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Wang J, Du B. hsa_circRNA_092488 Exacerbates the Progression of Deep Vein Thrombosis Through the NLRP3/NF-κB Signaling Pathway. Turk J Haematol 2025; 42:108-118. [PMID: 40045742 PMCID: PMC12099489 DOI: 10.4274/tjh.galenos.2025.2024.0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 03/04/2025] [Indexed: 05/23/2025] Open
Abstract
Objective Deep vein thrombosis (DVT) is a vascular disorder with an incidence rate of about 0.1%. Endothelial progenitor cells (EPCs) are precursor cells of endothelial cells and contribute to vascular repair and regeneration. Circular RNA (circRNA) has become a new focus of research as circRNAs are involved in various biological processes including the progression of DVT. This study explored the upregulation of hsa_circRNA_092488 in DVT patients. Materials and Methods The expression of hsa_circRNA_092488 was evaluated in venous blood samples obtained from DVT patients (n=42) and healthy controls (n=42). Gain- and loss-of-function studies of hsa_circRNA_092488 were carried out. The expression levels of related RNAs and proteins were examined by quantitative real-time reverse-transcription polymerase chain reaction, western blotting and immunofluorescence assays. The proliferation, migration, cell cycle progression, and apoptosis of transfected cells were measured by CCK-8 assay, transwell assay, and flow cytometry. The association of hsa_circRNA_092488 and NOD-like receptor protein 3 (NLRP3) in EPCs was revealed using RNA pull-down analysis. Furthermore, the stability of NLRP3 mRNA was examined in transfected EPCs. Results Upregulation of hsa_circRNA_092488 was detected in blood samples from DVT patients and it had the ability to suppress the proliferation and migration of EPCs, induce cell cycle arrest from the S to the G0/G1 phase, and trigger cellular apoptosis. Furthermore, NLRP3 was identified as the potential downstream target molecule of hsa_circRNA_092488 and it could exert its regulatory functions by activating the NLRP3/nuclear factor (NF)-κB signaling pathway. Overexpression of hsa_circRNA_092488 in cells notably elevated the protein expression of caspase-1, interleukin-1β, P-NF-κB-p65/NF-κB-p65, and P-IκBα/IκBα, while knockdown of hsa_circRNA_092488 significantly reduced the levels of those proteins in EPCs. Conclusion hsa_circRNA_092488/NLRP3/NF-κB signaling could be a novel therapeutic candidate for the treatment of DVT.
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Affiliation(s)
- Jian Wang
- The First Affiliated Hospital of Jinzhou Medical University, Department of Geriatric Medicine, Jinzhou, P.R. China
| | - Binghui Du
- The First Affiliated Hospital of Jinzhou Medical University, Department of Vascular Surgery, Jinzhou, P.R. China
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Molani-Gol R, Rafraf M. Effects of the Mediterranean diet on the secondary prevention of cardiovascular diseases: a systematic review of randomised controlled trials. Int J Food Sci Nutr 2025; 76:226-238. [PMID: 40011219 DOI: 10.1080/09637486.2025.2466111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 01/31/2025] [Accepted: 02/07/2025] [Indexed: 02/28/2025]
Abstract
This systematic review aimed to summarise the current knowledge regarding the effects of the Mediterranean diet (MD) on the secondary prevention of cardiovascular diseases (CVDs). A systematic search was done on Web of Sciences, PubMed, Scopus, and Google Scholar databases until January 2025. The majority of the included studies (15 of 16 RCTs) supported the role of MD following in the secondary prevention of CVDs. According to the RCT results, the patients in the MD group had lower cardiovascular deaths, non-fatal myocardial infarction, and other events. They also had healthier lipid profiles and blood fatty acids, higher flow-mediated dilation and endothelial progenitor cell levels, and lower endothelial progenitor cells compared to a low-fat diet. However, both MD and control (low-fat diet) groups promoted similar decreases in blood pressure and body mass index. The findings of this review suggested that adherence to the MD could be beneficial in the secondary prevention of CVD.
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Affiliation(s)
- Roghayeh Molani-Gol
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Nutrition Research Center, Department of Community Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Rafraf
- Nutrition Research Center, Department of Community Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
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3
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Gao Q, Wang J, Zhang H, Wang J, Jing Y, Su J. Organoid Vascularization: Strategies and Applications. Adv Healthc Mater 2025:e2500301. [PMID: 40285576 DOI: 10.1002/adhm.202500301] [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: 01/17/2025] [Revised: 03/24/2025] [Indexed: 04/29/2025]
Abstract
Organoids provide 3D structures that replicate native tissues in biomedical research. The development of vascular networks within organoids enables oxygen and nutrient delivery while facilitating metabolic waste removal, which supports organoid growth and maturation. Recent studies demonstrate that vascularized organoid models offer insights into tissue interactions and promote tissue regeneration. However, the current limitations in establishing functional vascular networks affect organoid growth, viability, and clinical translation potential. This review examines the development of vascularized organoids, including the mechanisms of angiogenesis and vasculogenesis, construction strategies, and biomedical applications. The approaches are categorized into in vivo and in vitro methods, with analysis of their specific advantages and limitations. The review also discusses emerging techniques such as bioprinting and gene editing for improving vascularization and functional integration in organoid-based therapies. Current developments in organoid vascularization indicate potential applications in modeling human diseases and developing therapeutic strategies, contributing to advances in translational research.
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Affiliation(s)
- Qianmin Gao
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, P. R. China
- Organoid Research Center, Shanghai University, Shanghai, 200444, P. R. China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, P. R. China
| | - Jian Wang
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, P. R. China
- Organoid Research Center, Shanghai University, Shanghai, 200444, P. R. China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, P. R. China
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Hao Zhang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Jianhua Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, P. R. China
- Organoid Research Center, Shanghai University, Shanghai, 200444, P. R. China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, P. R. China
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, P. R. China
- Organoid Research Center, Shanghai University, Shanghai, 200444, P. R. China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, P. R. China
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, P. R. China
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4
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Chen D, Wang X, Zhang S, Huang J, Li M, Wang L, Jiang T. The experimental study of the effect of fluid shear force on the migration rate of human umbilical vein endothelial cells. Biochem Biophys Res Commun 2025; 758:151619. [PMID: 40117976 DOI: 10.1016/j.bbrc.2025.151619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND The vascular endothelium is a continuous monolayer of flattened cells that cover the surface of the lumen of blood vessels. Endothelial cell damage can readily result in thrombus formation and thickening of the intima. Accelerating the migration and repair of peripheral endothelial cells is essential. Shear force is an important hydrodynamic factor affecting endothelial cell function. We aimed to investigate the effect of different shear forces on the migration rate of endothelial cells. METHODS Human umbilical vein endothelial cells (HUVECs) were used instead of endothelial cells to establish a cell scratch model. Plate flow chambers were then used to intervene in HUVECs growth with different shear force magnitudes (4 dyn/cm2, 8 dyn/cm2, and 12 dyn/cm2). The healing rate of the scratches was observed under light microscopy, and finally the expression of RhoA and CDC42 was detected by molecular experiments. The expression of CDC42 factor was inhibited by siRNA interference, and the wound healing ability of HUVECs in the control group and the CDC42 inhibition group under different fluid shear forces was observed under light microscopy. RESULTS High shear forces promote the healing of scratches. In addition, relatively strong shear forces promoted the expression of cytokines RhoA and CDC42. Compared with untransfected HUVECs, HUVECs with inhibition of CDC42 expression by siRNA interference showed weak migration ability in different fluid shear groups. CONCLUSION Increasing fluid shear force in a range (4-12 dyn/cm2) contributes to endothelial cell migration. Inhibition of CDC42 expression weakened the migration ability of HUVECs under different fluid shear forces.
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Affiliation(s)
- Dong Chen
- Dalian University of Technology, China; Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China; China Medical University, Shenyang, China
| | - Xianwei Wang
- Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China.
| | - Sen Zhang
- Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China; Dalian Medical University, Dalian, China
| | - Jiaming Huang
- Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China
| | - Mei Li
- Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China
| | | | - Tao Jiang
- Department of Neurosurgery, Dalian University of Technology Affiliated Central Hospital, China; China Medical University, Shenyang, China; West China Hospital, Sichuan University, Chengdu, China.
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García Granado JF, Rodríguez Esparragón FJ, González Martín JM, Cazorla Rivero SE, González Hernández AN. Endothelial and circulating progenitor cells as prognostic biomarkers of stroke: A systematic review and meta-analysis. Thromb Res 2025; 245:109224. [PMID: 39571224 DOI: 10.1016/j.thromres.2024.109224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/19/2024] [Accepted: 11/15/2024] [Indexed: 12/30/2024]
Abstract
PURPOSE Endothelial progenitor cells (EPCs) are biomarkers of neurovascular repair in cerebral vascular disease (CVD). Low quantification of EPCs and/or their dysfunction has been associated with stroke severity and post-stroke functionality. This systematic review (SR) and meta-analysis aimed to analyze whether EPC quantification contributes to stroke severity and functional prognosis. METHODS Articles were selected from the PubMed, ScienceDirect, and Ovid MEDLINE databases, according to the guidelines of the PRISMA 2020 [1] statement. Detailed observational studies of samples from subjects with a clinical diagnosis of CVD (ischemic stroke-IS, hemorrhagic stroke-HS, or transient ischemic attack-TIA) aged >45 years during 2003-2023 were included. Evaluation of study quality was based on the Critical Appraisal Skills Programme checklist(Santamaría, 2017 [2]). RESULTS We included 22 articles in our SR. Patients with IS and good functional outcomes had higher EPC levels during the first week of admission than those with worse functional outcomes. Higher EPC levels were associated with reduced infarct growth, improved NIHSS scores at 48 h (OR 0.8; 95 % CI: 0.72-0.90; p < 0.0002) 7 (r = -0.607; p < 0.0001), and 90 days (r = -0.570; p < 0.0001), with a negative correlation between EPC levels and NIHSS score (overall pooled r = -0,32, 95 % CI: -0.39-0.24), and good functional outcomes with better mRS scores at 24 h, 3, 6, and 12 months (overall pooled SMD 4.51, CI 95 %: 0.70-0.83). Lower EPC quantification and worse functional outcomes during admission were predictors of IS recurrence. Higher EPC levels were associated with better functional outcomes and lower bleeding volumes in patients with HS and were protective markers for the progression high-risk TIA. CONCLUSION EPCs seems to be predictive biomarkers of better clinical outcomes in patients with CVD, exhibiting lower severity (NIHSS) and better functional prognosis (mRS).
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Affiliation(s)
- Juan Francisco García Granado
- Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain.
| | | | | | - Sara E Cazorla Rivero
- Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | - Ayoze Nauzet González Hernández
- Hospital Universitario de Gran Canaria Doctor Negrín, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
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Rieck S, Sharma K, Altringer C, Hesse M, Triantafyllou C, Zhang Y, Busskamp V, Fleischmann BK. Forward programming of human induced pluripotent stem cells via the ETS variant transcription factor 2: rapid, reproducible, and cost-effective generation of highly enriched, functional endothelial cells. Cardiovasc Res 2024; 120:1472-1484. [PMID: 38916487 DOI: 10.1093/cvr/cvae129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 03/13/2024] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
AIMS Endothelial cell (EC) dysfunction plays a key role in the initiation and progression of cardiovascular disease. However, studying these disorders in ECs from patients is challenging; hence, the use of human induced pluripotent stem cells (hiPSCs) and their in vitro differentiation into ECs represents a very promising approach. Still, the generation of hiPSC-derived ECs (hECs) remains demanding as a cocktail of growth factors and an intermediate purification step are required for hEC enrichment. Therefore, we probed the utility of a forward programming approach using transgenic hiPSC lines. METHODS AND RESULTS We have used the transgenic hiPSC line PGP1 ETV2 isoform 2 to explore the in vitro differentiation of hECs via doxycycline-dependent induction of the ETS variant transcription factor 2 (ETV2) and compared these with a standard differentiation protocol for hECs using non-transgenic control hiPSCs. The transgenic hECs were highly enriched without an intermediate purification step and expressed-as non-transgenic hECs and human umbilical vein endothelial cells-characteristic EC markers. The viability and yield of transgenic hECs were strongly improved by applying EC growth medium during differentiation. This protocol was successfully applied in two more transgenic hiPSC lines yielding reproducible results with low line-to-line variability. Transgenic hECs displayed typical functional properties, such as tube formation and LDL uptake, and a more mature phenotype than non-transgenic hECs. Transgenic hiPSCs preferentially differentiated into the arterial lineage; this was further enhanced by adding a high concentration of vascular endothelial growth factor to the medium. We also demonstrate that complexing lentivirus with magnetic nanoparticles and application of a magnetic field enables efficient transduction of transgenic hECs. CONCLUSION We have established a highly efficient, cost-effective, and reproducible differentiation protocol for the generation of functional hECs via forward programming. The transgenic hECs can be genetically modified and are a powerful tool for disease modelling, tissue engineering, and translational purposes.
