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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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Larrea Murillo L, Green M, Mahon N, Saiani A, Tsigkou O. Modelling Cancer Pathophysiology: Mechanisms and Changes in the Extracellular Matrix During Cancer Initiation and Early Tumour Growth. Cancers (Basel) 2025; 17:1675. [PMID: 40427172 PMCID: PMC12110603 DOI: 10.3390/cancers17101675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes.
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Affiliation(s)
- Luis Larrea Murillo
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
| | - Megan Green
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Niall Mahon
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Alberto Saiani
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester M1 7DN, UK
| | - Olga Tsigkou
- Department of Materials, School of Natural Sciences, Faculty of Science and Engineering, The University of Manchester, Manchester M13 9PL, UK; (M.G.)
- The Henry Royce Institute, Royce Hub Building, Manchester M13 9PL, UK
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Di Donna MG, Colona VL, Bagnato MR, Bonomi CG, Tirrito L, Marchionni E, Motta C, Sangiuolo FC, Martorana A. NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients. Neurol Sci 2025; 46:1637-1646. [PMID: 39652165 DOI: 10.1007/s10072-024-07908-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/25/2024] [Indexed: 03/19/2025]
Abstract
INTRODUCTION The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. RESULTS The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers -Cerebrospinal fluid (CSF) analysis negative for Alzheimer's Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). DISCUSSION AND CONCLUSION The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.
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Affiliation(s)
- M G Di Donna
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy.
- Stroke Unit, Ospedale F. Spaziani, Via A. Fabi 5, 03100, Frosinone, Italy.
| | - V L Colona
- Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Movement Analysis and Robotics Laboratory (MARlab), Research Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - M R Bagnato
- Stroke Unit, Ospedale F. Spaziani, Via A. Fabi 5, 03100, Frosinone, Italy
- Stroke Unit, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - C G Bonomi
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - L Tirrito
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - E Marchionni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - C Motta
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - F C Sangiuolo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - A Martorana
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
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Gonzalez‐Rubio J, Kubiza H, Xu Y, Koenigs‐Werner H, Schmitz MS, Schedel M, Apel C, Jockenhoevel S, Cornelissen CG, Thiebes AL. Pericytes Promote More Vascularization than Stromal Cells via an Interleukin-6-Dependent Mechanism in Microfluidic Chips. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408131. [PMID: 39887579 PMCID: PMC11984840 DOI: 10.1002/advs.202408131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 01/10/2025] [Indexed: 02/01/2025]
Abstract
Pericytes are a key player in vascularization, protecting endothelial cells from external harm and promoting the formation of new vessels when necessary. However, pericytic identity and its relationship with other cell types, such as mesenchymal stromal/stem cells, is highly debated. This study compares the role of pericytes and unselected stromal cells in vascularization using multichannel microfluidic chips. In both angiogenesis and vasculogenesis, pericytes promote more vessel formation than stromal cells. Pericytes can wrap around endothelial vessels acting as mural cells, while stromal cells remain separated. Whole-transcriptome sequencing confirms an upregulation of pro-vascularization genes in endothelial cell-pericyte co-cultures, while metabolism increases and inflammation decreases in stromal cell co-cultures. Treatment of stromal-endothelial cell co-cultures with either conditioned media or isolated extracellular vesicles from pericytes replicates the increase in vasculogenesis of the direct co-cultures. Cytokine quantification reveals that interleukin 6 (IL-6) is significantly increased in pericyte conditions. Blocking it with siltuximab results in a reduction of pericyte vasculogenic potential comparable to stromal cell levels, revealing that pericyte pro-vascularization is mediated by IL-6. This study provides new insights into the relationship between pericytes and endothelial cells and the elusive identity of mesenchymal stromal cells. These findings are relevant for both vascular biology and tissue engineering.
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Affiliation(s)
- Julian Gonzalez‐Rubio
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
| | - Hannah Kubiza
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
| | - Yong Xu
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
| | - Hiltrud Koenigs‐Werner
- Institute of PathologyElectron Microscopy FacilityRWTH Aachen University HospitalAachen, Pauwelsstrasse 3052074AachenGermany
| | - Mona Sophie Schmitz
- Department of Pulmonary MedicineUniversity Medicine Essen‐RuhrlandklinikTueschener Weg 4045239EssenGermany
- Department of Pulmonary MedicineUniversity Medicine EssenEssen, Hufelandstraße 5545147EssenGermany
| | - Michaela Schedel
- Department of Pulmonary MedicineUniversity Medicine Essen‐RuhrlandklinikTueschener Weg 4045239EssenGermany
- Department of Pulmonary MedicineUniversity Medicine EssenEssen, Hufelandstraße 5545147EssenGermany
| | - Christian Apel
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
| | - Stefan Jockenhoevel
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
| | - Christian G. Cornelissen
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
- Clinic for Pneumology and Internal Intensive Care Medicine (Medical Clinic V)RWTH Aachen University HospitalPauwelsstrasse 3052074AachenGermany
| | - Anja Lena Thiebes
- Department of Biohybrid & Medical Textiles (BioTex)AME – Institute of Applied Medical EngineeringHelmholtz InstituteRWTH Aachen UniversityForckenbeckstrasse 5552074AachenGermany
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Mei X, Yang Z, Wang X, Shi A, Blanchard J, Elahi F, Kang H, Orive G, Zhang YS. Integrating microfluidic and bioprinting technologies: advanced strategies for tissue vascularization. LAB ON A CHIP 2025; 25:764-786. [PMID: 39775452 DOI: 10.1039/d4lc00280f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Tissue engineering offers immense potential for addressing the unmet needs in repairing tissue damage and organ failure. Vascularization, the development of intricate blood vessel networks, is crucial for the survival and functions of engineered tissues. Nevertheless, the persistent challenge of ensuring an ample nutrient supply within implanted tissues remains, primarily due to the inadequate formation of blood vessels. This issue underscores the vital role of the human vascular system in sustaining cellular functions, facilitating nutrient exchange, and removing metabolic waste products. In response to this challenge, new approaches have been explored. Microfluidic devices, emulating natural blood vessels, serve as valuable tools for investigating angiogenesis and allowing the formation of microvascular networks. In parallel, bioprinting technologies enable precise placement of cells and biomaterials, culminating in vascular structures that closely resemble the native vessels. To this end, the synergy of microfluidics and bioprinting has further opened up exciting possibilities in vascularization, encompassing innovations such as microfluidic bioprinting. These advancements hold great promise in regenerative medicine, facilitating the creation of functional tissues for applications ranging from transplantation to disease modeling and drug testing. This review explores the potentially transformative impact of microfluidic and bioprinting technologies on vascularization strategies within the scope of tissue engineering.
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Affiliation(s)
- Xuan Mei
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
| | - Ziyi Yang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
- School of Biological Science, University of California Irvine, Irvine, CA 92697, USA
| | - Xiran Wang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, San Diego, CA 92161, USA
| | - Alan Shi
- Brookline High School, Brookline, MA 02445, USA
| | - Joel Blanchard
- Departments of Neurology, Neuroscience, and Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Fanny Elahi
- Departments of Neurology, Neuroscience, and Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468, USA
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, Seoul 02841, Republic of Korea.
- College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
- University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria-Gasteiz, 01007, Spain
- Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Yu Shrike Zhang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
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Li G, Gao J, Ding P, Gao Y. The role of endothelial cell-pericyte interactions in vascularization and diseases. J Adv Res 2025; 67:269-288. [PMID: 38246244 PMCID: PMC11725166 DOI: 10.1016/j.jare.2024.01.016] [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: 11/24/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining the inner layer of blood vessels and PCs surrounding capillaries to regulate blood flow and angiogenesis. Intercellular communication between ECs and PCs is vital for the formation, stability, and function of blood vessels. Various signaling pathways, such as the vascular endothelial growth factor/vascular endothelial growth factor receptor pathway and the platelet-derived growth factor-B/platelet-derived growth factor receptor-β pathway, play roles in communication between ECs and PCs. Dysfunctional communication between these cells is associated with various diseases, including vascular diseases, central nervous system disorders, and certain types of cancers. AIM OF REVIEW This review aimed to explore the diverse roles of ECs and PCs in the formation and reshaping of blood vessels. This review focused on the essential signaling pathways that facilitate communication between these cells and investigated how disruptions in these pathways may contribute to disease. Additionally, the review explored potential therapeutic targets, future research directions, and innovative approaches, such as investigating the impact of EC-PCs in novel systemic diseases, addressing resistance to antiangiogenic drugs, and developing novel antiangiogenic medications to enhance therapeutic efficacy. KEY SCIENTIFIC CONCEPTS OF REVIEW Disordered EC-PC intercellular signaling plays a role in abnormal blood vessel formation, thus contributing to the progression of various diseases and the development of resistance to antiangiogenic drugs. Therefore, studies on EC-PC intercellular interactions have high clinical relevance.
