research. MI is defined as cardiomyocytes death caused by an ischemic that resulted from the apoptosis, necrosis, necroptosis, and autophagy. The phases of normal repair following MI including inflammatory, proliferation, and maturation. Normal repair is slow and inefficient generally so that other treatments are required. Because of difficulties, outcomes, and backwashes of traditional therapies including coronary artery bypass grafting, balloon angioplasty, heart transplantation, and artificial heart operations, the novel strategy in the treatment of MI, cell therapy, was newly emerged. In cell therapy, a new population of cells has created that substitute with damaged cells. Different types of stem cell and progenitor cells have been shown to improve cardiac function through various mechanisms, including the formation of new myocytes, endothelial cells, and vascular smooth muscle cells. Bone marrow- and/or adipose tissue-derived mesenchymal stem cells, embryonic stem cells, autologous skeletal myoblasts, induced pluripotent stem cells, endothelial progenitor cells, cardiac progenitor cells and cardiac pericytes considered as a source for cell therapy. In this study, we focused on the point of view of the cell sources.
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Affiliation(s)
- Mehdi Hassanpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Omid Cheraghi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | | | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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Riaud M, Martinez MC, Montero-Menei CN. Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction. Pharmaceutics 2020; 12:E1195. [PMID: 33317141 PMCID: PMC7763019 DOI: 10.3390/pharmaceutics12121195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022] Open
Abstract
Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory actions, make it possible to act on all the damages caused by ischemia. The evolution of biomaterial engineering allows us to envisage their association with new major players in cardiac therapy, extracellular vesicles, in order to limit undesirable effects and to envisage a transfer to the clinic. This new therapeutic approach could be associated with the release of growth factors to potentialized the beneficial effect obtained.
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Affiliation(s)
- Melody Riaud
- SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, F-49800 Angers, France;
- CRCINA, UMR 1232, INSERM, Université de Nantes, Université d’Angers, F-49933 Angers, France
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Cacciapuoti M, Johnson B, Kapdia A, Powell S, Gallicano GI. The Role of Neuregulin and Stem Cells as Therapy Post-Myocardial Infarction. Stem Cells Dev 2020; 29:1266-1274. [PMID: 32731805 DOI: 10.1089/scd.2020.0099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Coronary artery disease, including myocardial infarction (MI), is a leading cause of morbidity and mortality in the United States. Due to the limited self-renewal capacity of cardiac tissue, MIs can lead to progressive heart disease with a lasting impact on health and quality of life. The recent discovery of cardiac stem cells has incited research into their potential therapeutic applications for patients suffering from cardiovascular disease. Studies have demonstrated the ability of stem cells to both generate cardiac tissues in vitro and aid in the recovery of cardiovascular function in vivo in animal models. However, the long-term efficacy of stem cells as regenerative therapy is still unknown. Exploration of alternative therapies is underway, including the use of cardiac growth factor neuregulin-1 (NRG-1). Research has demonstrated that NRG-1 not only has direct effects on cardiomyocytes (CM) but also acts within the tissues supporting the CM. Transplantation of NRG-1 into ischemic cardiac tissue mitigates the progression of heart failure and can reverse cardiac remodeling. Recent publications have sought to study the combined use of these agents, and while the results are promising, they do warrant further research. This review aims to consider these therapies separately as well as in combination.