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Affiliation(s)
- Sarah Rieck
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Kritika Sharma
- Department of Ophthalmology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Carlotta Altringer
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Michael Hesse
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Christos Triantafyllou
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Yanhui Zhang
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Volker Busskamp
- Department of Ophthalmology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Bernd K Fleischmann
- Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
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Conner AA, David D, Yim EKF. The Effects of Biomimetic Surface Topography on Vascular Cells: Implications for Vascular Conduits. Adv Healthc Mater 2024; 13:e2400335. [PMID: 38935920 DOI: 10.1002/adhm.202400335] [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: 01/28/2024] [Revised: 06/04/2024] [Indexed: 06/29/2024]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide and represent a pressing clinical need. Vascular occlusions are the predominant cause of CVD and necessitate surgical interventions such as bypass graft surgery to replace the damaged or obstructed blood vessel with a synthetic conduit. Synthetic small-diameter vascular grafts (sSDVGs) are desired to bypass blood vessels with an inner diameter <6 mm yet have limited use due to unacceptable patency rates. The incorporation of biophysical cues such as topography onto the sSDVG biointerface can be used to mimic the cellular microenvironment and improve outcomes. In this review, the utility of surface topography in sSDVG design is discussed. First, the primary challenges that sSDVGs face and the rationale for utilizing biomimetic topography are introduced. The current literature surrounding the effects of topographical cues on vascular cell behavior in vitro is reviewed, providing insight into which features are optimal for application in sSDVGs. The results of studies that have utilized topographically-enhanced sSDVGs in vivo are evaluated. Current challenges and barriers to clinical translation are discussed. Based on the wealth of evidence detailed here, substrate topography offers enormous potential to improve the outcome of sSDVGs and provide therapeutic solutions for CVDs.
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Affiliation(s)
- Abigail A Conner
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
| | - Dency David
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
| | - Evelyn K F Yim
- Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
- Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
- Center for Biotechnology and Bioengineering, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
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8
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Modugno P, Cilla S, Centritto EM, Picone V, Maiorano M, Amatuzio M, Petrilli MP, Fraticelli V, De Filippo CM, Caradonna E, Codispoti FA, Massetti M, Tshomba Y. Autologous Bone Marrow Stem Cells in Patients With Critical Limb Ischaemia not Eligible for Revascularization: A Single Centre Experience. Angiology 2024; 75:865-873. [PMID: 37728082 DOI: 10.1177/00033197231190512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Abstract
We evaluated the use of autologus bone marrow stem cells transplantation in patients with critical limb ischaemia (CLI) not eligible for revascularization. Eighty consecutive patients candidate to amputation were enrolled in a single-centre retrospective study. The primary endpoint was defined as the amputation-free rate from stem cells transplantation. Secondary endpoints were the evaluation of transcutaneous oximetry and its predictive potential for probability of amputation and the evaluation of rest pain. Ankle brachial index, transcutaneous oxygen (TcpO2) and radiological imaging were performed at the enrolment and during the follow-up times. All patients were treated with auto transplant of bone marrow stem cells. Two patients died due to acute renal and acute respiratory failures. 19 patients were amputated from the thigh or leg. In total, 59 of 80 patients intended to thigh amputation saved the limb, preserving the plantar support. TcpO2 was found a predictive metric with an AUC equal to .763, and a threshold for a risk of amputation of 10% and 5% at the values ≤22.7 and ≤26.9 mmHg, respectively. Auto transplant of bone marrow stem cells seems to be a safe and an efficient option for CLI not eligible to revascularizzation.
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Affiliation(s)
- Pietro Modugno
- Vascular Surgery Unit, Gemelli Molise Hospital, Campobasso, Italy
| | - Savino Cilla
- Medical Physics Unit, Gemelli Molise Hospital, Campobasso, Italy
| | | | - Veronica Picone
- Vascular Surgery Unit, Gemelli Molise Hospital, Campobasso, Italy
| | | | | | | | | | | | - Eugenio Caradonna
- Società italiana di medicina e chirurgia rigenerativa, Caserta, Italy
| | | | - Massimo Massetti
- Cardiac Surgery Unit, Universita' Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Yamume Tshomba
- Vascular Surgery Unit, Universita' Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Wan X, Ni X, Xie Y, Chen L, Cai B, Lin Q, Ke R, Huang T, Shan X, Wang B. Research progress and application prospect of adipose-derived stem cell secretome in diabetes foot ulcers healing. Stem Cell Res Ther 2024; 15:279. [PMID: 39227906 PMCID: PMC11373215 DOI: 10.1186/s13287-024-03912-z] [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: 07/17/2024] [Accepted: 08/29/2024] [Indexed: 09/05/2024] Open
Abstract
Diabetic foot ulcers (DFUs) are chronic wounds and one of the most common complications of diabetes, imposing significant physical and mental burdens on patients due to their poor prognosis and treatment efficacy. Adipose-derived stem cells (ADSCs) have been proven to promote wound healing, with studies increasingly attributing these beneficial effects to their paracrine actions. Consequently, research on ADSC secretome as a novel and promising alternative for DFU treatment has been extensively conducted. This article provides a comprehensive review of the mechanisms underlying refractory DFU wounds, the secretome of ADSCs, and its role in promoting wound healing in diabetes foot ulcers. And the review aims to provide reliable evidence for the clinical application of ADSC secretome in the treatment of refractory DFU wounds.
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Affiliation(s)
- Xiaofen Wan
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xuejun Ni
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yunjia Xie
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Lu Chen
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Beichen Cai
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Qian Lin
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Ruonan Ke
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Tao Huang
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Xiuying Shan
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
| | - Biao Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
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10
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Das A, Smith RJ, Andreadis ST. Harnessing the potential of monocytes/macrophages to regenerate tissue-engineered vascular grafts. Cardiovasc Res 2024; 120:839-854. [PMID: 38742656 PMCID: PMC11218695 DOI: 10.1093/cvr/cvae106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 02/19/2024] [Accepted: 04/02/2024] [Indexed: 05/16/2024] Open
Abstract
Cell-free tissue-engineered vascular grafts provide a promising alternative to treat cardiovascular disease, but timely endothelialization is essential for ensuring patency and proper functioning post-implantation. Recent studies from our lab showed that blood cells like monocytes (MCs) and macrophages (Mϕ) may contribute directly to cellularization and regeneration of bioengineered arteries in small and large animal models. While MCs and Mϕ are leucocytes that are part of the innate immune response, they share common developmental origins with endothelial cells (ECs) and are known to play crucial roles during vessel formation (angiogenesis) and vessel repair after inflammation/injury. They are highly plastic cells that polarize into pro-inflammatory and anti-inflammatory phenotypes upon exposure to cytokines and differentiate into other cell types, including EC-like cells, in the presence of appropriate chemical and mechanical stimuli. This review focuses on the developmental origins of MCs and ECs; the role of MCs and Mϕ in vessel repair/regeneration during inflammation/injury; and the role of chemical signalling and mechanical forces in Mϕ inflammation that mediates vascular graft regeneration. We postulate that comprehensive understanding of these mechanisms will better inform the development of strategies to coax MCs/Mϕ into endothelializing the lumen and regenerate the smooth muscle layers of cell-free bioengineered arteries and veins that are designed to treat cardiovascular diseases and perhaps the native vasculature as well.
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Affiliation(s)
- Arundhati Das
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, 908 Furnas Hall, Buffalo, NY 14260-4200, USA
| | - Randall J Smith
- Department of Biomedical Engineering, University at Buffalo, The State University of New York, 332 Bonner Hall, Buffalo, NY 14260-1920, USA
| | - Stelios T Andreadis
- Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, 908 Furnas Hall, Buffalo, NY 14260-4200, USA
- Department of Biomedical Engineering, University at Buffalo, The State University of New York, 332 Bonner Hall, Buffalo, NY 14260-1920, USA
- Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, The State University of New York, 701 Ellicott St, Buffalo, NY 14203, USA
- Cell, Gene and Tissue Engineering (CGTE) Center, University at Buffalo, The State University of New York, 813 Furnas Hall, Buffalo, NY 14260-4200, USA
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Ramirez-Velandia F, Mensah E, Salih M, Wadhwa A, Young M, Muram S, Taussky P, Ogilvy CS. Endothelial Progenitor Cells: A Review of Molecular Mechanisms in the Pathogenesis and Endovascular Treatment of Intracranial Aneurysms. Neuromolecular Med 2024; 26:25. [PMID: 38886284 DOI: 10.1007/s12017-024-08791-4] [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: 02/19/2024] [Accepted: 05/09/2024] [Indexed: 06/20/2024]
Abstract
This comprehensive review explores the multifaceted role of endothelial progenitor cells (EPCs) in vascular diseases, focusing on their involvement in the pathogenesis and their contributions to enhancing the efficacy of endovascular treatments for intracranial aneurysms (IAs). Initially discovered as CD34+ bone marrow-derived cells implicated in angiogenesis, EPCs have been linked to vascular repair, vasculogenesis, and angiogenic microenvironments. The origin and differentiation of EPCs have been subject to debate, challenging the conventional notion of bone marrow origin. Quantification methods, including CD34+ , CD133+ , and various assays, reveal the influence of factors, like age, gender, and comorbidities on EPC levels. Cellular mechanisms highlight the interplay between bone marrow and angiogenic microenvironments, involving growth factors, matrix metalloproteinases, and signaling pathways, such as phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). In the context of the pathogenesis of IAs, EPCs play a role in maintaining vascular integrity by replacing injured and dysfunctional endothelial cells. Recent research has also suggested the therapeutic potential of EPCs after coil embolization and flow diversion, and this has led the development of device surface modifications aimed to enhance endothelialization. The comprehensive insights underscore the importance of further research on EPCs as both therapeutic targets and biomarkers in IAs.
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Affiliation(s)
- Felipe Ramirez-Velandia
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Emmanuel Mensah
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Mira Salih
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Aryan Wadhwa
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
| | - Michael Young
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Sandeep Muram
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Philipp Taussky
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Christopher S Ogilvy
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA.
- Harvard Medical School, Boston, MA, USA.
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12
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Chou Y, Lee Y, Su C, Lee H, Hsieh C, Tien T, Lin C, Yeh H, Wu Y. Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells. J Cell Mol Med 2024; 28:e18489. [PMID: 38899522 PMCID: PMC11187746 DOI: 10.1111/jcmm.18489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 02/03/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.
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Affiliation(s)
- Yen‐Hung Chou
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Institute of Biomedical SciencesMacKay Medical CollegeNew TaipeiTaiwan
| | - Yi‐Nan Lee
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Cheng‐Huang Su
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Hsin‐I Lee
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
| | - Chin‐Ling Hsieh
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Ting‐Yi Tien
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Chao‐Feng Lin
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Hung‐I Yeh
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
| | - Yih‐Jer Wu
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Institute of Biomedical SciencesMacKay Medical CollegeNew TaipeiTaiwan
- Division of Preventive Cardiology & Pulmonary Circulation Medicine, Department of Cardiovascular Medicine, Department of Internal Medicine and Department of Medical ResearchMacKay Memorial HospitalNew TaipeiTaiwan
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13
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Ding H, Hou X, Gao Z, Guo Y, Liao B, Wan J. Challenges and Strategies for Endothelializing Decellularized Small-Diameter Tissue-Engineered Vessel Grafts. Adv Healthc Mater 2024; 13:e2304432. [PMID: 38462702 DOI: 10.1002/adhm.202304432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/26/2024] [Indexed: 03/12/2024]
Abstract
Vascular diseases are the leading cause of ischemic necrosis in tissues and organs, necessitating using vascular grafts to restore blood supply. Currently, small vessels for coronary artery bypass grafts are unavailable in clinical settings. Decellularized small-diameter tissue-engineered vessel grafts (SD-TEVGs) hold significant potential. However, they face challenges, as simple implantation of decellularized SD-TEVGs in animals leads to thrombosis and calcification due to incomplete endothelialization. Consequently, research and development focus has shifted toward enhancing the endothelialization process of decellularized SD-TEVGs. This paper reviews preclinical studies involving decellularized SD-TEVGs, highlighting different strategies and their advantages and disadvantages for achieving rapid endothelialization of these vascular grafts. Methods are analyzed to improve the process while addressing potential shortcomings. This paper aims to contribute to the future commercial viability of decellularized SD-TEVGs.