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Affiliation(s)
- Gan Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Shanghai Sixth People's Hospital Fujian, No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, China
| | - Peng Ding
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Youshui Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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Rodrigues FAP, Oliveira CS, Sá SC, Tavaria FK, Lee SJ, Oliveira AL, Costa JB. Molecules in Motion: Unravelling the Dynamics of Vascularization Control in Tissue Engineering. Macromol Biosci 2024; 24:e2400139. [PMID: 39422632 DOI: 10.1002/mabi.202400139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 08/14/2024] [Indexed: 10/19/2024]
Abstract
Significant progress has been made in tissue engineering (TE), aiming at providing personalized solutions and overcoming the current limitations of traditional tissue and organ transplantation. 3D bioprinting has emerged as a transformative technology in the field, able to mimic key properties of the natural architecture of the native tissues. However, most successes in the area are still limited to avascular or thin tissues due to the difficulties in controlling the vascularization of the engineered tissues. To address this issue, several molecules, biomaterials, and cells with pro- and anti-angiogenic potential have been intensively investigated. Furthermore, different bioreactors capable to provide a dynamic environment for in vitro vascularization control have been also explored. The present review summarizes the main molecules and TE strategies used to promote and inhibit vascularization in TE, as well as the techniques used to deliver them. Additionally, it also discusses the current challenges in 3D bioprinting and in tissue maturation to control in vitro/in vivo vascularization. Currently, this field of investigation is of utmost importance and may open doors for the design and development of more precise and controlled vascularization strategies in TE.
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Affiliation(s)
- Francisco A P Rodrigues
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - Cláudia S Oliveira
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - Simone C Sá
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - Freni K Tavaria
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Ana L Oliveira
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - João B Costa
- CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Universidade Católica Portuguesa, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, Porto, 4169-005, Portugal
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McIntyre G, Jackson Z, Colina J, Sekhar S, DiFeo A. miR-181a: regulatory roles, cancer-associated signaling pathway disruptions, and therapeutic potential. Expert Opin Ther Targets 2024; 28:1061-1091. [PMID: 39648331 PMCID: PMC12054384 DOI: 10.1080/14728222.2024.2433687] [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: 08/01/2024] [Accepted: 11/20/2024] [Indexed: 12/10/2024]
Abstract
INTRODUCTION microRNA-181a (miR-181a) is a crucial post-transcriptional regulator of many mRNA transcripts and noncoding-RNAs, influencing cell proliferation, cancer cell stemness, apoptosis, and immune responses. Its abnormal expression is well-characterized in numerous cancers, establishing it as a significant genomic vulnerability and biomarker in cancer research. AREAS COVERED Here, we summarize miR-181a's correlation with poor patient outcomes across numerous cancers and the mechanisms governing miR-181a's activity and processing. We comprehensively describe miR-181a's involvement in multiple regulatory cancer signaling pathways, cellular processes, and the tumor microenvironment. We also discuss current therapeutic approaches to targeting miR-181a, highlighting their limitations and future potential. EXPERT OPINION miR-181a is a clinically relevant pan-cancer biomarker with potential as a therapeutic target. Its regulatory control of tumorigenic signaling pathways and immune responses positions it as a promising candidate for personalized treatments. The success of miR-181a as a target relies on the development of specific therapeutics platforms. Future research on miR-181a's role in the tumor microenvironment and the RNA binding proteins that regulate its stability will help uncover new techniques to targeting miR-181a. Further research into miR-181a serum levels in patients undergoing therapy will help to better stratify patients and enhance therapeutic success.
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Affiliation(s)
- Grace McIntyre
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Zoe Jackson
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Jose Colina
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Sreeja Sekhar
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Analisa DiFeo
- Department of Pathology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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9
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Limbu S, McCloskey KE. An Endothelial Cell Is Not Simply an Endothelial Cell. Stem Cells Dev 2024; 33:517-527. [PMID: 39030822 PMCID: PMC11564855 DOI: 10.1089/scd.2024.0088] [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: 04/30/2024] [Accepted: 07/18/2024] [Indexed: 07/22/2024] Open
Abstract
Endothelial cells (ECs) are a multifaceted component of the vascular system with roles in immunity, maintaining tissue fluid balance, and vascular tone. Dysregulation or dysfunction of ECs can have far-reaching implications, leading pathologies ranging from cardiovascular diseases, such as hypertension and atherosclerosis, ischemia, chronic kidney disease, blood-brain barrier integrity, dementia, and tumor metastasis. Recent advancements in regenerative medicine have highlighted the potential of stem cell-derived ECs, particularly from induced pluripotent stem cells, to treat ischemic tissues, as well as models of vascular integrity. This review summarizes what is known in the generation of ECs with an emphasis on tissue-specific ECs and EC subphenotypes important in the development of targeted cell-based therapies for patient treatment.
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Affiliation(s)
- Shiwani Limbu
- Quantitative and System Biology Graduate Program, University of California, Merced, USA
| | - Kara E. McCloskey
- Quantitative and System Biology Graduate Program, University of California, Merced, USA
- Materials Science and Engineering Department, University of California, Merced, USA
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Chen F, Zhao J, Meng F, He F, Ni J, Fu Y. The vascular contribution of apolipoprotein E to Alzheimer's disease. Brain 2024; 147:2946-2965. [PMID: 38748848 DOI: 10.1093/brain/awae156] [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: 12/24/2023] [Revised: 03/23/2024] [Accepted: 04/21/2024] [Indexed: 09/04/2024] Open
Abstract
Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset Alzheimer's disease, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavours.
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Affiliation(s)
- Feng Chen
- Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jing Zhao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Fanxia Meng
- Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Fangping He
- Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jie Ni
- Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yuan Fu
- Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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11
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Larionov A, Hammer CM, Fiedler K, Filgueira L. Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease. Cells 2024; 13:1276. [PMID: 39120307 PMCID: PMC11312403 DOI: 10.3390/cells13151276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/19/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.
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Affiliation(s)
- Alexey Larionov
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Christian Manfred Hammer
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Klaus Fiedler
- Independent Researcher, CH-1700 Fribourg, Switzerland;
| | - Luis Filgueira
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
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12
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Pal D, Das P, Mukherjee P, Roy S, Chaudhuri S, Kesh SS, Ghosh D, Nandi SK. Biomaterials-Based Strategies to Enhance Angiogenesis in Diabetic Wound Healing. ACS Biomater Sci Eng 2024; 10:2725-2741. [PMID: 38630965 DOI: 10.1021/acsbiomaterials.4c00216] [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: 04/19/2024]
Abstract
Amidst the present healthcare issues, diabetes is unique as an emerging class of affliction with chronicity in a majority of the population. To check and control its effects, there have been huge turnover and constant development of management strategies, and though a bigger part of the health care area is involved in achieving its control and the related issues such as the effect of diabetes on wound healing and care and many of the works have reached certain successful outcomes, still there is a huge lack in managing it, with maximum effect yet to be attained. Studying pathophysiology and involvement of various treatment options, such as tissue engineering, application of hydrogels, drug delivery methods, and enhancing angiogenesis, are at constantly developing stages either direct or indirect. In this review, we have gathered a wide field of information and different new therapeutic methods and targets for the scientific community, paving the way toward more settled ideas and research advances to cure diabetic wounds and manage their outcomes.
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Affiliation(s)
- Debajyoti Pal
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Pratik Das
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Prasenjit Mukherjee
- Department of Veterinary Clinical Complex, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Subhasis Roy
- Department of Veterinary Clinical Complex, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Shubhamitra Chaudhuri
- Department of Veterinary Clinical Complex, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Shyam Sundar Kesh
- Department of Veterinary Clinical Complex, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Debaki Ghosh
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
| | - Samit Kumar Nandi
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata 700037, India
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13
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Fu Y, Zhang Z, Webster KA, Paulus YM. Treatment Strategies for Anti-VEGF Resistance in Neovascular Age-Related Macular Degeneration by Targeting Arteriolar Choroidal Neovascularization. Biomolecules 2024; 14:252. [PMID: 38540673 PMCID: PMC10968528 DOI: 10.3390/biom14030252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 05/04/2024] Open
Abstract
Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declining responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.
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Affiliation(s)
- Yingbin Fu
- Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (Z.Z.); (K.A.W.)
- Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhao Zhang
- Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (Z.Z.); (K.A.W.)
| | - Keith A. Webster
- Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (Z.Z.); (K.A.W.)
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Yannis M. Paulus
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA;
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
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14
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Ateeq M, Broadwin M, Sellke FW, Abid MR. Extracellular Vesicles' Role in Angiogenesis and Altering Angiogenic Signaling. Med Sci (Basel) 2024; 12:4. [PMID: 38249080 PMCID: PMC10801520 DOI: 10.3390/medsci12010004] [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: 11/16/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/23/2024] Open
Abstract
Angiogenesis, the process of new blood vessels formation from existing vasculature, plays a vital role in development, wound healing, and various pathophysiological conditions. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators in intercellular communication and have gained significant attention for their role in modulating angiogenic processes. This review explores the multifaceted role of EVs in angiogenesis and their capacity to modulate angiogenic signaling pathways. Through comprehensive analysis of a vast body of literature, this review highlights the potential of utilizing EVs as therapeutic tools to modulate angiogenesis for both physiological and pathological purposes. A good understanding of these concepts holds promise for the development of novel therapeutic interventions targeting angiogenesis-related disorders.
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Affiliation(s)
- Maryam Ateeq
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
| | - Frank W. Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
| | - M. Ruhul Abid
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA; (M.A.); (M.B.); (F.W.S.)
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15
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Wang J, Chen T, Ruszaj DM, Mager DE, Straubinger RM. Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models. J Pharm Sci 2024; 113:72-84. [PMID: 37844759 DOI: 10.1016/j.xphs.2023.10.019] [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: 08/14/2023] [Revised: 10/11/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023]
Abstract
Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of monoclonal antibodies (mAb). A linked pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to integrate the plasma and tumor PK of a sHHi priming agent with its effects upon downstream stromal biomarkers Gli1, hyaluronic acid, and interstitial fluid pressure in PDAC patient-derived xenograft (PDX) tumors. In parallel, in situ tumor concentrations of cetuximab (CTX: anti-epidermal growth factor receptor; EGFR) were quantified as a marker for tumor delivery of mAb or antibody-drug conjugates. A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve.