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Affiliation(s)
- Maria Cacciapuoti
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Bria Johnson
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Anjani Kapdia
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Sarah Powell
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - G Ian Gallicano
- Georgetown University School of Medicine, Washington, District of Columbia, USA
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Hume RD, Chong JJH. The Cardiac Injury Immune Response as a Target for Regenerative and Cellular Therapies. Clin Ther 2020; 42:1923-1943. [PMID: 33010930 DOI: 10.1016/j.clinthera.2020.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/20/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Despite modern reperfusion and pharmacologic therapies, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Therefore, the development of further therapeutics affecting post-MI recovery poses significant benefits. This review focuses on the post-MI immune response and immunomodulatory therapeutics that could improve the wound-healing response. METHODS This narrative review used OVID versions of MEDLINE and EMBASE searching for clinical therapeutics targeting the immune system during MI. Preclinical models and clinical trials were included. Additional studies were sourced from the reference lists of relevant articles and other personal files. FINDINGS After MI, cardiomyocytes are starved of oxygen and undergo cell death via coagulative necrosis. This process activates the immune system and a multifaceted wound-healing response, comprising a number of complex and overlapping phases. Overactivation or persistence of one or more of these phases can have potentially lethal implications. This review describes the immune response post-MI and any adverse events that can occur during these different phases. Second, we describe immunomodulatory therapies that attempt to target these immune cell aberrations by mitigating or diminishing their effects on the wound-healing response. Also discussed are adult stem/progenitor cell therapies, exosomes, and regulatory T cells, and their immunomodulatory effects in the post-MI setting. IMPLICATIONS An updated understanding into the importance of various inflammatory cell phenotypes, coupled with new technologies, may hold promise for a new era of immunomodulatory therapeutics. The implications of such therapies could dramatically improve patients' quality of life post-MI and reduce the incidence of progressive heart failure.
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Affiliation(s)
- Robert D Hume
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW 2145, Australia
| | - James J H Chong
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW 2145, Australia; Department of Cardiology, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia.
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Wang J, Lee CJ, Deci MB, Jasiewicz N, Verma A, Canty JM, Nguyen J. MiR-101a loaded extracellular nanovesicles as bioactive carriers for cardiac repair. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2020; 27:102201. [PMID: 32278100 PMCID: PMC7647388 DOI: 10.1016/j.nano.2020.102201] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 02/25/2020] [Accepted: 03/16/2020] [Indexed: 12/19/2022]
Abstract
Myocardial infarction (MI) remains a major cause of mortality worldwide. Despite significant advances in MI treatment, many who survive the acute event are at high risk of chronic cardiac morbidity. Here we developed a cell-free therapeutic that capitalizes on the antifibrotic effects of micro(mi)RNA-101a and exploits the multi-faceted regenerative activity of mesenchymal stem cell (MSC) extracellular nanovesicles (eNVs). While the majority of MSC eNVs require local delivery via intramyocardial injection to exert therapeutic efficacy, we have developed MSC eNVs that can be administered in a minimally invasive manner, all while remaining therapeutically active. When loaded with miR-101a, MSC eNVs substantially decreased infarct size (9.2 ± 1.7% vs. 20.0 ± 6.5%) and increased ejection fraction (53.6 ± 7.6% vs. 40.3 ± 6.0%) and fractional shortening (23.6 ± 4.3% vs. 16.6 ± 3.0%) compared to control. These findings are significant as they represent an advance in the development of minimally invasive cardio-therapies.
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Affiliation(s)
- Jinli Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, USA; Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Christine J Lee
- Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Michael B Deci
- Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Natalie Jasiewicz
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anjali Verma
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - John M Canty
- Department of Medicine, Department of Physiology and Biophysics, Department of Biomedical Engineering, The Clinical and Translational Research Center of the University at Buffalo, Buffalo, NY, USA; VA Western New York Healthcare System, Buffalo, NY, USA
| | - Juliane Nguyen
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Fan C, Joshi J, Li F, Xu B, Khan M, Yang J, Zhu W. Nanoparticle-Mediated Drug Delivery for Treatment of Ischemic Heart Disease. Front Bioeng Biotechnol 2020; 8:687. [PMID: 32671049 PMCID: PMC7326780 DOI: 10.3389/fbioe.2020.00687] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/02/2020] [Indexed: 12/26/2022] Open
Abstract
The regenerative capacity of an adult cardiac tissue is insufficient to repair the massive loss of heart tissue, particularly cardiomyocytes (CMs), following ischemia or other catastrophic myocardial injuries. The delivery methods of therapeutics agents, such as small molecules, growth factors, exosomes, cells, and engineered tissues have significantly advanced in medical science. Furthermore, with the controlled release characteristics, nanoparticle (NP) systems carrying drugs are promising in enhancing the cardioprotective potential of drugs in patients with cardiac ischemic events. NPs can provide sustained exposure precisely to the infarcted heart via direct intramyocardial injection or intravenous injection with active targets. In this review, we present the recent advances and challenges of different types of NPs loaded with agents for the repair of myocardial infarcted heart tissue.