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Affiliation(s)
- Heng Ding
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Xiaojie Hou
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhen Gao
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100069, China
| | - Yingqiang Guo
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Juyi Wan
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
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14
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Tkacz M, Zgutka K, Tomasiak P, Tarnowski M. Responses of Endothelial Progenitor Cells to Chronic and Acute Physical Activity in Healthy Individuals. Int J Mol Sci 2024; 25:6085. [PMID: 38892272 PMCID: PMC11173310 DOI: 10.3390/ijms25116085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Endothelial progenitor cells (EPCs) are circulating cells of various origins that possess the capacity for renewing and regenerating the endothelial lining of blood vessels. During physical activity, in response to factors such as hypoxia, changes in osmotic pressure, and mechanical forces, endothelial cells undergo intense physiological stress that results in endothelial damage. Circulating EPCs participate in blood vessel repair and vascular healing mainly through paracrine signalling. Furthermore, physical activity may play an important role in mobilising this important cell population. In this narrative review, we summarise the current knowledge on the biology of EPCs, including their characteristics, assessment, and mobilisation in response to both chronic and acute physical activity in healthy individuals.
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Affiliation(s)
- Marta Tkacz
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
| | - Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
| | - Patrycja Tomasiak
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
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15
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Kussie HC, Hahn W, Sivaraj D, Quintero F, Knochel A, Alfsharif AM, Yasmeh JP, Fischer K, Mojadidi S, Hostler A, Granoski M, McKenna E, Henn D, Litmanovich B, Miller AA, Schurr DK, Li VW, Li WW, Gurtner GC, Chen K. Avenanthramide and β-Glucan Therapeutics Accelerate Wound Healing Via Distinct and Nonoverlapping Mechanisms. Adv Wound Care (New Rochelle) 2024; 13:155-166. [PMID: 38299969 DOI: 10.1089/wound.2023.0050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024] Open
Abstract
Objective: Given the significant economic, health care, and personal burden of acute and chronic wounds, we investigated the dose dependent wound healing mechanisms of two Avena sativa derived compounds: avenanthramide (AVN) and β-Glucan. Approach: We utilized a splinted excisional wound model that mimics human-like wound healing and performed subcutaneous AVN and β-Glucan injections in 15-week-old C57BL/6 mice. Histologic and immunohistochemical analysis was performed on the explanted scar tissue to assess changes in collagen architecture and cellular responses. Results: AVN and β-Glucan treatment provided therapeutic benefits at a 1% dose by weight in a phosphate-buffered saline vehicle, including accelerated healing time, beneficial cellular recruitment, and improved tissue architecture of healed scars. One percent AVN treatment promoted an extracellular matrix (ECM) architecture similar to unwounded skin, with shorter, more randomly aligned collagen fibers and reduced inflammatory cell presence in the healed tissue. One percent β-Glucan treatment promoted a tissue architecture characterized by long, thick bundles of collagen with increased blood vessel density. Innovation: AVN and β-Glucan have previously shown promise in promoting wound healing, although the therapeutic efficacies and mechanisms of these bioactive compounds remain incompletely understood. Furthermore, the healed ECM architecture of these wounds has not been characterized. Conclusions: AVN and β-Glucan accelerated wound closure compared to controls through distinct mechanisms. AVN-treated scars displayed a more regenerative tissue architecture with reduced inflammatory cell recruitment, while β-Glucan demonstrated increased angiogenesis with more highly aligned tissue architecture more indicative of fibrosis. A deeper understanding of the mechanisms driving healing in these two naturally derived therapeutics will be important for translation to human use.
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Affiliation(s)
- Hudson C Kussie
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - William Hahn
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Dharshan Sivaraj
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Filiberto Quintero
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Amelia Knochel
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | | | - Jonathan P Yasmeh
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Katharina Fischer
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Sultana Mojadidi
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Andrew Hostler
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Maia Granoski
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Eamonn McKenna
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Dominic Henn
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Ben Litmanovich
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | | | | | - Vincent W Li
- The Angiogenesis Foundation, Cambridge, Massachusetts, USA
| | - William W Li
- The Angiogenesis Foundation, Cambridge, Massachusetts, USA
| | - Geoffrey C Gurtner
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
- Department of Biomedical Engineering, University of Arizona, College of Medicine, Tucson, Arizona, USA
| | - Kellen Chen
- Department of Surgery, University of Arizona, College of Medicine, Tucson, Arizona, USA
- Department of Biomedical Engineering, University of Arizona, College of Medicine, Tucson, Arizona, USA
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16
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Fahad MAA, Lee HY, Park S, Choi M, Shanto PC, Park M, Bae SH, Lee BT. Small-diameter vascular graft composing of core-shell structured micro-nanofibers loaded with heparin and VEGF for endothelialization and prevention of neointimal hyperplasia. Biomaterials 2024; 306:122507. [PMID: 38367300 DOI: 10.1016/j.biomaterials.2024.122507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/19/2024]
Abstract
Despite the significant progress made in recent years, clinical issues with small-diameter vascular grafts related to low mechanical strength, thrombosis, intimal hyperplasia, and insufficient endothelialization remain unresolved. This study aims to design and fabricate a core-shell fibrous small-diameter vascular graft by co-axial electrospinning process, which will mechanically and biologically meet the benchmarks for blood vessel replacement. The presented graft (PGHV) comprised polycaprolactone/gelatin (shell) loaded with heparin-VEGF and polycaprolactone (core). This study hypothesized that the shell structure of the fibers would allow rapid degradation to release heparin-VEGF, and the core would provide mechanical strength for long-term application. Physico-mechanical evaluation, in vitro biocompatibility, and hemocompatibility assays were performed to ensure safe in vivo applications. After 25 days, the PGHV group released 79.47 ± 1.54% of heparin and 86.25 ± 1.19% of VEGF, and degradation of the shell was observed but the core remained pristine. Both the control (PG) and PGHV groups demonstrated robust mechanical properties. The PGHV group showed excellent biocompatibility and hemocompatibility compared to the PG group. After four months of rat aorta implantation, PGHV exhibited smooth muscle cell regeneration and complete endothelialization with a patency rate of 100%. The novel core-shell structured graft could be pivotal in vascular tissue regeneration application.
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Affiliation(s)
- Md Abdullah Al Fahad
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Hyun-Yong Lee
- Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, 31151, Republic of Korea
| | - Seongsu Park
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Minji Choi
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Prayas Chakma Shanto
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Myeongki Park
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Sang Ho Bae
- Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, 31151, Republic of Korea; Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, 31151, Republic of Korea
| | - Byong-Taek Lee
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea; Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, 31151, Republic of Korea.
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17
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He X, Cui Y, Li T, Luo L, Zeng Z, Ma Y, Chen Y. PU.1 alleviates the inhibitory effects of cigarette smoke on endothelial progenitor cell function and lung-homing through Wnt/β-catenin and CXCL12/CXCR4 pathways. Tob Induc Dis 2024; 22:TID-22-27. [PMID: 38274000 PMCID: PMC10809061 DOI: 10.18332/tid/174661] [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: 10/06/2022] [Revised: 02/18/2023] [Accepted: 10/30/2023] [Indexed: 01/27/2024] Open
Abstract
INTRODUCTION Endothelial progenitor cells (EPCs) dysfunction is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis. However, the role of PU.1 in COPD and its effects on EPC function and lung-homing, remain unclear. This study aimed to explore the protective activity of PU.1 and the underlying mechanisms in a cigarette smoke extract (CSE)-induced emphysema mouse model. METHODS C57BL/6 mice were treated with CSE to establish a murine emphysema model and injected with overexpressed PU.1 or negative control adeno-associated virus. Morphometry of lung slides, lung function, and apoptosis of lung tissues were evaluated. Immunofluorescence co-localization was used to analyze EPCs homing into the lung. Flow cytometry was performed to detect EPC count in lung tissues and bone marrow (BM). The angiogenic ability of BM-derived EPCs cultured in vitro was examined by tube formation assay. We determined the expression levels of PU.1, β-catenin, C-X-C motif ligand 12 (CXCL12), C-X-C motif receptor 4 (CXCR4), stem cell antigen-1 (Sca-1), and stemness genes. RESULTS CSE exposure significantly reduced the expression of PU.1 in mouse lung tissues, BM, and BM-derived EPCs. PU.1 overexpression attenuated CSE-induced emphysematous changes, lung function decline, and apoptosis. In emphysematous mice, PU.1 overexpression markedly reversed the decreased proportion of EPCs in BM and promoted the lung-homing of EPCs. The impaired angiogenic ability of BM-derived EPCs induced by CSE could be restored by the overexpression of PU.1. In addition, PU.1 upregulation evidently reversed the decreased expression of β-catenin, CXCL12, CXCR4, Scal-1, and stemness genes in mouse lung tissues, BM, and BM-derived EPCs after CSE exposure. CONCLUSIONS PU.1 alleviates the inhibitory effects of CSE on EPC function and lung-homing via activating the canonical Wnt/β-catenin pathway and CXCL12/CXCR4 axis. While further research is needed, our research may indicate a potential therapeutic target for COPD patients.
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Affiliation(s)
- Xue He
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yanan Cui
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Tiao Li
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Lijuan Luo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Zihang Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yiming Ma
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
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18
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Huang C, Huang W, Meng Y, Zhou C, Wang X, Zhang C, Tian Y, Wei W, Li Y, Zhou Q, Chen W, Tang Y. T1-weighted MRI of targeting atherosclerotic plaque based on CD40 expression on engulfed USPIO's cell surface. Biomed Mater 2024; 19:025019. [PMID: 38215489 DOI: 10.1088/1748-605x/ad1df6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/12/2024] [Indexed: 01/14/2024]
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a zeta potential of -47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10-100 μg ml-1, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentrations exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 μg ml-1USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). In order to substantiate our hypothesis that CD40 protein on the cell surface facilitates migration towards inflammatory cells, we utilized AuNPs-PEI (gold nanoparticles-polyethylenimine) carrying siRNACD40to knockout CD40 expression in MAECs. It has been documented that gold nanoparticle-oligonucleotide complexes could be employed as intracellular gene regulation agents for the control of protein level in cells. Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC(control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40(reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone). In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue andin vivolevel, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.
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Affiliation(s)
- Chen Huang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Medical Imaging Institute of Panyu District, Guangzhou 511400, People's Republic of China
| | - Wentao Huang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, People's Republic of China
| | - Yixuan Meng
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, People's Republic of China
| | - Chengqian Zhou
- Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States of America
| | - Xiaozhuan Wang
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People's Republic of China
| | - Chunyu Zhang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, People's Republic of China
| | - Yuzhen Tian
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, People's Republic of China
| | - Wei Wei
- Guangdong Cord Blood Bank, Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, People's Republic of China
| | - Yongsheng Li
- Guangdong Cord Blood Bank, Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, People's Republic of China
| | - Quan Zhou
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People's Republic of China
| | - Wenli Chen
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, People's Republic of China
| | - Yukuan Tang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Medical Imaging Institute of Panyu District, Guangzhou 511400, People's Republic of China
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19
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Ya J, Pellumbaj J, Hashmat A, Bayraktutan U. The Role of Stem Cells as Therapeutics for Ischaemic Stroke. Cells 2024; 13:112. [PMID: 38247804 PMCID: PMC10814781 DOI: 10.3390/cells13020112] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/01/2024] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. This paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration, and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. The treatment of stroke patients with different types of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. The priming or pre-conditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later-phase trials are required to consolidate these findings.
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Affiliation(s)
| | | | | | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neurosciences, Queens Medical Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
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20
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Afzal A, Thomas N, Warraich Z, Barbay S, Mocco J. Hematopoietic Endothelial Progenitor cells enhance motor function and cortical motor map integrity following cerebral ischemia. Restor Neurol Neurosci 2024; 42:139-149. [PMID: 38820024 DOI: 10.3233/rnn-231378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Background Hematopoietic stem cells (HSC) are recruited to ischemic areas in the brain and contribute to improved functional outcome in animals. However, little is known regarding the mechanisms of improvement following HSC administration post cerebral ischemia. To better understand how HSC effect post-stroke improvement, we examined the effect of HSC in ameliorating motor impairment and cortical dysfunction following cerebral ischemia. Methods Baseline motor performance of male adult rats was established on validated motor tests. Animals were assigned to one of three experimental cohorts: control, stroke, stroke + HSC. One, three and five weeks following a unilateral stroke all animals were tested on motor skills after which intracortical microstimulation was used to derive maps of forelimb movement representations within the motor cortex ipsilateral to the ischemic injury. Results Stroke + HSC animals significantly outperformed stroke animals on single pellet reaching at weeks 3 and 5 (28±3% and 33±3% versus 11±4% and 17±3%, respectively, p < 0.05 at both time points). Control animals scored 44±1% and 47±1%, respectively. Sunflower seed opening task was significantly improved in the stroke + HSC cohort versus the stroke cohort at week five-post stroke (79±4 and 48±5, respectively, p < 0.05). Furthermore, Stroke + HSC animals had significantly larger forelimb motor maps than animals in the stroke cohort. Overall infarct size did not significantly differ between the two stroked cohorts. Conclusion These data suggest that post stroke treatment of HSC enhances the functional integrity of residual cortical tissue, which in turn supports improved behavioral outcome, despite no observed reduction in infarct size.