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Affiliation(s)
- Jun Wang
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Ting Chen
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Donna M Ruszaj
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Donald E Mager
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA
| | - Robert M Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Department of Cell Stress Biochemistry and Biophysics, Roswell Park Comprehenhsive Cancer Center, Buffalo, NY, USA; Department of Pharmacology and Therapeutics, Roswell Park Comprehenhsive Cancer Center, Buffalo, NY, USA.
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16
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Mannan A, Dhiamn S, Garg N, Singh TG. Pharmacological modulation of Sonic Hedgehog signaling pathways in Angiogenesis: A mechanistic perspective. Dev Biol 2023; 504:58-74. [PMID: 37739118 DOI: 10.1016/j.ydbio.2023.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
The Sonic hedgehog (SHh) signaling pathway is an imperative operating network that helps in regulates the critical events during the development processes like multicellular embryo growth and patterning. Disruptions in SHh pathway regulation can have severe consequences, including congenital disabilities, stem cell renewal, tissue regeneration, and cancer/tumor growth. Activation of the SHh signal occurs when SHh binds to the receptor complex of Patch (Ptc)-mediated Smoothened (Smo) (Ptc-smo), initiating downstream signaling. This review explores how pharmacological modulation of the SHh pathway affects angiogenesis through canonical and non-canonical pathways. The canonical pathway for angiogenesis involves the activation of angiogenic cytokines such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), stromal cell-derived factor 1α, transforming growth factor-β1 (TGF-β1), and angiopoietins (Ang-1 and Ang-2), which facilitate the process of angiogenesis. The Non-canonical pathway includes indirect activation of certain pathways like iNOS/Netrin-1/PKC, RhoA/Rock, ERK/MAPK, PI3K/Akt, Wnt/β-catenin, Notch signaling pathway, and so on. This review will provide a better grasp of the mechanistic approach of SHh in mediating angiogenesis, which can aid in the suppression of certain cancer and tumor growths.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiamn
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Nikhil Garg
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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17
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Debski T, Siennicka K, Idaszek J, Roszkowski B, Swieszkowski W, Pojda Z. Effect of adipose-derived stem cells seeding and surgical prefabrication on composite scaffold vascularization. J Biomater Appl 2023; 38:548-561. [PMID: 37732423 DOI: 10.1177/08853282231202601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
The study aimed to evaluate an angiogenic effect of adipose-derived stem cells (ASCs) seeding and surgical prefabrication (placing a vascular pedicle inside the scaffold) on developed composite scaffolds made of poly-ε-caprolactone (PCL), β-tricalcium phosphate (β-TCP), and poly (lactic-co-glycolic acid) (PLGA) (PCL+β-TCP+PLGA). Moreover, we aimed to compare our data with previously tested PCL scaffolds to assess whether the new material has better angiogenic properties. The study included 18 inbred male WAG rats. There were three scaffold groups (six animals each): with non-seeded PCL+β-TCP+PLGA scaffolds, with PCL+β-TCP+PLGA scaffolds seeded with ASCs and with PCL+β-TCP+PLGA scaffolds seeded with ASCs and osteogenic-induced. Each rat was implanted with two scaffolds in the inguinal region (one prefabricated and one non-prefabricated). After 2 months from implantation, the scaffolds were explanted, and vessel density was determined by histopathological examination. Prefabricated ASC-seeded PCL+β-TCP+PLGA scaffolds promoted greater vessel formation than non-seeded scaffolds (19.73 ± 5.46 vs 12.54 ± 0.81; p = .006) and those seeded with osteogenic-induced ASCs (19.73 ± 5.46 vs 11.87±2.21; p = .004). The developed composite scaffold promotes vessel formation more effectively than the previously described PCL scaffold.
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Affiliation(s)
- Tomasz Debski
- Department of Regenerative Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Katarzyna Siennicka
- Department of Regenerative Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Joanna Idaszek
- Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw, Poland
| | - Bartlomiej Roszkowski
- Department of Regenerative Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Wojciech Swieszkowski
- Materials Design Division, Faculty of Materials Science and Engineering, Warsaw University of Technology, Warsaw, Poland
| | - Zygmunt Pojda
- Department of Regenerative Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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18
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Shi L, Song H, Zhou B, Morrow BE. Crk/Crkl regulates early angiogenesis in mouse embryos by accelerating endothelial cell maturation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.12.548782. [PMID: 37503032 PMCID: PMC10369973 DOI: 10.1101/2023.07.12.548782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Rationale Ubiquitously expressed cytoplasmic adaptors CRK and CRKL mediate multiple signaling pathways in mammalian embryogenesis. They are also associated with cardiovascular defects occurring in Miller-Dieker syndrome and 22q11.2 deletion syndrome, respectively. The embryonic mesoderm contributes to the formation of the cardiovascular system, yet the roles that Crk and Crkl play there are not understood on a single cell level. Objectives To determine functions of Crk and Crkl in the embryonic mesoderm during early mouse vascular development. Secondly, we will examine the molecular mechanisms responsible for early embryonic endothelial cell (EC) defects by performing single cell RNA-sequencing (scRNA-seq) and in vivo validation experiments. Methods and Results Inactivation of both Crk and Crkl together using Mesp1 Cre resulted embryonic lethality with severe vascular defects. Although vasculogenesis appeared normal, angiogenesis was disrupted both in the yolk sac and embryo proper, leading to disorganized vascular networks. We performed scRNA-seq of the Mesp1 Cre mesodermal lineage and found that there was upregulation of a great number of angiogenesis and cell migration related genes in ECs in the mutants, including NOTCH signaling genes such as Dll4 and Hey1 . Further bioinformatic analysis of EC subpopulations identified a relative increase in the number of more differentiated angiogenic ECs and decrease in EC progenitors. Consistent with this, we identified an expansion of Dll4 expressing cells within abnormal arteries, in vivo . Also, our bioinformatic data indicates that there is dysregulated expression of lineage genes that promote EC differentiation causing accelerated cell fate progression during EC differentiation. Conclusions Our results show that Crk and Crkl are crucial for regulating early embryonic angiogenesis. Combined inactivation of Crk/Crkl caused precocious EC maturation with an increase of atypical differentiated angiogenic ECs and failed vascular remodeling. This is in part due to increased NOTCH signaling and altered expression of cell migration genes.
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Georgieva I, Tchekalarova J, Iliev D, Tzoneva R. Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer's Disease. Int J Mol Sci 2023; 24:11344. [PMID: 37511104 PMCID: PMC10379128 DOI: 10.3390/ijms241411344] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer's disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer's disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer's disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions.
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Affiliation(s)
- Irina Georgieva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
| | - Jana Tchekalarova
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 23, 1113 Sofia, Bulgaria
| | - Dimitar Iliev
- Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
| | - Rumiana Tzoneva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
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20
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Neriyanuri S, Bedggood P, Symons RCA, Metha AB. Flow Heterogeneity and Factors Contributing to the Variability in Retinal Capillary Blood Flow. Invest Ophthalmol Vis Sci 2023; 64:15. [PMID: 37450310 DOI: 10.1167/iovs.64.10.15] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023] Open
Abstract
Purpose Capillary flow plays an important role in the nourishment and maintenance of healthy neural tissue and can be observed directly and non-invasively in the living human retina. Despite their importance, patterns of normal capillary flow are not well understood due to limitations in spatial and temporal resolution of imaging data. Methods Capillary flow characteristics were studied in the retina of three healthy young individuals using a high-resolution adaptive optics ophthalmoscope. Imaging with frame rates of 200 to 300 frames per second was sufficient to capture details of the single-file flow of red blood cells in capillaries over the course of about 3 seconds. Results Erythrocyte velocities were measured from 72 neighboring vessels of the parafoveal capillary network for each subject. We observed strong variability among vessels within a given subject, and even within a given imaged field, across a range of capillary flow parameters including maximum and minimum velocities, pulsatility, abruptness of the systolic peak, and phase of the cardiac cycle. The observed variability was not well explained by "local" factors such as the vessel diameter, tortuosity, length, linear cell density, or hematocrit of the vessel. Within a vessel, a moderate relation between the velocities and hematocrit was noted, suggesting a redistribution of plasma between cells with changes in flow. Conclusions These observations advance our fundamental understanding of normal capillary physiology and raise questions regarding the potential role of network-level effects in explaining the observed flow heterogeneity.
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Affiliation(s)
- Srividya Neriyanuri
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Phillip Bedggood
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - R C Andrew Symons
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
- Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
- Centre for Eye Research Australia, East Melbourne, Victoria, Australia
- Department of Surgery, Alfred Hospital, Monash University, Melbourne, Victoria, Australia
| | - Andrew B Metha
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
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Chopra M, Bhagwani A, Kumar H. The Provenance, Providence, and Position of Endothelial Cells in Injured Spinal Cord Vascular Pathology. Cell Mol Neurobiol 2023; 43:1519-1535. [PMID: 35945301 PMCID: PMC11412425 DOI: 10.1007/s10571-022-01266-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 07/21/2022] [Indexed: 11/03/2022]
Abstract
Endothelial cells (ECs) and pericytes are present in all blood vessels. Their position confers an important role in controlling oxygen and nutrient transportation to the different organs. ECs can adopt different morphologies based on their need and functions. Both ECs and pericytes express different surface markers that help in their identification, but heterogeneity and overlapping between markers among different cells pose a challenge for their precise identification. Spatiotemporal association of ECs and pericytes have great importance in sprout formation and vessel stabilization. Any traumatic injury in CNS may lead to vascular damage along with neuronal damage. Hence, ECs-pericyte interaction by physical contact and paracrine molecules is crucial in recovering the epicenter region by promoting angiogenesis. ECs can transform into other types of cells through endothelial-mesenchymal transition (EndMT), promoting wound healing in the epicenter region. Various signaling pathways mediate the interaction of ECs with pericytes that have an extensive role in angiogenesis. In this review, we discussed ECs and pericytes surface markers, the spatiotemporal association and interaction of ECs-pericytes, and signaling associated with the pathology of traumatic SCI. Linking the brain or spinal cord-specific pathologies and human vascular pathology will pave the way toward identifying new therapeutic targets and developing innovative preventive strategies. Endothelial-pericyte interaction strategic for formation of functional neo-vessels that are crucial for neurological recovery.