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Affiliation(s)
- Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jyotsna Joshi
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, United States
| | - Fan Li
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, United States
| | - Bing Xu
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, United States
| | - Mahmood Khan
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jinfu Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wuqiang Zhu
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, United States
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
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Fathi E, Valipour B, Vietor I, Farahzadi R. An overview of the myocardial regeneration potential of cardiac c-Kit + progenitor cells via PI3K and MAPK signaling pathways. Future Cardiol 2020; 16:199-209. [PMID: 32125173 DOI: 10.2217/fca-2018-0049] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In recent years, several studies have investigated cell transplantation as an innovative strategy to restore cardiac function following heart failure. Previous studies have also shown cardiac progenitor cells as suitable candidates for cardiac cell therapy compared with other stem cells. Cellular kit (c-kit) plays an important role in the survival and migration of cardiac progenitor cells. Like other types of cells, in the heart, cellular responses to various stimuli are mediated via coordinated pathways. Activation of c-kit+ cells leads to subsequent activation of several downstream mediators such as PI3K and the MAPK pathways. This review aims to outline current research findings on the role of PI3K/AKT and the MAPK pathways in myocardial regeneration potential of c-kit+.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behnaz Valipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ilja Vietor
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020, Innsbruck, Austria
| | - Raheleh Farahzadi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz 5166616471, Iran.,Hematology & Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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António N. Combining mesenchymal stem cell therapy and exercise training in myocardial infarction: The perfect symbiosis? Rev Port Cardiol 2019; 38:657-659. [PMID: 31785853 DOI: 10.1016/j.repc.2019.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Natália António
- Department of Cardiology, Coimbra Hospital and Universitary Center (Polo HUC), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal.
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40
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Boeri L, Albani D, Raimondi MT, Jacchetti E. Mechanical regulation of nucleocytoplasmic translocation in mesenchymal stem cells: characterization and methods for investigation. Biophys Rev 2019; 11:817-831. [PMID: 31628607 PMCID: PMC6815268 DOI: 10.1007/s12551-019-00594-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have immune-modulatory and tissue-regenerative properties that make them a suitable and promising tool for cell-based therapy application. Since the bio-chemo-mechanical environment influences MSC fate and behavior, the understanding of the mechanosensors involved in the transduction of mechanical inputs into chemical signals could be pivotal. In this context, the nuclear pore complex is a molecular machinery that is believed to have a key role in force transmission and in nucleocytoplasmic shuttling regulation. To fully understand the nuclear pore complex role and the nucleocytoplasmic transport dynamics, recent advancements in fluorescence microscopy provided the possibility to study passive and facilitated nuclear transports also in mechanically stimulated cell culture conditions. Here, we review the current available methods for the investigation of nucleocytoplasmic shuttling, including photo-perturbation-based approaches, fluorescence correlation spectroscopy, and single-particle tracking techniques. For each method, we analyze the advantages, disadvantages, and technical limitations. Finally, we summarize the recent knowledge on mechanical regulation of nucleocytoplasmic translocation in MSC, the relevant progresses made so far, and the future perspectives in the field.
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Affiliation(s)
- Lucia Boeri
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Piazza Leonardo da Vinci 32, 20123, Milan, Italy
| | - Diego Albani
- Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Manuela Teresa Raimondi
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Piazza Leonardo da Vinci 32, 20123, Milan, Italy
| | - Emanuela Jacchetti
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Piazza Leonardo da Vinci 32, 20123, Milan, Italy.