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Affiliation(s)
- Aqeela Afzal
- Department of Neurological Surgery, Vanderbilt University, Nashville, TN, USA
| | - Nagheme Thomas
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA
| | | | - Scott Barbay
- Department of Physical Medicine and Rehabilitation, University of Kansas Medical Center, Kansas City, Kansas, KS, USA
| | - J Mocco
- Department of Neurological Surgery, Mount Sinai Health, New York, NY, USA
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21
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Soria B, Escacena N, Gonzaga A, Soria-Juan B, Andreu E, Hmadcha A, Gutierrez-Vilchez AM, Cahuana G, Tejedo JR, De la Cuesta A, Miralles M, García-Gómez S, Hernández-Blasco L. Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation? Int J Mol Sci 2023; 24:17512. [PMID: 38139339 PMCID: PMC10743405 DOI: 10.3390/ijms242417512] [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: 10/27/2023] [Revised: 12/07/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.
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Affiliation(s)
- Bernat Soria
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
| | - Natalia Escacena
- Fresci Consultants, Human Health Innovation, 08025 Barcelona, Spain
| | - Aitor Gonzaga
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
| | - Barbara Soria-Juan
- Reseaux Hôpitalieres Neuchatelois et du Jura, 2000 Neuchâtel, Switzerland
| | - Etelvina Andreu
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
- Department of Applied Physics, University Miguel Hernández Elche, 03202 Elche, Spain
| | - Abdelkrim Hmadcha
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), 46002 Valencia, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Ana Maria Gutierrez-Vilchez
- Institute of Bioengineering, University Miguel Hernández, 03202 Elche, Spain
- Department of Pharmacology, Pediatrics and Organic Chemistry, University Miguel Hernández, 03202 Elche, Spain
| | - Gladys Cahuana
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | - Juan R. Tejedo
- CIBERDEM Network Research Center for Diabetes and Associated Metabolic Diseases, Carlos III Health Institute, 28029 Madrid, Spain
- Department of Molecular Biology, University Pablo de Olavide, 41013 Sevilla, Spain
| | | | - Manuel Miralles
- University and Polytechnic Hospital La Fe, 46026 Valencia, Spain
| | | | - Luis Hernández-Blasco
- Institute of Biomedical Research ISABIAL of the University Miguel Hernández, Dr. Balmis General and University Hospital, 03010 Alicante, Spain
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22
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Polo-Montalvo A, Cicuéndez M, Casarrubios L, Barroca N, da Silva D, Feito MJ, Diez-Orejas R, Serrano MC, Marques PAAP, Portolés MT. Effects of graphene oxide and reduced graphene oxide nanomaterials on porcine endothelial progenitor cells. NANOSCALE 2023; 15:17173-17183. [PMID: 37853851 DOI: 10.1039/d3nr03145d] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
Graphene oxide (GO) and reduced graphene oxide (rGO) have been widely used in the field of tissue regeneration and various biomedical applications. In order to use these nanomaterials in organisms, it is imperative to possess an understanding of their impact on different cell types. Due to the potential of these nanomaterials to enter the bloodstream, interact with the endothelium and accumulate within diverse tissues, it is highly relevant to probe them when in contact with the cellular components of the vascular system. Endothelial progenitor cells (EPCs), involved in blood vessel formation, have great potential for tissue engineering and offer great advantages to study the possible angiogenic effects of biomaterials. Vascular endothelial growth factor (VEGF) induces angiogenesis and regulates vascular permeability, mainly activating VEGFR2 on endothelial cells. The effects of GO and two types of reduced GO, obtained after vacuum-assisted thermal treatment for 15 min (rGO15) and 30 min (rGO30), on porcine endothelial progenitor cells (EPCs) functionality were assessed by analyzing the nanomaterial intracellular uptake, reactive oxygen species (ROS) production and VEGFR2 expression by EPCs. The results evidence that short annealing (15 and 30 minutes) at 200 °C of GO resulted in the mitigation of both the increased ROS production and decline in VEGFR2 expression of EPCs upon GO exposure. Interestingly, after 72 hours of exposure to rGO30, VEGFR2 was higher than in the control culture, suggesting an early angiogenic potential of rGO30. The present work reveals that discrete variations in the reduction of GO may significantly affect the response of porcine endothelial progenitor cells.
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Affiliation(s)
- Alberto Polo-Montalvo
- Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain
| | - Mónica Cicuéndez
- Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain
| | - Laura Casarrubios
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain.
| | - Nathalie Barroca
- Centre for Mechanical Technology & Automation (TEMA), Department of Mechanical Engineering, University of Aveiro, 3810-193 Aveiro, Portugal.
- LASI-Intelligent Systems Associate Laboratory, 4804-533 Guimaräes, Portugal
| | - Daniela da Silva
- Centre for Mechanical Technology & Automation (TEMA), Department of Mechanical Engineering, University of Aveiro, 3810-193 Aveiro, Portugal.
- LASI-Intelligent Systems Associate Laboratory, 4804-533 Guimaräes, Portugal
| | - María José Feito
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain.
| | - Rosalía Diez-Orejas
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain
| | - María Concepción Serrano
- Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain
| | - Paula A A P Marques
- Centre for Mechanical Technology & Automation (TEMA), Department of Mechanical Engineering, University of Aveiro, 3810-193 Aveiro, Portugal.
- LASI-Intelligent Systems Associate Laboratory, 4804-533 Guimaräes, Portugal
| | - María Teresa Portolés
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040-Madrid, Spain.
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, ISCIII, 28040-Madrid, Spain
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23
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West-Livingston L, Lim JW, Lee SJ. Translational tissue-engineered vascular grafts: From bench to bedside. Biomaterials 2023; 302:122322. [PMID: 37713761 DOI: 10.1016/j.biomaterials.2023.122322] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 09/01/2023] [Accepted: 09/09/2023] [Indexed: 09/17/2023]
Abstract
Cardiovascular disease is a primary cause of mortality worldwide, and patients often require bypass surgery that utilizes autologous vessels as conduits. However, the limited availability of suitable vessels and the risk of failure and complications have driven the need for alternative solutions. Tissue-engineered vascular grafts (TEVGs) offer a promising solution to these challenges. TEVGs are artificial vascular grafts made of biomaterials and/or vascular cells that can mimic the structure and function of natural blood vessels. The ideal TEVG should possess biocompatibility, biomechanical mechanical properties, and durability for long-term success in vivo. Achieving these characteristics requires a multi-disciplinary approach involving material science, engineering, biology, and clinical translation. Recent advancements in scaffold fabrication have led to the development of TEVGs with improved functional and biomechanical properties. Innovative techniques such as electrospinning, 3D bioprinting, and multi-part microfluidic channel systems have allowed the creation of intricate and customized tubular scaffolds. Nevertheless, multiple obstacles must be overcome to apply these innovations effectively in clinical practice, including the need for standardized preclinical models and cost-effective and scalable manufacturing methods. This review highlights the fundamental approaches required to successfully fabricate functional vascular grafts and the necessary translational methodologies to advance their use in clinical practice.
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Affiliation(s)
- Lauren West-Livingston
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA; Department of Vascular and Endovascular Surgery, Duke University, Durham, NC, 27712, USA
| | - Jae Woong Lim
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA; Department of Thoracic and Cardiovascular Surgery, Soonchunhyang University Hospital, Bucheon-Si, Gyeonggi-do, 420-767, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
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24
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Ibrahim DM, Fomina A, Bouten CVC, Smits AIPM. Functional regeneration at the blood-biomaterial interface. Adv Drug Deliv Rev 2023; 201:115085. [PMID: 37690484 DOI: 10.1016/j.addr.2023.115085] [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: 10/31/2022] [Revised: 06/01/2023] [Accepted: 09/07/2023] [Indexed: 09/12/2023]
Abstract
The use of cardiovascular implants is commonplace in clinical practice. However, reproducing the key bioactive and adaptive properties of native cardiovascular tissues with an artificial replacement is highly challenging. Exciting new treatment strategies are under development to regenerate (parts of) cardiovascular tissues directly in situ using immunomodulatory biomaterials. Direct exposure to the bloodstream and hemodynamic loads is a particular challenge, given the risk of thrombosis and adverse remodeling that it brings. However, the blood is also a source of (immune) cells and proteins that dominantly contribute to functional tissue regeneration. This review explores the potential of the blood as a source for the complete or partial in situ regeneration of cardiovascular tissues, with a particular focus on the endothelium, being the natural blood-tissue barrier. We pinpoint the current scientific challenges to enable rational engineering and testing of blood-contacting implants to leverage the regenerative potential of the blood.
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Affiliation(s)
- Dina M Ibrahim
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
| | - Aleksandra Fomina
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Graduate School of Life Sciences, Utrecht University, Utrecht, the Netherlands.
| | - Carlijn V C Bouten
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
| | - Anthal I P M Smits
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
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25
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Laursen KR, Christensen NV, Mulder FA, Schullehner J, Hoffmann HJ, Jensen A, Møller P, Loft S, Olin AC, Rasmussen BB, Rosati B, Strandberg B, Glasius M, Bilde M, Sigsgaard T. Airway and systemic biomarkers of health effects after short-term exposure to indoor ultrafine particles from cooking and candles - A randomized controlled double-blind crossover study among mild asthmatic subjects. Part Fibre Toxicol 2023; 20:26. [PMID: 37430267 DOI: 10.1186/s12989-023-00537-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/28/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND There is insufficient knowledge about the systemic health effects of exposure to fine (PM2.5) and ultrafine particles emitted from typical indoor sources, including cooking and candlelight burning. We examined whether short-term exposure to emissions from cooking and burning candles cause inflammatory changes in young individuals with mild asthma. Thirty-six non-smoking asthmatics participated in a randomized controlled double-blind crossover study attending three exposure sessions (mean PM2.5 µg/m3; polycyclic aromatic hydrocarbons ng/m3): (a) air mixed with emissions from cooking (96.1; 1.1), (b) air mixed with emissions from candles (89.8; 10), and (c) clean filtered air (5.8; 1.0). Emissions were generated in an adjacent chamber and let into a full-scale exposure chamber where participants were exposed for five hours. Several biomarkers were assessed in relation to airway and systemic inflammatory changes; the primary outcomes of interest were surfactant Protein-A (SP-A) and albumin in droplets in exhaled air - novel biomarkers for changes in the surfactant composition of small airways. Secondary outcomes included cytokines in nasal lavage, cytokines, C-reactive protein (CRP), epithelial progenitor cells (EPCs), genotoxicity, gene expression related to DNA-repair, oxidative stress, and inflammation, as well as metabolites in blood. Samples were collected before exposure start, right after exposure and the next morning. RESULTS SP-A in droplets in exhaled air showed stable concentrations following candle exposure, while concentrations decreased following cooking and clean air exposure. Albumin in droplets in exhaled air increased following exposure to cooking and candles compared to clean air exposure, although not significant. Oxidatively damaged DNA and concentrations of some lipids and lipoproteins in the blood increased significantly following exposure to cooking. We found no or weak associations between cooking and candle exposure and systemic inflammation biomarkers including cytokines, CRP, and EPCs. CONCLUSIONS Cooking and candle emissions induced effects on some of the examined health-related biomarkers, while no effect was observed in others; Oxidatively damaged DNA and concentrations of lipids and lipoproteins were increased in blood after exposure to cooking, while both cooking and candle emissions slightly affected the small airways including the primary outcomes SP-A and albumin. We found only weak associations between the exposures and systemic inflammatory biomarkers. Together, the results show the existence of mild inflammation following cooking and candle exposure.