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Affiliation(s)
- Manjeet Chopra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ankita Bhagwani
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat, 382355, India.
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22
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Xing Y, Zhang Y, Li C, Luo L, Hua Y, Hu J, Bai Y. Repetitive Transcranial Magnetic Stimulation of the Brain After Ischemic Stroke: Mechanisms from Animal Models. Cell Mol Neurobiol 2023; 43:1487-1497. [PMID: 35917043 PMCID: PMC11412424 DOI: 10.1007/s10571-022-01264-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/20/2022] [Indexed: 11/24/2022]
Abstract
Stroke is a common cerebrovascular disease with high morbidity, mortality, and disability worldwide. Post-stroke dysfunction is related to the death of neurons and impairment of synaptic structure, which results from cerebral ischemic damage. Currently, transcranial magnetic stimulation (TMS) techniques are available to provide clinically effective interventions and quantitative diagnostic and prognostic biomarkers. The development of TMS has been 40 years and a range of repetitive TMS (rTMS) protocols are now available to regulate neuronal plasticity in many neurological disorders, such as stroke, Parkinson disease, psychiatric disorders, Alzheimer disease, and so on. Basic studies in an animal model with ischemic stroke are significant for demonstrating potential mechanisms of neural restoration induced by rTMS. In this review, the mechanisms were summarized, involving synaptic plasticity, neural cell death, neurogenesis, immune response, and blood-brain barrier (BBB) disruption in vitro and vivo experiments with ischemic stroke models. Those findings can contribute to the understanding of how rTMS modulated function recovery and the exploration of novel therapeutic targets. The mechanisms of rTMS in treating ischemic stroke from animal models. rTMS can prompt synaptic plasticity by increasing NMDAR, AMPAR and BDNF expression; rTMS can inhibit pro-inflammatory cytokines TNF and facilitate the expression of anti-inflammatory cytokines IL-10 by shifting astrocytic phenotypes from A1 to A2, and shifting microglial phenotypes from M1 to M2; rTMS facilitated the release of angiogenesis-related factors TGFβ and VEGF in A2 astrocytes, which can contribute to vasculogenesis and angiogenesis; rTMS can suppress apoptosis by increasing Bcl-2 expression and inhibiting Bax, caspase-3 expression; rTMS can also suppress pyroptosis by decreasing caspase-1, IL-1β, ASC, GSDMD and NLRP1 expression. rTMS, repetitive transcranial magnetic stimulation; NMDAR, N-methyl-D-aspartic acid receptors; AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor; GSDMD: cleaved Caspase-1 cleaves Gasdermin D; CBF: cerebral blood flow.
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Affiliation(s)
- Ying Xing
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Yuqian Zhang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Congqin Li
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Lu Luo
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Yan Hua
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Jian Hu
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China
| | - Yulong Bai
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing'an District, Shanghai, 200040, China.
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23
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Ahmed TA, Eldaly B, Eldosuky S, Elkhenany H, El-Derby AM, Elshazly MF, El-Badri N. The interplay of cells, polymers, and vascularization in three-dimensional lung models and their applications in COVID-19 research and therapy. Stem Cell Res Ther 2023; 14:114. [PMID: 37118810 PMCID: PMC10144893 DOI: 10.1186/s13287-023-03341-4] [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: 10/15/2022] [Accepted: 04/14/2023] [Indexed: 04/30/2023] Open
Abstract
Millions of people have been affected ever since the emergence of the corona virus disease of 2019 (COVID-19) outbreak, leading to an urgent need for antiviral drug and vaccine development. Current experimentation on traditional two-dimensional culture (2D) fails to accurately mimic the in vivo microenvironment for the disease, while in vivo animal model testing does not faithfully replicate human COVID-19 infection. Human-based three-dimensional (3D) cell culture models such as spheroids, organoids, and organ-on-a-chip present a promising solution to these challenges. In this report, we review the recent 3D in vitro lung models used in COVID-19 infection and drug screening studies and highlight the most common types of natural and synthetic polymers used to generate 3D lung models.
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Affiliation(s)
- Toka A Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - Bassant Eldaly
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Shadwa Eldosuky
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Hoda Elkhenany
- Department of Surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, 22785, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Muhamed F Elshazly
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt.
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24
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Davis GE, Kemp SS. Extracellular Matrix Regulation of Vascular Morphogenesis, Maturation, and Stabilization. Cold Spring Harb Perspect Med 2023; 13:a041156. [PMID: 35817544 PMCID: PMC10578078 DOI: 10.1101/cshperspect.a041156] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The extracellular matrix represents a critical regulator of tissue vascularization during embryonic development and postnatal life. In this perspective, we present key information and concepts that focus on how the extracellular matrix controls capillary assembly, maturation, and stabilization, and, in addition, contributes to tissue stability and health. In particular, we present and discuss mechanistic details underlying (1) the role of the extracellular matrix in controlling different steps of vascular morphogenesis, (2) the ability of endothelial cells (ECs) and pericytes to coassemble into elongated and narrow capillary EC-lined tubes with associated pericytes and basement membrane matrices, and (3) the identification of specific growth factor combinations ("factors") and peptides as well as coordinated "factor" and extracellular matrix receptor signaling pathways that are required to form stabilized capillary networks.
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Affiliation(s)
- George E Davis
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, Florida 33612, USA
| | - Scott S Kemp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa, Florida 33612, USA
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25
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Cabral KA, Srivastava V, Graham AJ, Coyle MC, Stashko C, Weaver V, Gartner ZJ. Programming the Self-Organization of Endothelial Cells into Perfusable Microvasculature. Tissue Eng Part A 2023; 29:80-92. [PMID: 36181350 PMCID: PMC10266707 DOI: 10.1089/ten.tea.2022.0072] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 09/15/2022] [Indexed: 11/12/2022] Open
Abstract
The construction of three-dimensional (3D) microvascular networks with defined structures remains challenging. Emerging bioprinting strategies provide a means of patterning endothelial cells (ECs) into the geometry of 3D microvascular networks, but the microenvironmental cues necessary to promote their self-organization into cohesive and perfusable microvessels are not well known. To this end, we reconstituted microvessel formation in vitro by patterning thin lines of closely packed ECs fully embedded within a 3D extracellular matrix (ECM) and observed how different microenvironmental parameters influenced EC behaviors and their self-organization into microvessels. We found that the inclusion of fibrillar matrices, such as collagen I, into the ECM positively influenced cell condensation into extended geometries such as cords. We also identified the presence of a high-molecular-weight protein(s) in fetal bovine serum that negatively influenced EC condensation. This component destabilized cord structure by promoting cell protrusions and destabilizing cell-cell adhesions. Endothelial cords cultured in the presence of fibrillar collagen and in the absence of this protein activity were able to polarize, lumenize, incorporate mural cells, and support fluid flow. These optimized conditions allowed for the construction of branched and perfusable microvascular networks directly from patterned cells in as little as 3 days. These findings reveal important design principles for future microvascular engineering efforts based on bioprinting and micropatterning techniques. Impact statement Bioprinting is a potential strategy to achieve microvascularization in engineered tissues. However, the controlled self-organization of patterned endothelial cells into perfusable microvasculature remains challenging. We used DNA Programmed Assembly of Cells to create cell-dense, capillary-sized cords of endothelial cells with complete control over their structure. We optimized the matrix and media conditions to promote self-organization and maturation of these endothelial cords into stable and perfusable microvascular networks.
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Affiliation(s)
- Katelyn A. Cabral
- Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, Berkeley, California, USA
| | - Vasudha Srivastava
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
| | - Austin J. Graham
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
- Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, California, USA
| | - Maxwell C. Coyle
- Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California, USA
| | - Connor Stashko
- Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, Berkeley, California, USA
| | - Valerie Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Zev J. Gartner
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
- Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, California, USA
- Center for Cellular Construction, University of California, San Francisco, San Francisco, California, USA
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26
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Chen Y, Ding BS. Comprehensive Review of the Vascular Niche in Regulating Organ Regeneration and Fibrosis. Stem Cells Transl Med 2022; 11:1135-1142. [PMID: 36169406 DOI: 10.1093/stcltm/szac070] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/28/2022] [Indexed: 11/14/2022] Open
Abstract
The vasculature occupies a large area of the body, and none of the physiological activities can be carried out without blood vessels. Blood vessels are not just passive conduits and barriers for delivering blood and nutrients. Meanwhile, endothelial cells covering the vascular lumen establish vascular niches by deploying some growth factors, known as angiocrine factors, and actively participate in the regulation of a variety of physiological processes, such as organ regeneration and fibrosis and the occurrence and development of cancer. After organ injury, vascular endothelial cells regulate the repair process by secreting various angiocrine factors, triggering the proliferation and differentiation process of stem cells. Therefore, analyzing the vascular niche and exploring the factors that maintain vascular homeostasis can provide strong theoretical support for clinical treatment targeting blood vessels. Here we mainly discuss the regulatory mechanisms of the vascular niche in organ regeneration and fibrosis.