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41
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António N. Combining mesenchymal stem cell therapy and exercise training in myocardial infarction: The perfect symbiosis? REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2019. [DOI: 10.1016/j.repce.2019.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Li Z, Solomonidis EG, Meloni M, Taylor RS, Duffin R, Dobie R, Magalhaes MS, Henderson BEP, Louwe PA, D’Amico G, Hodivala-Dilke KM, Shah AM, Mills NL, Simons BD, Gray GA, Henderson NC, Baker AH, Brittan M. Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction. Eur Heart J 2019; 40:2507-2520. [PMID: 31162546 PMCID: PMC6685329 DOI: 10.1093/eurheartj/ehz305] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/12/2019] [Accepted: 04/25/2019] [Indexed: 12/11/2022] Open
Abstract
AIMS A better understanding of the pathways that regulate regeneration of the coronary vasculature is of fundamental importance for the advancement of strategies to treat patients with heart disease. Here, we aimed to investigate the origin and clonal dynamics of endothelial cells (ECs) associated with neovascularization in the adult mouse heart following myocardial infarction (MI). Furthermore, we sought to define murine cardiac endothelial heterogeneity and to characterize the transcriptional profiles of pro-angiogenic resident ECs in the adult mouse heart, at single-cell resolution. METHODS AND RESULTS An EC-specific multispectral lineage-tracing mouse (Pdgfb-iCreERT2-R26R-Brainbow2.1) was used to demonstrate that structural integrity of adult cardiac endothelium following MI was maintained through clonal proliferation by resident ECs in the infarct border region, without significant contributions from bone marrow cells or endothelial-to-mesenchymal transition. Ten transcriptionally discrete heterogeneous EC states, as well as the pathways through which each endothelial state is likely to enhance neovasculogenesis and tissue regeneration following ischaemic injury were defined. Plasmalemma vesicle-associated protein (Plvap) was selected for further study, which showed an endothelial-specific and increased expression in both the ischaemic mouse and human heart, and played a direct role in regulating human endothelial proliferation in vitro. CONCLUSION We present a single-cell gene expression atlas of cardiac specific resident ECs, and the transcriptional hierarchy underpinning endogenous vascular repair following MI. These data provide a rich resource that could assist in the development of new therapeutic interventions to augment endogenous myocardial perfusion and enhance regeneration in the injured heart.
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Affiliation(s)
- Ziwen Li
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Emmanouil G Solomonidis
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Marco Meloni
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Richard S Taylor
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Rodger Duffin
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Ross Dobie
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Marlene S Magalhaes
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Beth E P Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Pieter A Louwe
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Gabriela D’Amico
- Centre for Tumour Biology, Barts Cancer Institute, CRUK-Barts Centre, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, UK
| | - Kairbaan M Hodivala-Dilke
- Centre for Tumour Biology, Barts Cancer Institute, CRUK-Barts Centre, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, UK
| | - Ajay M Shah
- Department for Cardiovascular Sciences, King’s College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Nicholas L Mills
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Benjamin D Simons
- Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge, UK
- The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, UK
- Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Gillian A Gray
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Andrew H Baker
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mairi Brittan
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Therapeutic Cell Protective Role of Histochrome under Oxidative Stress in Human Cardiac Progenitor Cells. Mar Drugs 2019; 17:md17060368. [PMID: 31234277 PMCID: PMC6628112 DOI: 10.3390/md17060368] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022] Open
Abstract
Cardiac progenitor cells (CPCs) are resident stem cells present in a small portion of ischemic hearts and function in repairing the damaged heart tissue. Intense oxidative stress impairs cell metabolism thereby decreasing cell viability. Protecting CPCs from undergoing cellular apoptosis during oxidative stress is crucial in optimizing CPC-based therapy. Histochrome (sodium salt of echinochrome A—a common sea urchin pigment) is an antioxidant drug that has been clinically used as a pharmacologic agent for ischemia/reperfusion injury in Russia. However, the mechanistic effect of histochrome on CPCs has never been reported. We investigated the protective effect of histochrome pretreatment on human CPCs (hCPCs) against hydrogen peroxide (H2O2)-induced oxidative stress. Annexin V/7-aminoactinomycin D (7-AAD) assay revealed that histochrome-treated CPCs showed significant protective effects against H2O2-induced cell death. The anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and Bcl-xL were significantly upregulated, whereas the pro-apoptotic proteins BCL2-associated X (Bax), H2O2-induced cleaved caspase-3, and the DNA damage marker, phosphorylated histone (γH2A.X) foci, were significantly downregulated upon histochrome treatment of hCPCs in vitro. Further, prolonged incubation with histochrome alleviated the replicative cellular senescence of hCPCs. In conclusion, we report the protective effect of histochrome against oxidative stress and present the use of a potent and bio-safe cell priming agent as a potential therapeutic strategy in patient-derived hCPCs to treat heart disease.