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Affiliation(s)
- Karin Rosenkilde Laursen
- Environment, Occupation and Health, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Nichlas Vous Christensen
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark
- Department of Chemistry, Aarhus University, Aarhus, Denmark
| | - Frans Aa Mulder
- Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark
- Department of Chemistry, Aarhus University, Aarhus, Denmark
| | - Jörg Schullehner
- Environment, Occupation and Health, Department of Public Health, Aarhus University, Aarhus, Denmark
- Geological Survey of Denmark and Greenland, Aarhus, Denmark
| | - Hans Jürgen Hoffmann
- Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark
| | - Annie Jensen
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Aarhus, Denmark
| | - Peter Møller
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Aarhus, Denmark
| | - Steffen Loft
- Section of Environmental Health, Department of Public Health, University of Copenhagen, Aarhus, Denmark
| | - Anna-Carin Olin
- Department of Public Health and Community Medicine, University of Gothenburg, Gothenburg, Sweden
| | | | - Bernadette Rosati
- Department of Chemistry, Aarhus University, Aarhus, Denmark
- Faculty of Physics, University of Vienna, Vienna, Austria
| | - Bo Strandberg
- Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden
| | | | - Merete Bilde
- Department of Chemistry, Aarhus University, Aarhus, Denmark
| | - Torben Sigsgaard
- Environment, Occupation and Health, Department of Public Health, Aarhus University, Aarhus, Denmark.
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26
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Paro MR, Chakraborty AR, Angelo S, Nambiar S, Bulsara KR, Verma R. Molecular mediators of angiogenesis and neurogenesis after ischemic stroke. Rev Neurosci 2023; 34:425-442. [PMID: 36073599 PMCID: PMC12051358 DOI: 10.1515/revneuro-2022-0049] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/22/2022] [Indexed: 11/15/2022]
Abstract
The mechanisms governing neurological and functional recovery after ischemic stroke are incompletely understood. Recent advances in knowledge of intrinsic repair processes of the CNS have so far translated into minimal improvement in outcomes for stroke victims. Better understanding of the processes underlying neurological recovery after stroke is necessary for development of novel therapeutic approaches. Angiogenesis and neurogenesis have emerged as central mechanisms of post-stroke recovery and potential targets for therapeutics. Frameworks have been developed for conceptualizing cerebral angiogenesis and neurogenesis at the tissue and cellular levels. These models highlight that angiogenesis and neurogenesis are linked to each other and to functional recovery. However, knowledge of the molecular framework linking angiogenesis and neurogenesis after stroke is limited. Studies of potential therapeutics typically focus on one mediator or pathway with minimal discussion of its role within these multifaceted biochemical processes. In this article, we briefly review the current understanding of the coupled processes of angiogenesis and neurogenesis after stroke. We then identify the molecular mediators and signaling pathways found in pre-clinical studies to upregulate both processes after stroke and contextualizes them within the current framework. This report thus contributes to a more-unified understanding of the molecular mediators governing angiogenesis and neurogenesis after stroke, which we hope will help guide the development of novel therapeutic approaches for stroke survivors.
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Affiliation(s)
- Mitch R. Paro
- UConn School of Medicine, 200 Academic Way, Farmington, Connecticut 06032, United States of America
- Department of Neuroscience, UConn School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06032, United States of America
| | - Arijit R. Chakraborty
- UConn School of Medicine, 200 Academic Way, Farmington, Connecticut 06032, United States of America
| | - Sophia Angelo
- UConn School of Medicine, 200 Academic Way, Farmington, Connecticut 06032, United States of America
| | - Shyam Nambiar
- University of Connecticut, 75 North Eagleville Rd, Storrs, Connecticut 06269, United States of America
| | - Ketan R. Bulsara
- UConn School of Medicine, 200 Academic Way, Farmington, Connecticut 06032, United States of America
- Division of Neurosurgery, UConn Health, 135 Dowling Way, Farmington, Connecticut 06030, United States of America
| | - Rajkumar Verma
- UConn School of Medicine, 200 Academic Way, Farmington, Connecticut 06032, United States of America
- Department of Neuroscience, UConn School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06032, United States of America
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27
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In Search of the Holy Grail: Stem Cell Therapy as a Novel Treatment of Heart Failure with Preserved Ejection Fraction. Int J Mol Sci 2023; 24:ijms24054903. [PMID: 36902332 PMCID: PMC10003723 DOI: 10.3390/ijms24054903] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/20/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, a growing body of evidence suggests stem cell transplantation, due to its immunomodulatory effect, may decrease fibrosis and improve microcirculation and therefore, could be the first etiology-based therapy of the disease. In this review, we explain the complex pathogenesis of HFpEF, delineate the beneficial effects of stem cells in cardiovascular therapy, and summarize the current knowledge concerning cell therapy in diastolic dysfunction. Furthermore, we identify outstanding knowledge gaps that may indicate directions for future clinical studies.
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28
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Wu Y, Yazdani SK, Bolander JEM, Wagner WD. Syndecan-4 and stromal cell-derived factor-1 alpha functionalized endovascular scaffold facilitates adhesion, spreading and differentiation of endothelial colony forming cells and functions under flow and shear stress conditions. J Biomed Mater Res B Appl Biomater 2023; 111:538-550. [PMID: 36208170 PMCID: PMC10092721 DOI: 10.1002/jbm.b.35170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/22/2022] [Accepted: 09/03/2022] [Indexed: 01/25/2023]
Abstract
Acellular vascular scaffolds with capture molecules have shown great promise in recruiting circulating endothelial colony forming cells (ECFCs) to promote in vivo endothelialization. A microenvironment conducive to cell spreading and differentiation following initial cell capture are key to the eventual formation of a functional endothelium. In this study, syndecan-4 and stromal cell-derived factor-1 alpha were used to functionalize an elastomeric biomaterial composed of poly(glycerol sebacate), Silk Fibroin and Type I Collagen, termed PFC, to enhance ECFC-material interaction. Functionalized PFC (fPFC) showed significantly greater ECFCs capture capability under physiological flow. Individual cell spreading area on fPFC (1474 ± 63 μm2 ) was significantly greater than on PFC (1187 ± 54 μm2 ) as early as 2 h, indicating enhanced cell-material interaction. Moreover, fPFC significantly upregulated the expression of endothelial cell specific markers such as platelet endothelial cell adhesion molecule (24-fold) and Von Willebrand Factor (11-fold) compared with tissue culture plastic after 7 days, demonstrating differentiation of ECFCs into endothelial cells. fPFC fabricated as small diameter conduits and tested using a pulsatile blood flow bioreactor were stable and maintained function. The findings suggest that the new surface functionalization strategy proposed here results in an endovascular material with enhanced endothelialization.
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Affiliation(s)
- Yidi Wu
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.,Biomedical Engineering and Sciences, Virginia Tech - Wake Forest University School, Winston-Salem, North Carolina, USA
| | - Saami K Yazdani
- Department of Engineering, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Johanna Elin Marie Bolander
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, USA
| | - William D Wagner
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.,Biomedical Engineering and Sciences, Virginia Tech - Wake Forest University School, Winston-Salem, North Carolina, USA.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, USA
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29
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Maximal Exercise Improves the Levels of Endothelial Progenitor Cells in Heart Failure Patients. Curr Issues Mol Biol 2023; 45:1950-1960. [PMID: 36975495 PMCID: PMC10046939 DOI: 10.3390/cimb45030125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/05/2023] Open
Abstract
The impact of exercise on the levels of endothelial progenitor cells (EPCs), a marker of endothelial repair and angiogenesis, and circulating endothelial cells (CECs), an indicator of endothelial damage, in heart failure patients is largely unknown. This study aims to evaluate the effects of a single exercise bout on the circulating levels of EPCs and CECs in heart failure patients. Thirteen patients with heart failure underwent a symptom-limited maximal cardiopulmonary exercise test to assess exercise capacity. Before and after exercise testing, blood samples were collected to quantify EPCs and CECs by flow cytometry. The circulating levels of both cells were also compared to the resting levels of 13 volunteers (age-matched group). The maximal exercise bout increased the levels of EPCs by 0.5% [95% Confidence Interval, 0.07 to 0.93%], from 4.2 × 10−3 ± 1.5 × 10−3% to 4.7 × 10−3 ± 1.8 × 10−3% (p = 0.02). No changes were observed in the levels of CECs. At baseline, HF patients presented reduced levels of EPCs compared to the age-matched group (p = 0.03), but the exercise bout enhanced circulating EPCs to a level comparable to the age-matched group (4.7 × 10−3 ± 1.8 × 10−3% vs. 5.4 × 10−3 ± 1.7 × 10−3%, respectively, p = 0.14). An acute bout of exercise improves the potential of endothelial repair and angiogenesis capacity by increasing the circulating levels of EPCs in patients with heart failure.
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Amraotkar AR, Owolabi US, Malovichko MV, Majid S, Weisbrod RM, Benjamin EJ, Fetterman JL, Hirsch GA, Srivastava S, Poudel R, Robertson RM, Bhatnagar A, Hamburg NM, Keith RJ. Association of electronic cigarette use with circulating angiogenic cell levels in healthy young adults: Evidence for chronic systemic injury. Vasc Med 2023; 28:18-27. [PMID: 36503365 DOI: 10.1177/1358863x221126205] [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] [Indexed: 12/14/2022]
Abstract
BACKGROUND Circulating angiogenic cells (CACs) are indicative of vascular health and repair capacity; however, their relationship with chronic e-cigarette use is unclear. This study aims to assess the association between e-cigarette use and CAC levels. METHODS We analyzed CAC levels in 324 healthy participants aged 21-45 years from the cross-sectional Cardiovascular Injury due to Tobacco Use study in four groups: never tobacco users (n = 65), sole e-cigarette users (n = 19), sole combustible cigarette users (n = 212), and dual users (n = 28). A total of 15 CAC subpopulations with four cell surface markers were measured using flow cytometry: CD146 (endothelial), CD34 (stem), CD45 (leukocyte), and AC133 (early progenitor/stem). Generalized linear models with gamma distribution and log-link were generated to assess association between CACs and smoking status. Benjamini-Hochberg were used to adjust p-values for multiple comparisons. RESULTS The cohort was 47% female, 51% Black/African American, with a mean (± SD) age of 31 ± 7 years. Sole cigarette use was significantly associated with higher levels of two endothelial marker CACs (Q ⩽ 0.05). Dual users had higher levels of four endothelial marker CACs and one early progenitor/stem marker CAC (Q ⩽ 0.05). Sole e-cigarette users had higher levels of one endothelial and one leukocyte marker CAC (Q ⩽ 0.05). CONCLUSION Dual use of e-cigarettes and combustible cigarettes was associated with higher levels of endothelial origin CACs, indicative of vascular injury. Sole use of e-cigarettes was associated with higher endothelial and inflammatory CACs, suggesting ongoing systemic injury. Distinct patterns of changes in CAC subpopulations suggest that CACs may be informative biomarkers of changes in vascular health due to tobacco product use.
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Affiliation(s)
- Alok R Amraotkar
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Ugochukwu S Owolabi
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marina V Malovichko
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.,Superfund Research Center, University of Louisville, Louisville, KY, USA
| | - Sana Majid
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Robert M Weisbrod
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Emelia J Benjamin
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.,Boston University School of Public Health, Boston, MA, USA.,Boston University Medical Center, Boston, MA, USA
| | - Jessica L Fetterman
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Glenn A Hirsch
- Department of Cardiology, National Jewish Health, Denver, CO, USA
| | - Sanjay Srivastava
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.,Superfund Research Center, University of Louisville, Louisville, KY, USA
| | - Ram Poudel
- American Heart Association, Dallas, TX, USA
| | | | - Aruni Bhatnagar
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Naomi M Hamburg
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Rachel J Keith
- Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
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Yoshida Y, Takeda Y, Yamahara K, Yamamoto H, Takagi T, Kuramoto Y, Nakano-Doi A, Nakagomi T, Soma T, Matsuyama T, Doe N, Yoshimura S. Enhanced angiogenic properties of umbilical cord blood primed by OP9 stromal cells ameliorates neurological deficits in cerebral infarction mouse model. Sci Rep 2023; 13:262. [PMID: 36609640 PMCID: PMC9822952 DOI: 10.1038/s41598-023-27424-7] [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: 09/15/2022] [Accepted: 12/29/2022] [Indexed: 01/09/2023] Open
Abstract
Umbilical cord blood (UCB) transplantation shows proangiogenic effects and contributes to symptom amelioration in animal models of cerebral infarction. However, the effect of specific cell types within a heterogeneous UCB population are still controversial. OP9 is a stromal cell line used as feeder cells to promote the hematoendothelial differentiation of embryonic stem cells. Hence, we investigated the changes in angiogenic properties, underlying mechanisms, and impact on behavioral deficiencies caused by cerebral infarction in UCB co-cultured with OP9 for up to 24 h. In the network formation assay, only OP9 pre-conditioned UCB formed network structures. Single-cell RNA sequencing and flow cytometry analysis showed a prominent phenotypic shift toward M2 in the monocytic fraction of OP9 pre-conditioned UCB. Further, OP9 pre-conditioned UCB transplantation in mice models of cerebral infarction facilitated angiogenesis in the peri-infarct lesions and ameliorated the associated symptoms. In this study, we developed a strong, fast, and feasible method to augment the M2, tissue-protecting, pro-angiogenic features of UCB using OP9. The ameliorative effect of OP9-pre-conditioned UCB in vivo could be partly due to promotion of innate angiogenesis in peri-infarct lesions.