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Affiliation(s)
- Yutian Chen
- The Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China
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27
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Li Y, Gao S, Hu Q, Wu F. Functional Properties of Cancer Epithelium and Stroma-Derived Exosomes in Head and Neck Squamous Cell Carcinoma. Life (Basel) 2022; 12:life12050757. [PMID: 35629423 PMCID: PMC9145061 DOI: 10.3390/life12050757] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 05/13/2022] [Indexed: 12/24/2022] Open
Abstract
Stroma–cancer cell crosstalk involves a complex signaling network that contributes to tumor progression, including carcinogenesis, angiogenesis, migration, invasion, and therapy resistance in cancers. Exosomes, as extracellular membranous nanovesicles released by almost all types of cells, including tumor cells and stromal cells, play a critical role in signal delivery and material communication, in which the characteristics of their parent cells are reflected. The tumor or stroma-derived exosomes mediate cell–cell communication in the tumor microenvironment by transporting DNA, RNA, proteins, lipids, and metabolites. Recent studies on head and neck squamous cell carcinoma (HNSCC) have demonstrated that tumor-derived exosomes support various tumor biological behaviors, whereas the functional roles of stroma-derived exosomes remain largely unknown. Although these exosomes are emerging as promising targets in early diagnosis, prognostic prediction, and pharmaceutical carriers for antitumor therapy, there are still multiple hurdles to be overcome before they can be used in clinical applications. Herein, we systematically summarize the promotive roles of the epithelium and stroma-derived exosomes in HNSCC and highlight the potential clinical applications of exosomes in the treatment of HNSCC.
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Affiliation(s)
- Yang Li
- Department of Oral Pathology, College of Stomatology, Ningxia Medical University, South Sheng Li Street 804, Yinchuan 750004, China;
- Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Yang Qiao Middle Road 246, Fuzhou 350004, China
| | - Shengtao Gao
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, South Renmin Road, Sec. 3, No. 14, Chengdu 610041, China;
| | - Qi Hu
- College of Public Health and Management, Ningxia Medical University, South Sheng Li Street 1160, Yinchuan 750004, China;
| | - Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, South Renmin Road, Sec. 3, No. 14, Chengdu 610041, China
- Correspondence:
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28
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Yang C, Passos Gibson V, Hardy P. The Role of MiR-181 Family Members in Endothelial Cell Dysfunction and Tumor Angiogenesis. Cells 2022; 11:1670. [PMID: 35626707 PMCID: PMC9140109 DOI: 10.3390/cells11101670] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
Endothelial dysfunction plays a critical role in many human angiogenesis-related diseases, including cancer and retinopathies. Small non-coding microRNAs (miRNAs) repress gene expression at the post-transcriptional level. They are critical for endothelial cell gene expression and function and are involved in many pathophysiological processes. The miR-181 family is one of the essential angiogenic regulators. This review summarizes the current state of knowledge of the role of miR-181 family members in endothelial cell dysfunction, with emphasis on their pathophysiological roles in aberrant angiogenesis. The actions of miR-181 members are summarized concerning their targets and associated major angiogenic signaling pathways in a cancer-specific context. Elucidating the underlying functional mechanisms of miR-181 family members that are dysregulated in endothelial cells or cancer cells is invaluable for developing miRNA-based therapeutics for angiogenesis-related diseases such as retinopathies, angiogenic tumors, and cancer. Finally, potential clinical applications of miR-181 family members in anti-angiogenic tumor therapy are discussed.
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Affiliation(s)
- Chun Yang
- Research Center of CHU Sainte-Justine, University of Montréal, Quebec, QC H3T 1C5, Canada;
| | - Victor Passos Gibson
- Departments of Pharmacology and Physiology, University of Montréal, Quebec, QC H3T 1C5, Canada;
| | - Pierre Hardy
- Research Center of CHU Sainte-Justine, University of Montréal, Quebec, QC H3T 1C5, Canada;
- Departments of Pharmacology and Physiology, University of Montréal, Quebec, QC H3T 1C5, Canada;
- Departments of Pediatrics, University of Montréal, Quebec, QC H3T 1C5, Canada
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29
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Ze Y, Li Y, Huang L, Shi Y, Li P, Gong P, Lin J, Yao Y. Biodegradable Inks in Indirect Three-Dimensional Bioprinting for Tissue Vascularization. Front Bioeng Biotechnol 2022; 10:856398. [PMID: 35402417 PMCID: PMC8990266 DOI: 10.3389/fbioe.2022.856398] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/09/2022] [Indexed: 02/05/2023] Open
Abstract
Mature vasculature is important for the survival of bioengineered tissue constructs, both in vivo and in vitro; however, the fabrication of fully vascularized tissue constructs remains a great challenge in tissue engineering. Indirect three-dimensional (3D) bioprinting refers to a 3D printing technique that can rapidly fabricate scaffolds with controllable internal pores, cavities, and channels through the use of sacrificial molds. It has attracted much attention in recent years owing to its ability to create complex vascular network-like channels through thick tissue constructs while maintaining endothelial cell activity. Biodegradable materials play a crucial role in tissue engineering. Scaffolds made of biodegradable materials act as temporary templates, interact with cells, integrate with native tissues, and affect the results of tissue remodeling. Biodegradable ink selection, especially the choice of scaffold and sacrificial materials in indirect 3D bioprinting, has been the focus of several recent studies. The major objective of this review is to summarize the basic characteristics of biodegradable materials commonly used in indirect 3D bioprinting for vascularization, and to address recent advances in applying this technique to the vascularization of different tissues. Furthermore, the review describes how indirect 3D bioprinting creates blood vessels and vascularized tissue constructs by introducing the methodology and biodegradable ink selection. With the continuous improvement of biodegradable materials in the future, indirect 3D bioprinting will make further contributions to the development of this field.
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Affiliation(s)
- Yiting Ze
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanxi Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Linyang Huang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yixin Shi
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peiran Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jie Lin
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yang Yao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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30
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Dai C, Waduge P, Ji L, Huang C, He Y, Tian H, Zuniga-Sanchez E, Bhatt A, Pang IH, Su G, Webster KA, Li W. Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy. Cell Mol Life Sci 2022; 79:63. [PMID: 35006382 PMCID: PMC9007175 DOI: 10.1007/s00018-021-04111-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/17/2021] [Indexed: 01/12/2023]
Abstract
Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.
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Affiliation(s)
- Chang Dai
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Prabuddha Waduge
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Liyang Ji
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Chengchi Huang
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Ye He
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
| | - Hong Tian
- Everglades Biopharma, LLC, Houston, TX, USA
| | | | - Amit Bhatt
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Texas Children Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Iok-Hou Pang
- Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas, Fort Worth, TX, USA
| | - Guanfang Su
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, Jilin, China
| | - Keith A Webster
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA
- Everglades Biopharma, LLC, Houston, TX, USA
| | - Wei Li
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA.
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31
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Vakhrushev IV, Nezhurina EK, Karalkin PA, Tsvetkova AV, Sergeeva NS, Majouga AG, Yarygin KN. Heterotypic Multicellular Spheroids as Experimental and Preclinical Models of Sprouting Angiogenesis. BIOLOGY 2021; 11:18. [PMID: 35053016 PMCID: PMC8772844 DOI: 10.3390/biology11010018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022]
Abstract
Sprouting angiogenesis is the common response of live tissues to physiological and pathological angiogenic stimuli. Its accurate evaluation is of utmost importance for basic research and practical medicine and pharmacology and requires adequate experimental models. A variety of assays for angiogenesis were developed, none of them perfect. In vitro approaches are generally less physiologically relevant due to the omission of essential components regulating the process. However, only in vitro models can be entirely non-xenogeneic. The limitations of the in vitro angiogenesis assays can be partially overcome using 3D models mimicking tissue O2 and nutrient gradients, the influence of the extracellular matrix (ECM), and enabling cell-cell interactions. Here we present a review of the existing models of sprouting angiogenesis that are based on the use of endothelial cells (ECs) co-cultured with perivascular or other stromal cells. This approach provides an excellent in vitro platform for further decoding of the cellular and molecular mechanisms of sprouting angiogenesis under conditions close to the in vivo conditions, as well as for preclinical drug testing and preclinical research in tissue engineering and regenerative medicine.