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Wang Z, Long DW, Huang Y, Chen WCW, Kim K, Wang Y. Decellularized neonatal cardiac extracellular matrix prevents widespread ventricular remodeling in adult mammals after myocardial infarction. Acta Biomater 2019; 87:140-151. [PMID: 30710713 DOI: 10.1016/j.actbio.2019.01.062] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/15/2022]
Abstract
Heart disease remains a leading killer in western society and irreversibly impacts the lives of millions of patients annually. While adult mammals do not possess the ability to regenerate functional cardiac tissue, neonatal mammals are capable of robust cardiomyocyte proliferation and regeneration within a week of birth. Given this change in regenerative function through development, the extracellular matrix (ECM) from adult tissues may not be conducive to promoting cardiac regeneration, although conventional ECM therapies rely exclusively on adult-derived tissues. Therefore the potential of ECM derived from neonatal mouse hearts (nmECM) to prevent adverse ventricular remodeling in adults was investigated using an in vivo model of acute myocardial infarction (MI). Following a single administration of nmECM, we observed a significant improvement in heart function while adult heart-derived ECM (amECM) did not improve these parameters. Treatment with nmECM limits scar expansion in the left ventricle and promotes revascularization of the injured region. Furthermore, nmECM induced expression of the ErbB2 receptor, simulating a neonatal-like environment and promoting neuregulin-1 associated cardiac function. Inhibition of the ErbB2 receptor effectively prevents these actions, suggesting its role in the context of nmECM as a therapy. This study shows the potential of a neonatal-derived biological material in vivo, diverting from the conventional use of adult-derived ECM therapies in research and the clinic. STATEMENT OF SIGNIFICANCE: The of use extracellular matrix biomaterials to aid tissue repair has been previously reported in many forms of injury. The majority of ECM studies to date utilized ECM derived from adult tissues that are not able to fully regenerate functional tissue. In contrast, this study tests the ability of ECM derived from a regenerative organ, the neonatal heart, to stimulate functional cardiac repair after MI. This study is the first to test its potential in vivo. Our results indicate that extracellular factors present in the neonatal environment can be used to alter the healing response in adults, and we have identified the role of ErbB2 in neonatal ECM-based cardiac repair.
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Affiliation(s)
- Zhouguang Wang
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325100, China
| | - Daniel W Long
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yan Huang
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325100, China
| | - William C W Chen
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Kang Kim
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine and Heart and Vascular Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15260, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA 15260, USA
| | - Yadong Wang
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA 15260, USA.
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Combination of Mesenchymal Stromal Cells and Cardiac Stem Cells in a Multilayer Cell Construct Promotes Activation of Notch Signaling and Initiation of Endothelial Differentiation. Bull Exp Biol Med 2019; 166:548-552. [PMID: 30783844 DOI: 10.1007/s10517-019-04390-7] [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] [Received: 08/22/2018] [Indexed: 10/27/2022]
Abstract
We showed the possibility of generating combined tissue-engineered cell consisting of layers of rat cardiac stem cells and mesenchymal stromal cells from the adipose tissue. Cell-cell interaction within the cell sheet promoted proliferation of cardiac stem cells, expression of endothelial differentiation marker ETS1, and Notch signaling activation. The obtained results provide new insights into possible mechanisms of stimulation of endogenous regeneration processes after myocardial damage and demonstrate potential of cell-based cardiomyoplasty with the use of these combined cell sheets.