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Affiliation(s)
- Yasunori Yoshida
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yuki Takeda
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Kenichi Yamahara
- Laboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Hanae Yamamoto
- grid.272264.70000 0000 9142 153XLaboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshinori Takagi
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yoji Kuramoto
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Akiko Nakano-Doi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Takayuki Nakagomi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshihiro Soma
- grid.272264.70000 0000 9142 153XDepartment of Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Tomohiro Matsuyama
- grid.272264.70000 0000 9142 153XDepartment of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Nobutaka Doe
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan ,grid.272264.70000 0000 9142 153XDepartment of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, 1-3-6 Minatojima, Chuo-Ku, Kobe, Hyogo 650-8530 Japan
| | - Shinichi Yoshimura
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
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Kumar N, Maher N, Amin F, Ghabbani H, Zafar MS, Rodríguez-Lozano FJ, Oñate-Sánchez RE. Biomimetic Approaches in Clinical Endodontics. Biomimetics (Basel) 2022; 7:biomimetics7040229. [PMID: 36546929 PMCID: PMC9775094 DOI: 10.3390/biomimetics7040229] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/19/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
In the last few decades, biomimetic concepts have been widely adopted in various biomedical fields, including clinical dentistry. Endodontics is an important sub-branch of dentistry which deals with the different conditions of pulp to prevent tooth loss. Traditionally, common procedures, namely pulp capping, root canal treatment, apexification, and apexigonesis, have been considered for the treatment of different pulp conditions using selected materials. However, clinically to regenerate dental pulp, tissue engineering has been advocated as a feasible approach. Currently, new trends are emerging in terms of regenerative endodontics which have led to the replacement of diseased and non-vital teeth into the functional and healthy dentine-pulp complex. Root- canal therapy is the standard management option when dental pulp is damaged irreversibly. This treatment modality involves soft-tissue removal and then filling that gap through the obturation technique with a synthetic material. The formation of tubular dentine and pulp-like tissue formation occurs when stem cells are transplanted into the root canal with an appropriate scaffold material. To sum up tissue engineering approach includes three components: (1) scaffold, (2) differentiation, growth, and factors, and (3) the recruitment of stem cells within the pulp or from the periapical region. The aim of this paper is to thoroughly review and discuss various pulp-regenerative approaches and materials used in regenerative endodontics which may highlight the current trends and future research prospects in this particular area.
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Affiliation(s)
- Naresh Kumar
- Department of Science of Dental Materials, Dr. Ishrat Ul Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences, Karachi 74200, Pakistan
- Correspondence: ; Tel.: +92-333-2818500
| | - Nazrah Maher
- Department of Science of Dental Materials, Dr. Ishrat Ul Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Faiza Amin
- Department of Science of Dental Materials, Dow Dental College, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Hani Ghabbani
- Department of Restorative Dentistry, College of Dentistry, Taibah University, Al Madinah, Al Munawwarah 41311, Saudi Arabia
| | - Muhammad Sohail Zafar
- Department of Restorative Dentistry, College of Dentistry, Taibah University, Al Madinah, Al Munawwarah 41311, Saudi Arabia
- Department of Dental Materials, Islamic International Dental College, Riphah International University, Islamabad 44000, Pakistan
| | | | - Ricardo E. Oñate-Sánchez
- Department of Special Care in Dentistry, Hospital Morales Meseguer, IMIB-Arrixaca, University of Murcia, 30008 Murcia, Spain
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Matson J, Lange P, Honore PM, Chung KK. Adverse outcomes with extracorporeal adsorbent blood treatments in toxic systemic inflammation: a perspective on possible mechanisms. Ann Intensive Care 2022; 12:105. [PMID: 36370238 PMCID: PMC9652582 DOI: 10.1186/s13613-022-01078-6] [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: 06/08/2022] [Accepted: 10/27/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Extracorporeal blood purification (EBP) treatments may be used in patients with sepsis and related conditions to mitigate toxic systemic inflammation, prevent or reverse vital organ injury, and improve outcome. These treatments lack demonstrable efficacy, but are generally considered safe. However, since late 2020, four clinical studies of EBP treatment using adsorbent devices in inflammatory disease reported significantly increased patient mortality associated with the adsorbent treatments. Criticisms of study design and execution were published, but revealed no decisive flaws. None of these critiques considered possible toxic effects of the adsorbent treatments per se. PERSPECTIVE AND CONCLUSION In adsorbent EBP treatment of systemic inflammatory disease the adsorbent media are deployed in patient blood or plasma flow for the purpose of broad spectrum, non-specific adsorptive removal of inflammatory mediators. Adsorption and sequestration of inflammatory mediators by adsorbent media is intended to reduce mediator concentrations in circulating blood and neutralize their activity. However, in the past two decades developments in both biomedical engineering and the science of cytokine molecular dynamics suggest that immobilization of inflammatory proteins on solid scaffolds or molecular carriers may stabilize protein structure and preserve or amplify protein function. It is unknown if these mechanisms are operative in EBP adsorbent treatments. If these mechanisms are operative, then the adsorbent medium could become reactive, promoting inflammatory activity which could result in negative outcomes. Considering the recent reports of harm with adsorbent treatments in diverse inflammatory conditions, caution urges investigation of these potentially harmful mechanisms in these devices. Candidate mechanisms for possible inquiry are discussed.
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Affiliation(s)
| | - Paul Lange
- Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI, USA
- Medical Director, Donor Alliance, Inc., Denver, CO, USA
| | - Patrick M Honore
- ICU Dept-Brugmann University Hospital, Faculty of Medicine of the ULB University, Brussels, Belgium
| | - Kevin K Chung
- Department of Medicine, Uniformed Services University, Bethesda, MD, USA
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Wang Y, Li G, Yang L, Luo R, Guo G. Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2201971. [PMID: 35654586 DOI: 10.1002/adma.202201971] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/29/2022] [Indexed: 06/15/2023]
Abstract
Cardiovascular diseases have become the leading cause of death worldwide. The increasing burden of cardiovascular diseases has become a major public health problem and how to carry out efficient and reliable treatment of cardiovascular diseases has become an urgent global problem to be solved. Recently, implantable biomaterials and devices, especially minimally invasive interventional ones, such as vascular stents, artificial heart valves, bioprosthetic cardiac occluders, artificial graft cardiac patches, atrial shunts, and injectable hydrogels against heart failure, have become the most effective means in the treatment of cardiovascular diseases. Herein, an overview of the challenges and research frontier of innovative biomaterials and devices for the treatment of cardiovascular diseases is provided, and their future development directions are discussed.
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Affiliation(s)
- Yunbing Wang
- National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China
| | - Gaocan Li
- National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China
| | - Li Yang
- National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China
| | - Rifang Luo
- National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China
| | - Gaoyang Guo
- National Engineering Research Center for Biomaterials and College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, China
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Rudnicka-Drożak E, Drożak P, Mizerski G, Drożak M. Endothelial Progenitor Cells in Neurovascular Disorders—A Comprehensive Overview of the Current State of Knowledge. Biomedicines 2022; 10:biomedicines10102616. [PMID: 36289878 PMCID: PMC9599182 DOI: 10.3390/biomedicines10102616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/11/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer’s disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer’s disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy.
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Affiliation(s)
- Ewa Rudnicka-Drożak
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Paulina Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
- Correspondence: ; Tel.: +48-669-084-455
| | - Grzegorz Mizerski
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Martyna Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
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Douglass M, Garren M, Devine R, Mondal A, Handa H. Bio-inspired hemocompatible surface modifications for biomedical applications. PROGRESS IN MATERIALS SCIENCE 2022; 130:100997. [PMID: 36660552 PMCID: PMC9844968 DOI: 10.1016/j.pmatsci.2022.100997] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
When blood first encounters the artificial surface of a medical device, a complex series of biochemical reactions is triggered, potentially resulting in clinical complications such as embolism/occlusion, inflammation, or device failure. Preventing thrombus formation on the surface of blood-contacting devices is crucial for maintaining device functionality and patient safety. As the number of patients reliant on blood-contacting devices continues to grow, minimizing the risk associated with these devices is vital towards lowering healthcare-associated morbidity and mortality. The current standard clinical practice primarily requires the systemic administration of anticoagulants such as heparin, which can result in serious complications such as post-operative bleeding and heparin-induced thrombocytopenia (HIT). Due to these complications, the administration of antithrombotic agents remains one of the leading causes of clinical drug-related deaths. To reduce the side effects spurred by systemic anticoagulation, researchers have been inspired by the hemocompatibility exhibited by natural phenomena, and thus have begun developing medical-grade surfaces which aim to exhibit total hemocompatibility via biomimicry. This review paper aims to address different bio-inspired surface modifications that increase hemocompatibility, discuss the limitations of each method, and explore the future direction for hemocompatible surface research.
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Affiliation(s)
- Megan Douglass
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Mark Garren
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Ryan Devine
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Arnab Mondal
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA
| | - Hitesh Handa
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, Athens, GA, USA
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA
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Bauer CJ, Findlay M, Koliamitra C, Zimmer P, Schick V, Ludwig S, Gurtner GC, Riedel B, Schier R. Preoperative exercise induces endothelial progenitor cell mobilisation in patients undergoing major surgery – A prospective randomised controlled clinical proof-of-concept trial. Heliyon 2022; 8:e10705. [PMID: 36200018 PMCID: PMC9529507 DOI: 10.1016/j.heliyon.2022.e10705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/10/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Prehabilitation is increasingly recognised as a therapeutic option to reduce postoperative complications. Investigating the beneficial effects of exercise on cellular mechanisms, we have previously shown that a single episode of exhaustive exercise effectively stimulates endothelial progenitor cells (a cell population associated with vascular maintenance, repair, angiogenesis, and neovascularization) in correlation with fewer postoperative complications, despite the ongoing debate about the appropriate cell surface marker profiles of these cells (common phenotypical definitions include CD45dim, CD133+, CD34+ and/or CD31+). In order to translate these findings into clinical application, a feasible prehabilitation programme achieving both functional and cellular benefits in a suitable timeframe to expedite surgery is necessary. Objective The objective of this study was to test the hypothesis that a four-week prehabilitation programme of vigorous-intensity interval exercise training is feasible, increases physical capacity (primary outcome) and the circulatory number of endothelial progenitor cells within peripheral blood. Methods In this unblinded, parallel-group, randomised controlled proof-of-concept clinical trial (German Clinical Trial Register number: DRKS00000527) conducted between 01st December 2014 and 30th November 2016, fifteen female adult patients scheduled for incontinence surgery with abdominal laparotomy at the University Hospital Cologne were allocated to either an exercise (n = 8, exclusion of 1 patient, analysed n = 7) or non-exercise group (n = 7, exclusion of 1 patient, analysed n = 6). The exercise group's intervention consisted of a vigorous-intensity interval training for four weeks preoperatively. Cardiopulmonary Exercise Testing accompanied by peripheral blood collection was performed before and after the (non-)training phase. Cellular investigations were conducted by flow cytometry and cluster-based analyses. Results Vigorous-intensity interval training over four weeks was feasible in the exercise group (successful completion by 8 out of 8 patients without any harms), with significant improvements in patients' functional capacity (increased oxygen uptake at anaerobic threshold [intervention group mean + 1.71 ± 3.20 mL/min/kg vs. control group mean −1.83 ± 2.14 mL/min/kg; p = 0.042] and peak exercise [intervention group mean + 1.71 ± 1.60 mL/min/kg vs. control group mean −1.67 ± 1.37 mL/min/kg; p = 0.002]) and a significant increase in the circulatory number of endothelial progenitor cells (proportionate CD45dim/CD14dim/CD133+/CD309+/CD34+/CD31 + subpopulation within the circulating CD45-pool [p = 0.016]). Conclusions We introduce a novel prehabilitation concept that shows effective stimulation of an endothelial progenitor cell subpopulation within four weeks of preoperative exercise, serving as a clinical cell-mediated intervention with the aim to reduce surgical complications. Funding Institutional funding. DFG (German Research Foundation, 491454339) support for the Article Processing Charge.