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Affiliation(s)
- Igor V. Vakhrushev
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, 119121 Moscow, Russia;
| | - Elizaveta K. Nezhurina
- P.A. Hertsen Moscow Oncology Research Center, National Medical Research Radiological Center, 125284 Moscow, Russia;
| | - Pavel A. Karalkin
- Institute for Cluster Oncology, Sechenov University, 119435 Moscow, Russia;
| | | | - Nataliya S. Sergeeva
- Department of Biology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Alexander G. Majouga
- Faculty of Chemical and Pharmaceutical Technologies and Biomedical Products, D. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia;
| | - Konstantin N. Yarygin
- Laboratory of Cell Biology, Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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32
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Chis AF, Râjnoveanu RM, Man MA, Todea DA, Chis BA, Stancu B, Arghir IA, Alexescu TG, Pop CM. Increased Vascular Endothelial Growth Factor Serum Level and the Role of +936C/T Gene Polymorphism in Chronic Obstructive Pulmonary Disease. Medicina (B Aires) 2021; 57:medicina57121351. [PMID: 34946296 PMCID: PMC8707840 DOI: 10.3390/medicina57121351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/30/2021] [Accepted: 12/05/2021] [Indexed: 11/16/2022] Open
Abstract
Background and Objectives: Chronic obstructive pulmonary disease (COPD) represents a debilitating disease, with rising morbidity and mortality. Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, vascular permeability, and airway remodeling. The purpose of this study was to investigate the relationship between VEGF serum levels and VEGF +936 C/T gene polymorphism (rs3025039) with COPD, for the first time in a Romanian population. Materials and Methods: In total, 120 participants from Transylvania were included in this case-control study. Serum levels of VEGF were determined using an enzyme-linked immune-sorbent assay and rs3025039 was investigated by high molecular weight genomic deoxyribonucleic acid (DNA). Spirometric values, arterial blood gas analysis, and the Six Minute Walk Test (6MWT) outcome were also determined. Results: The serum level of VEGF was higher in the COPD group versus controls (p < 0.001), with a positive correlation with the 6MWT outcome. No significant difference was observed in the VEGF serum levels between VEGF +936C/T genotypes. There was no difference in the VEGF +936C/T genotype between COPD patients and healthy subjects (chi2 test p = 0.92, OR = 1.04, 95%CI = 0.41–2.62), but the presence of the T allele was significantly linked to the presence of COPD (chi2 test p = 0.02, OR = 2.36, 95%CI = 1.12–4.97). Conclusions: Higher VEGF serum levels were found in moderate and severe COPD and were positively correlated with the distance in the 6MWT. No significant difference was found between CC, CT, and TT genotypes of rs3025039 and the presence of COPD. The presence of the T allele was found to be linked to COPD and also to the degree of airway obstruction.
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Affiliation(s)
- Ana Florica Chis
- Department of Pneumology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 8th Victor Babeș Street, 400012 Cluj, Romania; (A.F.C.); (R.-M.R.); (M.A.M.); (D.A.T.); (C.M.P.)
- “Leon Daniello” Clinical Hospital of Pneumology, 6th Bogdan Petriceicu Hașdeu Street, 400332 Cluj, Romania
| | - Ruxandra-Mioara Râjnoveanu
- Department of Pneumology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 8th Victor Babeș Street, 400012 Cluj, Romania; (A.F.C.); (R.-M.R.); (M.A.M.); (D.A.T.); (C.M.P.)
- “Leon Daniello” Clinical Hospital of Pneumology, 6th Bogdan Petriceicu Hașdeu Street, 400332 Cluj, Romania
| | - Milena Adina Man
- Department of Pneumology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 8th Victor Babeș Street, 400012 Cluj, Romania; (A.F.C.); (R.-M.R.); (M.A.M.); (D.A.T.); (C.M.P.)
- “Leon Daniello” Clinical Hospital of Pneumology, 6th Bogdan Petriceicu Hașdeu Street, 400332 Cluj, Romania
| | - Doina Adina Todea
- Department of Pneumology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 8th Victor Babeș Street, 400012 Cluj, Romania; (A.F.C.); (R.-M.R.); (M.A.M.); (D.A.T.); (C.M.P.)
- “Leon Daniello” Clinical Hospital of Pneumology, 6th Bogdan Petriceicu Hașdeu Street, 400332 Cluj, Romania
| | - Bogdan Augustin Chis
- 2nd Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8th Victor Babeș Street, 400012 Cluj, Romania
- Correspondence: ; Tel.: +40-740047253
| | - Bogdan Stancu
- 2nd Department of General Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, 8th Victor Babeș Street, 400012 Cluj, Romania;
| | - Ioan Anton Arghir
- 4th Department of Clinical Medical Disciplines II, “Ovidius” University of Medicine and Pharmacy, Mamaia Boulevard, No. 124, 900527 Constanța, Romania;
| | - Teodora Gabriela Alexescu
- 5th Departament Internal Medicine, 4th Medical Clinic, University of Medicine and Pharmacy, 400015 Cluj, Romania;
| | - Carmen Monica Pop
- Department of Pneumology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 8th Victor Babeș Street, 400012 Cluj, Romania; (A.F.C.); (R.-M.R.); (M.A.M.); (D.A.T.); (C.M.P.)
- “Leon Daniello” Clinical Hospital of Pneumology, 6th Bogdan Petriceicu Hașdeu Street, 400332 Cluj, Romania
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Catalá-Gregori P, Montero E, Cortés V, Viana D, Sevilla-Navarro S. New vascular structure in broiler breast: breast-vessel. Poult Sci 2021; 101:101565. [PMID: 34844109 PMCID: PMC8633678 DOI: 10.1016/j.psj.2021.101565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 11/27/2022] Open
Abstract
Chickens intensively selected for accelerating growth rate and enhanced muscle mass has resulted in the occurrence of breast alterations with a negative consumers perception. Together with the already known breast abnormalities (White Striping, Wooden Breast and Spaghetti Meat) a new one has been described by the consumers as a "long and thin worm". For this reason, the aim of this work was to macroscopically and microscopically describe this structure in broiler breast. To this end, 2 different experiments were performed. In the first one, 4 broiler breasts from a supermarket were analysed. Thereafter, a second experiment was carried out on an experimental farm simulating field management conditions in order to confirm the results of the first experiment. To this end, 120 chickens were reared in an experimental farm up to 42 d. Breast samples were collected and analysed macroscopically and microscopically to assess the abnormality on the broiler breast. In both experiments, the results of the analysis showed the finding of tubular structures located on the surface of pectoralis major muscle compatible with arteries. So far, currently, this occurrence has not been described in the literature and we propose calling this new broiler breast feature as breast-vessel.
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Affiliation(s)
- P Catalá-Gregori
- Poultry Quality and Animal Nutrition Center of the Valencia Region (CECAV), Alquerías del Niño Perdido, Castellón 12539, Spain; Department of Animal Production and Health, Veterinary Public Health and Food Science and Technology, Institute of Biomedical Sciences, Faculty of Veterinary Medicine, Cardenal Herrera-CEU University, 46113 Moncada, Spain.
| | - E Montero
- Biomedical Research Institute (PASAPTA-Pathology group), Faculty of Veterinary Medicine, Cardenal Herrera-CEU University, Alfara del Patriarca, Valencia 46115, Spain
| | - V Cortés
- Poultry Quality and Animal Nutrition Center of the Valencia Region (CECAV), Alquerías del Niño Perdido, Castellón 12539, Spain
| | - D Viana
- Biomedical Research Institute (PASAPTA-Pathology group), Faculty of Veterinary Medicine, Cardenal Herrera-CEU University, Alfara del Patriarca, Valencia 46115, Spain
| | - S Sevilla-Navarro
- Poultry Quality and Animal Nutrition Center of the Valencia Region (CECAV), Alquerías del Niño Perdido, Castellón 12539, Spain; Department of Animal Production and Health, Veterinary Public Health and Food Science and Technology, Institute of Biomedical Sciences, Faculty of Veterinary Medicine, Cardenal Herrera-CEU University, 46113 Moncada, Spain
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34
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Mathur T, Tronolone JJ, Jain A. Comparative Analysis of Blood-Derived Endothelial Cells for Designing Next-Generation Personalized Organ-on-Chips. J Am Heart Assoc 2021; 10:e022795. [PMID: 34743553 PMCID: PMC8751908 DOI: 10.1161/jaha.121.022795] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Organ‐on‐chip technology has accelerated in vitro preclinical research of the vascular system, and a key strength of this platform is its promise to impact personalized medicine by providing a primary human cell–culture environment where endothelial cells are directly biopsied from individual tissue or differentiated through stem cell biotechniques. However, these methods are difficult to adopt in laboratories, and often result in impurity and heterogeneity of cells. This limits the power of organ‐chips in making accurate physiological predictions. In this study, we report the use of blood‐derived endothelial cells as alternatives to primary and induced pluripotent stem cell–derived endothelial cells. Methods and Results Here, the genotype, phenotype, and organ‐chip functional characteristics of blood‐derived outgrowth endothelial cells were compared against commercially available and most used primary endothelial cells and induced pluripotent stem cell–derived endothelial cells. The methods include RNA‐sequencing, as well as criterion standard assays of cell marker expression, growth kinetics, migration potential, and vasculogenesis. Finally, thromboinflammatory responses under shear using vessel‐chips engineered with blood‐derived endothelial cells were assessed. Blood‐derived endothelial cells exhibit the criterion standard hallmarks of typical endothelial cells. There are differences in gene expression profiles between different sources of endothelial cells, but blood‐derived cells are relatively closer to primary cells than induced pluripotent stem cell–derived. Furthermore, blood‐derived endothelial cells are much easier to obtain from individuals and yet, they serve as an equally effective cell source for functional studies and organ‐chips compared with primary cells or induced pluripotent stem cell–derived cells. Conclusions Blood‐derived endothelial cells may be used in preclinical research for developing more robust and personalized next‐generation disease models using organ‐on‐chips.