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Li J, Chen Y, Teng W, Wang Q. [Osteogenic differentiation of bone marrow mesenchymal stem cells induced by gene-loaded lipopolysaccharide-amine nanopolymersomes]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:1469-1476. [PMID: 30417627 PMCID: PMC8414119 DOI: 10.7507/1002-1892.201804125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 10/22/2018] [Indexed: 11/03/2022]
Abstract
Objective To investigate the ability of gene-loaded lipopolysaccharide-amine nanopolymersomes (LNPs) in inducing osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by in vitro gene transfection, where LNPs were used as a non-viral cationic carrier, and their properties were optimized during synthesis. Methods LNPs were synthesized by a graft-copolymerization method, and the effects of different pH environments during synthesis on physicochemical properties of LNPs and LNPs/plasmid of bone morphogenetic protein 2-green fluorescent protein (pBMP-2-GFP) complexes were explored. Then, optimized LNPs with maximum transfection efficiency and safe cytotoxicity in rat BMSCs were identified by cytotoxicity and transfection experiments in vitro. Thereafter, the optimized LNPs were used to mediate pBMP-2-GFP to transfect rat BMSCs, and the influences of LNPs/pBMP-2-GFP on osteogenic differentiation of BMSCs were evaluated by monitoring the cell morphology, concentration of BMP-2 protein, activity of alkaline phosphatase (ALP), and the formation of calcium nodules. Results The nitrogen content, particle size, and zeta potential of LNPs synthesized at pH 8.5 were lower than those of the other pH groups, with the lowest cytotoxicity (96.5%±1.4%) and the highest transfection efficiency (98.8%±0.1%). After transfection treatment, within the first 4 days, BMSCs treated by LNPs/pBMP-2-GFP expressed BMP-2 protein significantly higher than that treated by Lipofectamine2000 (Lipo)/pBMP-2-GFP, polyethylenimine 25K/pBMP-2-GFP, and the blank (non-treated). At 14 days after transfection, ALP activity in BMSCs treated by LNPs/pBMP-2-GFP was higher than that treated by Lipo/pBMP-2-GFP and the blank, comparable to that induced by osteogenic medium; with alizarin red staining, visible calcium nodules were found in BMSCs treated by LNPs/pBMP-2-GFP or osteogenic medium, but absent in BMSCs treated by Lipo/pBMP-2-GFP or the blank with apoptosis. At 21 days after transfection, transparent massive nodules were discovered in BMSCs treated by LNPs/pBMP-2-GFP, and BMSCs exhibited the morphologic features of osteoblasts. Conclusion LNPs synthesized at pH 8.5 has optimal transfection efficiency and cytotoxicity, they can efficiently mediate pBMP-2-GFP to transfect BMSCs, and successfully induce their directional osteogenic differentiation, whose inducing effect is comparable to the osteogenic medium. The results suggest that gene transfection mediated by LNPs may be a convenient and effective strategy in inducing directional differentiation of stem cells.