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Affiliation(s)
- Claus Juergen Bauer
- Department of Internal Medicine—Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
| | - Michael Findlay
- Department of Surgery, Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Christina Koliamitra
- Institute for Cardiovascular Research and Sports Medicine, German Sports University Cologne, Cologne, Germany
| | - Philipp Zimmer
- Institute of Sports and Sports Medicine, TU Dortmund University, Dortmund, Germany
| | - Volker Schick
- Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sebastian Ludwig
- Department of Obstetrics and Gynaecology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Geoffrey C. Gurtner
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, USA
| | - Bernhard Riedel
- Department of Anaesthetics, Perioperative Medicine and Pain Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Robert Schier
- Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Corresponding author.
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Park S, Avera AD, Kim Y. BIOMANUFACTURING OF GLIOBLASTOMA ORGANOIDS EXHIBITING HIERARCHICAL AND SPATIALLY ORGANIZED TUMOR MICROENVIRONMENT VIA TRANSDIFFERENTIATION. Biotechnol Bioeng 2022; 119:3252-3274. [DOI: 10.1002/bit.28191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/14/2022] [Accepted: 07/20/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Seungjo Park
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Alexandra D. Avera
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Yonghyun Kim
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
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Kourek C, Briasoulis A, Zouganeli V, Karatzanos E, Nanas S, Dimopoulos S. Exercise Training Effects on Circulating Endothelial and Progenitor Cells in Heart Failure. J Cardiovasc Dev Dis 2022; 9:222. [PMID: 35877584 PMCID: PMC9322098 DOI: 10.3390/jcdd9070222] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a major public health issue worldwide with increased prevalence and a high number of hospitalizations. Patients with chronic HF and either reduced ejection fraction (HFrEF) or mildly reduced ejection fraction (HFmrEF) present vascular endothelial dysfunction and significantly decreased circulating levels of endothelial progenitor cells (EPCs). EPCs are bone marrow-derived cells involved in endothelium regeneration, homeostasis, and neovascularization. One of the unsolved issues in the field of EPCs is the lack of an established method of identification. The most widely approved method is the use of monoclonal antibodies and fluorescence-activated cell sorting (FACS) analysis via flow cytometry. The most frequently used markers are CD34, VEGFR-2, CD45, CD31, CD144, and CD146. Exercise training has demonstrated beneficial effects on EPCs by increasing their number in peripheral circulation and improving their functional capacities in patients with HFrEF or HFmrEF. There are two potential mechanisms of EPCs mobilization: shear stress and the hypoxic/ischemic stimulus. The combination of both leads to the release of EPCs in circulation promoting their repairment properties on the vascular endothelium barrier. EPCs are important therapeutic targets and one of the most promising fields in heart failure and, therefore, individualized exercise training programs should be developed in rehabilitation centers.
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Affiliation(s)
- Christos Kourek
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
- Department of Cardiology, 417 Army Share Fund Hospital of Athens (NIMTS), 11521 Athens, Greece
| | - Alexandros Briasoulis
- Department of Clinical Therapeutics, Alexandra Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Division of Cardiovascular Medicine, Section of Heart Failure and Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Virginia Zouganeli
- Second Cardiology Department, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Eleftherios Karatzanos
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
| | - Serafim Nanas
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
| | - Stavros Dimopoulos
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
- Cardiac Surgery Intensive Care Unit, Onassis Cardiac Surgery Center, 17674 Athens, Greece
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Bone Marrow Stromal Cell Regeneration Profile in Treated B-Cell Precursor Acute Lymphoblastic Leukemia Patients: Association with MRD Status and Patient Outcome. Cancers (Basel) 2022; 14:cancers14133088. [PMID: 35804860 PMCID: PMC9265080 DOI: 10.3390/cancers14133088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 12/10/2022] Open
Abstract
For the last two decades, measurable residual disease (MRD) has become one of the most powerful independent prognostic factors in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the effect of therapy on the bone marrow (BM) microenvironment and its potential relationship with the MRD status and disease free survival (DFS) still remain to be investigated. Here we analyzed the distribution of mesenchymal stem cells (MSC) and endothelial cells (EC) in the BM of treated BCP-ALL patients, and its relationship with the BM MRD status and patient outcome. For this purpose, the BM MRD status and EC/MSC regeneration profile were analyzed by multiparameter flow cytometry (MFC) in 16 control BM (10 children; 6 adults) and 1204 BM samples from 347 children and 100 adult BCP-ALL patients studied at diagnosis (129 children; 100 adults) and follow-up (824 childhood samples; 151 adult samples). Patients were grouped into a discovery cohort (116 pediatric BCP-ALL patients; 338 samples) and two validation cohorts (74 pediatric BCP-ALL, 211 samples; and 74 adult BCP-ALL patients; 134 samples). Stromal cells (i.e., EC and MSC) were detected at relatively low frequencies in all control BM (16/16; 100%) and in most BCP-ALL follow-up samples (874/975; 90%), while they were undetected in BCP-ALL BM at diagnosis. In control BM samples, the overall percentage of EC plus MSC was higher in children than adults (p = 0.011), but with a similar EC/MSC ratio in both groups. According to the MRD status similar frequencies of both types of BM stromal cells were detected in BCP-ALL BM studied at different time points during the follow-up. Univariate analysis (including all relevant prognostic factors together with the percentage of stromal cells) performed in the discovery cohort was used to select covariates for a multivariate Cox regression model for predicting patient DFS. Of note, an increased percentage of EC (>32%) within the BCP-ALL BM stromal cell compartment at day +78 of therapy emerged as an independent unfavorable prognostic factor for DFS in childhood BCP-ALL in the discovery cohort—hazard ratio (95% confidence interval) of 2.50 (1−9.66); p = 0.05—together with the BM MRD status (p = 0.031). Further investigation of the predictive value of the combination of these two variables (%EC within stromal cells and MRD status at day +78) allowed classification of BCP-ALL into three risk groups with median DFS of: 3.9, 3.1 and 1.1 years, respectively (p = 0.001). These results were confirmed in two validation cohorts of childhood BCP-ALL (n = 74) (p = 0.001) and adult BCP-ALL (n = 40) (p = 0.004) treated at different centers. In summary, our findings suggest that an imbalanced EC/MSC ratio in BM at day +78 of therapy is associated with a shorter DFS of BCP-ALL patients, independently of their MRD status. Further prospective studies are needed to better understand the pathogenic mechanisms involved.
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Chen K, Li Y, Xu L, Qian Y, Liu N, Zhou C, Liu J, Zhou L, Xu Z, Jia R, Ge YZ. Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment. Stem Cell Res Ther 2022; 13:238. [PMID: 35672766 PMCID: PMC9172199 DOI: 10.1186/s13287-022-02921-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/29/2022] [Indexed: 12/21/2022] Open
Abstract
Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.
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Affiliation(s)
- Ke Chen
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yang Li
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Luwei Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yiguan Qian
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ning Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Liuhua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Zheng Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
| | - Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
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Li Y, Cui W, Song B, Ye X, Li Z, Lu C. Autophagy-Sirtuin1(SIRT1) Alleviated the Coronary Atherosclerosis (AS)in Mice through Regulating the Proliferation and Migration of Endothelial Progenitor Cells (EPCs) via wnt/β-catenin/GSK3β Signaling Pathway. J Nutr Health Aging 2022; 26:297-306. [PMID: 35297474 DOI: 10.1007/s12603-022-1750-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND PURPOSE SIRT1 was associated with AS risk and EPCs were reported to participate in the endothelial repair in Coronary Atherosclerosis (CAS). In this study, we explored the role of SIRT1 in AS mice and also its modulation in EPCs. METHODS AND MATERIALS ApoE-/-mice were fed on high-fat and high-glucose diet to establish the AS animal model with the normally-raised C57BL/6 mice as a control group. SIRT1 activator, SRT 2104 was injected intravenously into 5 ApoE-/-mice and its inhibitor Nicotinamide was injected in tail in another 5 ApoE-/-mice. Weight changes were recorded. Blood samples were taken from posterior orbital venous plexus and were detected by automatic biochemical analyzer. HE staining displayed the pathological conditions while Immunohistochemistry (IHC) evaluated the CD34+/VEGFR2+ relative density in the aorta tissues. EPCs were isolated from bone marrow and verified using immunofluorescence staining (IFS). The modulatory mechanism of SIRT1 in EPCs were studied by using RT-PCR, MTT, Western Blot and colony formation, scratch methods. RESULTS SIRT1 activator negatively regulated the weight and TC, TG and LDL levels, alleviated the lesion conditions and decreased the CD34+/VEGFR2+ density compared to the AS control. In vitro, SIRT1 activator promoted the proliferation and migration of EPCs and activated wnt/β-catenin/GSK3β signaling pathway. SIRT1 activator also inhibited the autophagy biomarkers ATG1 and LC3II. Furthermore, inhibitor of autophagy promoted SIRT1 expression and induced EPC proliferation, migration and activated wnt/β-catenin/GSK3β pathway. The suppression of the wnt/β-catenin/GSK3β pathway inhibited SIRT1 expression in EPCs, attenuated the proliferation and migration and promoted autophagy of EPCs. CONCLUSION SIRT1 activation might be protective in AS mice through autophagy inhibition in EPCs via wnt/β-catenin/GSK3β signaling pathway.
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Affiliation(s)
- Y Li
- Chengzhi Lu, Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300110, China, ,
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Ferentinos P, Tsakirides C, Swainson M, Davison A, Martyn-St James M, Ispoglou T. The impact of different forms of exercise on circulating endothelial progenitor cells in cardiovascular and metabolic disease. Eur J Appl Physiol 2022. [PMID: 35022875 DOI: 10.1007/s00421-021-04876-1.pmid:35022875;pmcid:pmc8927049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
UNLABELLED Circulating endothelial progenitor cells (EPCs) contribute to vascular repair and their monitoring could have prognostic clinical value. Exercise is often prescribed for the management of cardiometabolic diseases, however, it is not fully understood how it regulates EPCs. OBJECTIVES to systematically examine the acute and chronic effects of different exercise modalities on circulating EPCs in patients with cardiovascular and metabolic disease. METHODS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. RESULTS six electronic databases and reference lists of eligible studies were searched to April 2021. Thirty-six trials met the inclusion criteria including 1731 participants. Acute trials: in chronic heart failure (CHF), EPC mobilisation was acutely increased after high intensity interval or moderate intensity continuous exercise training, while findings were inconclusive after a cardiopulmonary cycling exercise test. Maximal exercise tests acutely increased EPCs in ischaemic or revascularized coronary artery disease (CAD) patients. In peripheral arterial disease (PAD), EPC levels increased up to 24 h post-exercise. In patients with compromised metabolic health, EPC mobilisation was blunted after a single exercise session. Chronic trials: in CHF and acute coronary syndrome, moderate intensity continuous protocols, with or without resistance exercise or calisthenics, increased EPCs irrespective of EPC identification phenotype. Findings were equivocal in CAD regardless of exercise mode, while in severe PAD disease EPCs increased. High intensity interval training increased EPCs in hypertensive metabolic syndrome and heart failure reduced ejection fraction. CONCLUSION the clinical condition and exercise modality influence the degree of EPC mobilisation and magnitude of EPC increases in the long term.