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Affiliation(s)
- Tanmay Mathur
- Department of Biomedical Engineering, College of Engineering Texas A&M University College Station TX
| | - James J Tronolone
- Department of Biomedical Engineering, College of Engineering Texas A&M University College Station TX
| | - Abhishek Jain
- Department of Biomedical Engineering, College of Engineering Texas A&M University College Station TX.,Department of Medical Physiology College of MedicineTexas A&M Health Science Center Bryan TX.,Department of Cardiovascular Sciences Houston Methodist Research Institute Houston TX
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Dight J, Zhao J, Styke C, Khosrotehrani K, Patel J. Resident vascular endothelial progenitor definition and function: the age of reckoning. Angiogenesis 2021; 25:15-33. [PMID: 34499264 PMCID: PMC8813834 DOI: 10.1007/s10456-021-09817-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Abstract
The cardiovascular system is composed around the central function of the endothelium that lines the inner surfaces of its vessels. In recent years, the existence of a progenitor population within the endothelium has been validated through the study of endothelial colony-forming cells (ECFCs) in human peripheral blood and certain vascular beds. However, our knowledge on endothelial populations in vivo that can give rise to ECFCs in culture has been limited. In this review we report and analyse recent attempts at describing progenitor populations in vivo from murine studies that reflect the self-renewal and stemness capacity observed in ECFCs. We pinpoint seminal discoveries within the field, which have phenotypically defined, and functionally scrutinised these endothelial progenitors. Furthermore, we review recent publications utilising single-cell sequencing technologies to better understand the endothelium in homeostasis and pathology.
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Affiliation(s)
- James Dight
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Jilai Zhao
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Cassandra Styke
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
| | - Jatin Patel
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia. .,Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
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36
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Ewald ML, Chen YH, Lee AP, Hughes CCW. The vascular niche in next generation microphysiological systems. LAB ON A CHIP 2021; 21:3244-3262. [PMID: 34396383 PMCID: PMC8635227 DOI: 10.1039/d1lc00530h] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
In recent years, microphysiological system (MPS, also known as, organ-on-a-chip or tissue chip) platforms have emerged with great promise to improve the predictive capacity of preclinical modeling thereby reducing the high attrition rates when drugs move into trials. While their designs can vary quite significantly, in general MPS are bioengineered in vitro microenvironments that recapitulate key functional units of human organs, and that have broad applications in human physiology, pathophysiology, and clinical pharmacology. A critical next step in the evolution of MPS devices is the widespread incorporation of functional vasculature within tissues. The vasculature itself is a major organ that carries nutrients, immune cells, signaling molecules and therapeutics to all other organs. It also plays critical roles in inducing and maintaining tissue identity through expression of angiocrine factors, and in providing tissue-specific milieus (i.e., the vascular niche) that can support the survival and function of stem cells. Thus, organs are patterned, maintained and supported by the vasculature, which in turn receives signals that drive tissue specific gene expression. In this review, we will discuss published vascularized MPS platforms and present considerations for next-generation devices looking to incorporate this critical constituent. Finally, we will highlight the organ-patterning processes governed by the vasculature, and how the incorporation of a vascular niche within MPS platforms will establish a unique opportunity to study stem cell development.
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Affiliation(s)
- Makena L Ewald
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
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Kapoor A, Nation DA. Role of Notch signaling in neurovascular aging and Alzheimer's disease. Semin Cell Dev Biol 2021; 116:90-97. [PMID: 33384205 PMCID: PMC8236496 DOI: 10.1016/j.semcdb.2020.12.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/03/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022]
Abstract
The Notch signaling pathway is an evolutionarily conserved cell signaling system known to be involved in vascular development and function. Recent evidence suggests that dysfunctional Notch signaling could play a critical role in the pathophysiology of neurodegenerative diseases. We reviewed current literature on the role of Notch signaling pathway, and specifically Notch receptor genes and proteins, in aging, cerebrovascular disease and Alzheimer's disease. We hypothesize that Notch signaling may represent a key point of overlap between age-related vascular and Alzheimer's pathophysiology contributing to their comorbidity and combined influence on cognitive decline and dementia. Numerous findings from studies of genetics, neuropathology and cell culture models all suggest a link between altered Notch signaling and Alzheimer's pathophysiology. Age-related changes in Notch signaling may also trigger neurovascular dysfunction, contributing to the development of neurodegenerative diseases; however, additional studies are warranted. Future research directly exploring the influence of aberrant Notch signaling in the development of Alzheimer's disease is needed to better understand this mechanism.
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Affiliation(s)
- Arunima Kapoor
- Department of Psychological Science, University of California, Irvine, Irvine, CA, USA
| | - Daniel A Nation
- Department of Psychological Science, University of California, Irvine, Irvine, CA, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
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38
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Mapanao AK, Che PP, Sarogni P, Sminia P, Giovannetti E, Voliani V. Tumor grafted - chick chorioallantoic membrane as an alternative model for biological cancer research and conventional/nanomaterial-based theranostics evaluation. Expert Opin Drug Metab Toxicol 2021; 17:947-968. [PMID: 33565346 DOI: 10.1080/17425255.2021.1879047] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/18/2021] [Indexed: 02/09/2023]
Abstract
Introduction: Advancements in cancer management and treatment are associated with strong preclinical research data, in which reliable cancer models are demanded. Indeed, inconsistent preclinical findings and stringent regulations following the 3Rs principle of reduction, refinement, and replacement of conventional animal models currently pose challenges in the development and translation of efficient technologies. The chick embryo chorioallantoic membrane (CAM) is a system for the evaluation of treatment effects on the vasculature, therefore suitable for studies on angiogenesis. Apart from vascular effects, the model is now increasingly employed as a preclinical cancer model following tumor-grafting procedures.Areas covered: The broad application of CAM tumor model is highlighted along with the methods for analyzing the neoplasm and vascular system. The presented and cited investigations focus on cancer biology and treatment, encompassing both conventional and emerging nanomaterial-based modalities.Expert opinion: The CAM tumor model finds increased significance given the influences of angiogenesis and the tumor microenvironment in cancer behavior, then providing a qualified miniature system for oncological research. Ultimately, the establishment and increased employment of such a model may resolve some of the limitations present in the standard preclinical tumor models, thereby redefining the preclinical research workflow.
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Affiliation(s)
- Ana Katrina Mapanao
- Center for Nanotechnology Innovation@NEST, Istituto Italiano Di Tecnologia, Pisa, Italy
- NEST-Scuola Normale Superiore, Pisa, Italy
| | - Pei Pei Che
- Department of Radiation Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, The Netherlands
| | - Patrizia Sarogni
- Center for Nanotechnology Innovation@NEST, Istituto Italiano Di Tecnologia, Pisa, Italy
| | - Peter Sminia
- Department of Radiation Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center, Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Valerio Voliani
- Center for Nanotechnology Innovation@NEST, Istituto Italiano Di Tecnologia, Pisa, Italy
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Yin H, Arpino JM, Lee JJ, Pickering JG. Regenerated Microvascular Networks in Ischemic Skeletal Muscle. Front Physiol 2021; 12:662073. [PMID: 34177614 PMCID: PMC8231913 DOI: 10.3389/fphys.2021.662073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Skeletal muscle is the largest organ in humans. The viability and performance of this metabolically demanding organ are exquisitely dependent on the integrity of its microcirculation. The architectural and functional attributes of the skeletal muscle microvasculature are acquired during embryonic and early postnatal development. However, peripheral vascular disease in the adult can damage the distal microvasculature, together with damaging the skeletal myofibers. Importantly, adult skeletal muscle has the capacity to regenerate. Understanding the extent to which the microvascular network also reforms, and acquires structural and functional competence, will thus be critical to regenerative medicine efforts for those with peripheral artery disease (PAD). Herein, we discuss recent advances in studying the regenerating microvasculature in the mouse hindlimb following severe ischemic injury. We highlight new insights arising from real-time imaging of the microcirculation. This includes identifying otherwise hidden flaws in both network microarchitecture and function, deficiencies that could underlie the progressive nature of PAD and its refractoriness to therapy. Recognizing and overcoming these vulnerabilities in regenerative angiogenesis will be important for advancing treatment options for PAD.
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Affiliation(s)
- Hao Yin
- Robarts Research Institute, Western University, London, ON, Canada
| | | | - Jason J Lee
- Robarts Research Institute, Western University, London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada
| | - J Geoffrey Pickering
- Robarts Research Institute, Western University, London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada.,Department of Medical Biophysics, Western University, London, ON, Canada.,Department of Biochemistry, Western University, London, ON, Canada
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40
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Mandrycky CJ, Howard CC, Rayner SG, Shin YJ, Zheng Y. Organ-on-a-chip systems for vascular biology. J Mol Cell Cardiol 2021; 159:1-13. [PMID: 34118217 DOI: 10.1016/j.yjmcc.2021.06.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/03/2021] [Accepted: 06/06/2021] [Indexed: 12/18/2022]
Abstract
Organ-on-a-chip (OOC) platforms involve the miniaturization of cell culture systems and enable a variety of novel experimental approaches. These range from modeling the independent effects of biophysical forces on cells to screening novel drugs in multi-organ microphysiological systems, all within microscale devices. As in living systems, the incorporation of vascular structure is a key feature common to almost all organ-on-a-chip systems. In this review we highlight recent advances in organ-on-a-chip technologies with a focus on the vasculature. We first present the developmental process of the blood vessels through which vascular cells assemble into networks and remodel to form complex vascular beds under flow. We then review self-assembled vascular models and flow systems for the study of vascular development and biology as well as pre-patterned vascular models for the generation of perfusable microvessels for modeling vascular and tissue function. We finally conclude with a perspective on developing future OOC approaches for studying different aspects of vascular biology. We highlight the fit for purpose selection of OOC models towards either simple but powerful testbeds for therapeutic development, or complex vasculature to accurately replicate human physiology for specific disease modeling and tissue regeneration.
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Affiliation(s)
- Christian J Mandrycky
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA.
| | - Caitlin C Howard
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA.
| | - Samuel G Rayner
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA; Department of Medicine; Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA 98195, USA.
| | - Yu Jung Shin
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA.
| | - Ying Zheng
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA; Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98195, USA.