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Affiliation(s)
- Jing Li
- Key Laboratory on Assisted Circulation of Health Ministry, First Affiliated Hospital, Sun Yat-sen University, Guangzhou Guangdong, 510089, P.R.China;School of Biomedical Engineering, Sun Yat-sen University, Guangzhou Guangdong, 510006, P.R.China
| | - Ying Chen
- Key Laboratory on Assisted Circulation of Health Ministry, First Affiliated Hospital, Sun Yat-sen University, Guangzhou Guangdong, 510089, P.R.China
| | - Wei Teng
- Department of Prosthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou Guangdong, 510060, P.R.China
| | - Qinmei Wang
- Key Laboratory on Assisted Circulation of Health Ministry, First Affiliated Hospital, Sun Yat-sen University, Guangzhou Guangdong, 510089,
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Li T, Liang W, Xiao X, Qian Y. Nanotechnology, an alternative with promising prospects and advantages for the treatment of cardiovascular diseases. Int J Nanomedicine 2018; 13:7349-7362. [PMID: 30519019 PMCID: PMC6233477 DOI: 10.2147/ijn.s179678] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular diseases (CVDs) are one of the most important causes of mortality and affecting the health status of patients. At the same time, CVDs cause a huge health and economic burden to the whole world. Although a variety of therapeutic drugs and measures have been produced to delay the progress of the disease and improve the quality of life of patients, most of the traditional therapeutic strategies can only cure the symptoms and cannot repair or regenerate the damaged ischemic myocardium. In addition, they may bring some unpleasant side effects. Therefore, it is vital to find and explore new technologies and drugs to solve the shortcomings of conventional treatments. Nanotechnology is a new way of using and manipulating the matter at the molecular scale, whose functional organization is measured in nanometers. Because nanoscale phenomena play an important role in cell signal transduction, enzyme action and cell cycle, nanotechnology is closely related to medical research. The application of nanotechnology in the field of medicine provides an alternative and novel direction for the treatment of CVDs, and shows excellent performance in the field of targeted drug therapy and the development of biomaterials. This review will briefly introduce the latest applications of nanotechnology in the diagnosis and treatment of common CVDs.
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Affiliation(s)
- Tao Li
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China,
| | - Weitao Liang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China,
| | - Xijun Xiao
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China,
| | - Yongjun Qian
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China,
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Vaez SA, Ebrahimi-Barough S, Soleimani M, Kolivand S, Farzamfar S, Ahmadi Tafti SH, Azami M, Noorbakhsh F, Ai J. The cardiac niche role in cardiomyocyte differentiation of rat bone marrow-derived stromal cells: comparison between static and microfluidic cell culture methods. EXCLI JOURNAL 2018; 17:762-774. [PMID: 30190666 PMCID: PMC6123612 DOI: 10.17179/excli2018-1539] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 07/30/2018] [Indexed: 12/11/2022]
Abstract
Due to the restricted potential of the heart to regenerate its damaged region, stem cell therapy is a promising treatment modality for myocardial infarction. It has been shown that incubation of bone marrow-derived stromal cells (BMSCs) with initial steps of cardiac differentiation in vitro, can have a significant effect on their therapeutic potential to treat myocardial infarction. Based on these well-established principals we were encouraged to study the direct co-culture of rat BMSCs with neonatal mouse almost pure cardiomyocytes (APCs) and cardiac niche cells (CNCs) in static 2D and microfluidic cell culture systems. Our results showed that the difference regarding the beating rate in isolated APCs and CNCs in both 2D and the microfluidic system was not statistically significant for 30 days. No beat rate could be observed in induced BMSCs in all groups during experiment time. Except for BMSCs cultured alone in both experimental culture conditions, data obtained from Real-time PCR analysis showed that differentiated BMSCs in all co-cultured groups expressed GATA4, Nkx2.5, CX43, cTnI, cTnT, and β-MHC during 4 weeks. BMSCs demonstrated a higher expression of these cardiac factors in microfluidic chips than those co-cultured in 24 well plates. Moreover, immunocytochemistry (ICC), also revealed the GATA4 expression in differentiated BMSCs in all co-cultured groups. It was found that, when combined with shear stress, co-culture with cardiomyocyte can differentiate BMSCs significantly toward cardiomyocyte rather than co-culture alone.
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Affiliation(s)
- Seyed Ahmad Vaez
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sedighe Kolivand
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Farzamfar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Ahmadi Tafti
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences
| | - Mahmoud Azami
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, Faculty of Medicine, Tehran University of Medical, Sciences, Tehran, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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