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Affiliation(s)
| | | | - Michelle Swainson
- Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
| | - Adam Davison
- Flow Cytometry Facility, Leeds Institute of Cancer and Pathology St James's University Hospital, University of Leeds, Leeds, UK
- Cytec Biosciences B.V, Amsterdam, The Netherlands
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ADAMTS9-AS2 Promotes Angiogenesis of Brain Microvascular Endothelial Cells Through Regulating miR-185-5p/IGFBP-2 Axis in Ischemic Stroke. Mol Neurobiol 2022; 59:2593-2604. [DOI: 10.1007/s12035-021-02641-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 11/07/2021] [Indexed: 12/21/2022]
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Effects of Shen-Yuan-Dan on Periprocedural Myocardial Injury and the Number of Peripheral Blood Endothelial Progenitor Cells in Patients with Unstable Angina Pectoris Undergoing Elective Percutaneous Coronary Intervention. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9055585. [PMID: 35035512 PMCID: PMC8759927 DOI: 10.1155/2022/9055585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/29/2021] [Indexed: 11/18/2022]
Abstract
OBJECTIVES We aimed to investigate the effects of Shen-Yuan-Dan (SYD), a Chinese medicine preparation, on periprocedural myocardial injury (PMI) and the number of peripheral blood endothelial progenitor cells (EPCs) in patients with unstable angina pectoris (UA) who underwent elective percutaneous coronary intervention (PCI). METHODS Patients were randomly divided into the experimental (group A) and control (group B) groups through the random number table method. In group A, patients concurrently received the conventional western treatment and SYD orally (4 capsules/time, 3 times/d, from 3 d before surgery to 7 d after surgery). In group B, patients received conventional Western medicine treatment. Both groups underwent coronary angiography, and patients undergoing PCI were eventually included in the study. The following patient data were collected: incidence of PMI, serum CK-MB content before PCI, 4 h, 24 h, and 7 d after PCI, number of CD45dim/-CD34+CD309+ peripheral venous EPCs, and number of CD184 coexpressed EPCs. The incidence of adverse reactions and 30-day major adverse cardiovascular events (MACEs) were also recorded. RESULTS Sixty-two patients were finally included in this study, with 32 and 30 in groups A and B, respectively. In group A, the number of peripheral blood EPCs and the number of CD184 coexpressed EPCs at 1 h before surgery were higher than those at 3 d before surgery (37.24 ± 25.20 vs. 22.78 ± 9.60/ml; P < 0.001 and 23.38 ± 15.30 vs. 13.54 ± 8.08/ml; P < 0.001, resp.). The number of peripheral blood EPCs and number of CD184 coexpressed EPCs at 4 h after surgery were lower than those at 1 h before surgery (25.30 ± 11.90 vs. 37.24 ± 25.20/ml; P=0.019 and 15.38 ± 8.78 vs. 23.38 ± 15.30/ml; P=0.013, resp.), but there was no difference at 24 h and at 7 d after surgery in comparison with that at 1 h before surgery (P > 0.05). In group B, compared with that at 1 h before surgery, there existed a decline in the number of EPCs in peripheral blood and the number of CD184 coexpressed EPCs at 4 h after surgery, but without a statistical difference (P > 0.05). Comparing both groups, it was found that the incidence of PMI in group A was lower (6.25% vs. 26.67%; P=0.04), and the serum CK-MB content at 4 and 24 h after surgery was also lower than that in group B (17.33 ± 5.83 vs. 20.38 ± 4.32 U/l; P=0.048 and 15.79 ± 5.32 vs. 19.10 ± 4.93 U/l; P=0.030, resp.). The number of EPCs in peripheral blood and the number of CD184 coexpressed EPCs in group A were higher than those in group B at 1 h before surgery (37.24 ± 25.20 vs. 22.36 ± 12.26/ml; P=0.034 and 23.38 ± 15.30 vs. 13.12 ± 14.62/ml; P=0.013, resp.). In addition, there were no obvious adverse reactions and no 30-day MACEs in both groups during the trial. CONCLUSION SYD can reduce PMI and promote the mobilization of EPCs in the perioperative period of elective PCI in patients with UA.
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Ferentinos P, Tsakirides C, Swainson M, Davison A, Martyn-St James M, Ispoglou T. The impact of different forms of exercise on circulating endothelial progenitor cells in cardiovascular and metabolic disease. Eur J Appl Physiol 2022; 122:815-860. [PMID: 35022875 PMCID: PMC8927049 DOI: 10.1007/s00421-021-04876-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/14/2021] [Indexed: 12/19/2022]
Abstract
Circulating endothelial progenitor cells (EPCs) contribute to vascular repair and their monitoring could have prognostic clinical value. Exercise is often prescribed for the management of cardiometabolic diseases, however, it is not fully understood how it regulates EPCs. OBJECTIVES to systematically examine the acute and chronic effects of different exercise modalities on circulating EPCs in patients with cardiovascular and metabolic disease. METHODS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. RESULTS six electronic databases and reference lists of eligible studies were searched to April 2021. Thirty-six trials met the inclusion criteria including 1731 participants. Acute trials: in chronic heart failure (CHF), EPC mobilisation was acutely increased after high intensity interval or moderate intensity continuous exercise training, while findings were inconclusive after a cardiopulmonary cycling exercise test. Maximal exercise tests acutely increased EPCs in ischaemic or revascularized coronary artery disease (CAD) patients. In peripheral arterial disease (PAD), EPC levels increased up to 24 h post-exercise. In patients with compromised metabolic health, EPC mobilisation was blunted after a single exercise session. Chronic trials: in CHF and acute coronary syndrome, moderate intensity continuous protocols, with or without resistance exercise or calisthenics, increased EPCs irrespective of EPC identification phenotype. Findings were equivocal in CAD regardless of exercise mode, while in severe PAD disease EPCs increased. High intensity interval training increased EPCs in hypertensive metabolic syndrome and heart failure reduced ejection fraction. CONCLUSION the clinical condition and exercise modality influence the degree of EPC mobilisation and magnitude of EPC increases in the long term.
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Affiliation(s)
| | | | - Michelle Swainson
- Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
| | - Adam Davison
- Flow Cytometry Facility, Leeds Institute of Cancer and Pathology St James's University Hospital, University of Leeds, Leeds, UK
- Cytec Biosciences B.V, Amsterdam, The Netherlands
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Yamaguchi J, Chiba R, Komuro H, Ihara K, Nozaki K, Nagai A, Furukawa T, Sasano T. Local Injection of Hydroxyapatite Electret Ameliorated Infarct Size After Myocardial Infarction. Circ Rep 2022; 4:38-47. [PMID: 35083387 PMCID: PMC8710644 DOI: 10.1253/circrep.cr-21-0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/01/2021] [Accepted: 11/04/2021] [Indexed: 11/17/2022] Open
Abstract
Background:
Previous studies showed that hydroxyapatite electret (HAE) accelerates the regeneration of vascular endothelial cells and angiogenesis. This study investigated the effects of HAE in myocardial infarction (MI) model mice. Methods and Results:
MI was induced in mice by ligating the left anterior descending artery. Immediately after ligation, HAE, non-polarized hydroxyapatite (HAN), or water (control) was injected into the infarct border myocardium. Functional and histological analyses were performed 2 weeks later. Echocardiography revealed that HAE injection preserved left ventricular systolic function and the wall thickness of the scar, whereas HAN-injected mice had impaired cardiac function and thinning of the wall, similar to control mice. Histological assessment showed that HAE injection significantly attenuated the length of the scar lesion. There was significant accumulation of CD31-positive cells and increased expression of vascular endothelial growth factor (Vegf), intercellular adhesion molecule-1 (Icam1), vascular cell adhesion molecule-1 (Vcam1), hypoxia-inducible factor-1α (Hif1a), and C-X-C motif chemokine ligand 12 (Cxcl12) genes in the infarct border zone of HAE-injected mice. These effects were not induced by HAN injection. Anti-VEGFR2 antibody canceled the beneficial effect of HAE. In vitro experiments in a human cardiovascular endothelial cell line showed that HAE dose-dependently increased
VEGFA
expression. Conclusions:
Local injection of HAE attenuated infarct size and improved cardiac function after MI, probably due to angiogenesis. The electric charge of HAE may stimulate angiogenesis via HIF1α-CXCL12/VEGF signaling.
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Affiliation(s)
- Junji Yamaguchi
- Department of Cardiovascular Medicine, Tokyo Medical and Dental University
| | - Risako Chiba
- Department of Cardiovascular Physiology, Tokyo Medical and Dental University
| | - Hiroaki Komuro
- Department of Cardiovascular Physiology, Tokyo Medical and Dental University
| | - Kensuke Ihara
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University
| | - Kosuke Nozaki
- Department of Fixed Prosthodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
| | - Akiko Nagai
- Department of Anatomy, Aichi-Gakuin University School of Dentistry
| | - Tetsushi Furukawa
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University
| | - Tetsuo Sasano
- Department of Cardiovascular Medicine, Tokyo Medical and Dental University
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Infantile hemangiomas β 3-adrenoceptor overexpression is associated with nonresponse to propranolol. Pediatr Res 2022; 91:163-170. [PMID: 33654276 DOI: 10.1038/s41390-021-01385-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/15/2020] [Accepted: 01/07/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. METHODS Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. RESULTS While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. CONCLUSIONS Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. IMPACT Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β2-ARs. However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.
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Quantitative Analysis of Factors Regulating Angiogenesis for Stem Cell Therapy. BIOLOGY 2021; 10:biology10111212. [PMID: 34827205 PMCID: PMC8614798 DOI: 10.3390/biology10111212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary The control of angiogenesis is essential in disease treatment or regenerative medicine. We conducted a clinical study of dedifferentiated fat (DFAT) cells, a kind of mesenchymal stem cells, by applying cell transplantation therapy to induce angiogenesis in patients with severe ischemic disease. This study aimed to analyze the effect of molecules that regulate angiogenesis in vitro and clarify their molecular mechanisms for therapeutic purposes. Normal human umbilical venous endothelial cells (HUVECs) were cultured in the presence of vascular endothelial growth factor (VEGF). Recombinant human angiopoietin-1-producing cells, conditioned media, mouse DFAT cells, and antioxidant polyphenols were added to this system at various concentrations. After 11 days, the cultures were immunostained with CD31 (PECAM-1), and microscopic images were subjected to analysis (area, length, joint, and path) by using software to quantitatively analyze blood vessel formation. The expression of angiogenic markers and COX pathway genes were analyzed by RT-PCR. As a result, the dose-dependent angiogenesis-promoting effect of rAng-1-producing cells, conditioned medium, or commercially available recombinant Ang-1 were observed. DFAT cells also promoted angiogenesis, whereas polyphenols inhibited angiogenesis in a dose-dependent manner. Abstract (1) Background: The control of angiogenesis is essential in disease treatment. We investigated angiogenesis-promoting or -suppressing factors and their molecular mechanisms. (2) Methods: Angiogenesis from HUVECs was quantitatively analyzed using the Angiogenesis Analysis Kit (Kurabo, Osaka, Japan). Human rAng-1-producing 107-35 CHO cells or mouse DFAT-D1 cells were co-cultured with HUVEC. Antioxidant polyphenols were added to the culture. Gene expression was analyzed by RT-PCR. (3) Results: The addition of rAng-1-producing cells, their culture supernatant, or commercially available rAng-1 showed a promoting effect on angiogenesis. The co-culture of DFAT-D1 cells promoted angiogenesis. Polyphenols showed a dose-dependent inhibitory effect on angiogenesis. Luteolin and quercetin showed remarkable anti-angiogenic effects. The expression of vWF, Flk1, and PECAM-1 was increased by adding rAng-1-producing cell culture supernatant. Polyphenols suppressed these genes. Apigenin and luteolin markedly suppressed α-SMA and Flk1. Resveratrol and quercetin enhanced the expression of PPARγ, and luteolin suppressed the expression of COX-1. The expression of endothelial nitric oxide synthase (eNOS), an oxidative stress-related gene, was slightly increased by luteolin. These results suggest that polyphenols induce ROS reduction. (4) Conclusions: We showed the promoting effect of Ang-1 or DFAT and the suppressing effect of polyphenols on angiogenesis and studied their molecular mechanisms. These results help control angiogenesis in regenerative therapy.
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Li C, Lin L, Zhang L, Xu R, Chen X, Ji J, Li Y. Long noncoding RNA p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway. Pharmacol Res 2021; 173:105920. [PMID: 34601081 DOI: 10.1016/j.phrs.2021.105920] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/22/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022]
Abstract
Vascular damage of hypertension has been the focus of hypertension treatment, and endothelial progenitor cells (EPCs) play an important role in the repair of vascular endothelial damage. Functional damage and decreased number of EPCs are observed in the peripheral circulation of hypertensive patients, but its mechanism is not yet elucidated. Here, we show that the number of EPCs in hypertensive patients is significantly lower than that of normal population, and the cell function decreases with a higher proportion of EPCs at later stages. A decrease in autophagy is responsible for the senescence and damage of EPCs induced by AngII. Moreover, lncRNA-p21 plays a critical regulator role in EPCs' senescence and dysfunction. Furthermore, lncRNA-p21 activates SESN2/AMPK/TSC2 pathway by promoting the transcriptional activity of p53 and enhances autophagy to protect against AngII-induced EPC damage. The data provide evidence that a reversal of decreased autophagy serves as the protective mechanism of EPC injury in hypertensive patients, and lncRNA-p21 is a new therapeutic target for vascular endothelial repair in hypertension.
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Affiliation(s)
- Chao Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Lin Lin
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Lei Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ran Xu
- Tianqiao District People's Hospital, Jinan 250031, China
| | - Xiaoqing Chen
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jingkang Ji
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yunlun Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250000, China.
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