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41
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Mettu PS, Allingham MJ, Cousins SW. Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res 2021; 82:100906. [PMID: 33022379 PMCID: PMC10368393 DOI: 10.1016/j.preteyeres.2020.100906] [Citation(s) in RCA: 219] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.
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Affiliation(s)
- Priyatham S Mettu
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC.
| | - Michael J Allingham
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC
| | - Scott W Cousins
- Duke Center for Macular Diseases, Department of Ophthalmology, Duke University School of Medicine, Durham, NC, NC; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
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Chico TJA, Kugler EC. Cerebrovascular development: mechanisms and experimental approaches. Cell Mol Life Sci 2021; 78:4377-4398. [PMID: 33688979 PMCID: PMC8164590 DOI: 10.1007/s00018-021-03790-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022]
Abstract
The cerebral vasculature plays a central role in human health and disease and possesses several unique anatomic, functional and molecular characteristics. Despite their importance, the mechanisms that determine cerebrovascular development are less well studied than other vascular territories. This is in part due to limitations of existing models and techniques for visualisation and manipulation of the cerebral vasculature. In this review we summarise the experimental approaches used to study the cerebral vessels and the mechanisms that contribute to their development.
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Affiliation(s)
- Timothy J A Chico
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
- The Bateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
- Insigneo Institute for in Silico Medicine, The Pam Liversidge Building, Sheffield, S1 3JD, UK.
| | - Elisabeth C Kugler
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
- The Bateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
- Insigneo Institute for in Silico Medicine, The Pam Liversidge Building, Sheffield, S1 3JD, UK.
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Yu WP, Gong Y, Wang Z, Lu C, Ding JL, Liu XL, Zhu GD, Lin F, Xu JJ, Zhou JL. The biofunctionalization of titanium nanotube with chitosan/genipin heparin hydrogel and the controlled release of IL-4 for anti-coagulation and anti-thrombus through accelerating endothelialization. RSC Adv 2021; 11:16510-16521. [PMID: 35479169 PMCID: PMC9031326 DOI: 10.1039/d0ra09295a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 04/18/2021] [Indexed: 12/29/2022] Open
Abstract
The valve replacement is the main treatment of heart valve disease. However, thrombus formation following valve replacement has always been a major clinical drawback. Accelerating the endothelialization of cardiac valve prosthesis is the main approach to reduce thrombus. In the current study, a titanium nanotube was biofunctionalized with a chitosan/genipin heparin hydrogel and the controlled release of interleukin-4 (IL-4), and its regulation of macrophages was investigated to see if it could influence endothelial cells to eventually accelerate endothelialization. TNT60 (titanium dioxide nanotubes, 60 V) with nanoarray was obtained by anodic oxidation of 60 V, and IL-4 was loaded into the nanotube by vacuum drying. The hydrogel (chitosan : genipin = 4 : 1) was applied to the surface of the nanotubes following drying, and the heparin drops were placed on the hydrogel surface with chitosan as the polycation and heparin as the polyanion. A TNT/IL-4/G (G = gel, chitosan/genipin heparin) delivery system was prepared. Our results demonstrated that the biofunctionalization of titanium nanotube with chitosan/genipin heparin hydrogel and the controlled release of IL-4 had a significant regulatory effect on macrophage M2 polarization, reducing the inflammatory factor release and higher secretion of VEGF (vascular endothelial growth factor), which can accelerate the endothelialization of the implant.
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Affiliation(s)
- Wen Peng Yu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Yi Gong
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Ziyao Wang
- Department of Clinical Pathology, The First Affiliated Hospital of Gannan Medical College Ganzhou China
| | - Chao Lu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Jing Li Ding
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University Nanchang China
| | - Xin Liang Liu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Guo Dong Zhu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Feng Lin
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Jian Jun Xu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
| | - Jian Liang Zhou
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University No. 1 Minde Road Nanchang 330006 Jiangxi China +86 137 6711 7511
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Shao C, Huang Y, Fu B, Pan S, Zhao X, Zhang N, Wang W, Zhang Z, Qiu Y, Wang R, Jin M, Kong D. Targeting c-Jun in A549 Cancer Cells Exhibits Antiangiogenic Activity In Vitro and In Vivo Through Exosome/miRNA-494-3p/PTEN Signal Pathway. Front Oncol 2021; 11:663183. [PMID: 33898323 PMCID: PMC8062808 DOI: 10.3389/fonc.2021.663183] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/18/2021] [Indexed: 01/08/2023] Open
Abstract
The oncogene c-Jun is activated by Jun N-terminal kinase (JNK). Exosomes are nanometer-sized membrane vesicles released from a variety of cell types, and are essential for cell-to-cell communication. By using specific JNK inhibitor SP600125 or CRISPR/Cas9 to delete c-Jun, we found that exosomes from SP600125-treated A549 cancer cells (Exo-SP) or from c-Jun-KO-A549 cells (Exo-c-Jun-KO) dramatically inhibited tube formation of HUVECs. And the miR-494 levels in SP600125 treated or c-Jun-KO A549 cells, Exo-SP or Exo-c-Jun-KO, and HUVECs treated with Exo-SP or Exo-c-Jun-KO were significantly decreased. Meanwhile, Exo-SP and Exo-c-Jun-KO enhanced expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Addition of miR-494 agomir in Exo-c-Jun-KO treated HUVECs inhibited PTEN expression and promoted tube formation, suggesting the target of miR-494 might be PTEN in HUVECs. Moreover, A549 tumor xenograft model and Matrigel plug assay demonstrated that Exo-c-Jun-KO attenuated tumor growth and angiogenesis through reducing miR-494. Taken together, inhibition of c-Jun in A549 cancer cells exhibited antiangiogenic activity in vitro and in vivo through exosome/miRNA-494-3p/PTEN signal pathway.
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Affiliation(s)
- Chen Shao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yingying Huang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Bingjie Fu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Shunli Pan
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xiaoxia Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Ning Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Wei Wang
- Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Ran Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Meihua Jin
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.,School of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, China
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Tronolone JJ, Jain A. Engineering new microvascular networks on-chip: ingredients, assembly, and best practices. ADVANCED FUNCTIONAL MATERIALS 2021; 31:2007199. [PMID: 33994903 PMCID: PMC8114943 DOI: 10.1002/adfm.202007199] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Indexed: 05/23/2023]
Abstract
Tissue engineered grafts show great potential as regenerative implants for diseased or injured tissues within the human body. However, these grafts suffer from poor nutrient perfusion and waste transport, thus decreasing their viability post-transplantation. Graft vascularization is therefore a major area of focus within tissue engineering because biologically relevant conduits for nutrient and oxygen perfusion can improve viability post-implantation. Many researchers utilize microphysiological systems as testing platforms for potential grafts due to an ability to integrate vascular networks as well as biological characteristics such as fluid perfusion, 3D architecture, compartmentalization of tissue-specific materials, and biophysical and biochemical cues. While many methods of vascularizing these systems exist, microvascular self-assembly has great potential for bench-to-clinic translation as it relies on naturally occurring physiological events. In this review, we highlight the past decade of literature and critically discuss the most important and tunable components yielding a self-assembled vascular network on chip: endothelial cell source, tissue-specific supporting cells, biomaterial scaffolds, biochemical cues, and biophysical forces. This article discusses the bioengineered systems of angiogenesis, vasculogenesis, and lymphangiogenesis, and includes a brief overview of multicellular systems. We conclude with future avenues of research to guide the next generation of vascularized microfluidic models and future tissue engineered grafts.
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Affiliation(s)
- James J Tronolone
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Abhishek Jain
- Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77808, USA
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Li K, Liu YY, Lv XF, Lin ZM, Zhang TT, Zhang FR, Guo JW, Hong Y, Liu X, Lin XC, Zhou JG, Wu QQ, Liang SJ, Shang JY. Reduced intracellular chloride concentration impairs angiogenesis by inhibiting oxidative stress-mediated VEGFR2 activation. Acta Pharmacol Sin 2021; 42:560-572. [PMID: 32694758 PMCID: PMC8115249 DOI: 10.1038/s41401-020-0458-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 06/07/2020] [Indexed: 12/13/2022]
Abstract
Chloride (Cl-) homeostasis is of great significance in cardiovascular system. Serum Cl- level is inversely associated with the mortality of patients with heart failure. Considering the importance of angiogenesis in the progress of heart failure, this study aims to investigate whether and how reduced intracellular Cl- concentration ([Cl-]i) affects angiogenesis. Human umbilical endothelial cells (HUVECs) were treated with normal Cl- medium or low Cl- medium. We showed that reduction of [Cl-]i (from 33.2 to 16.18 mM) inhibited HUVEC proliferation, migration, cytoskeleton reorganization, tube formation, and subsequently suppressed angiogenesis under basal condition, and VEGF stimulation or hypoxia treatment. Moreover, VEGF-induced NADPH-mediated reactive oxygen species (ROS) generation and VEGFR2 axis activation were markedly attenuated in low Cl- medium. We revealed that lowering [Cl-]i inhibited the expression of the membrane-bound catalytic subunits of NADPH, i.e., p22phox and Nox2, and blunted the translocation of cytosolic regulatory subunits p47phox and p67phox, thereby restricting NADPH oxidase complex formation and activation. Furthermore, reduced [Cl-]i enhanced ROS-associated protein tyrosine phosphatase 1B (PTP1B) activity and increased the interaction of VEGFR2 and PTP1B. Pharmacological inhibition of PTP1B reversed the effect of lowering [Cl-]i on VEGFR2 phosphorylation and angiogenesis. In mouse hind limb ischemia model, blockade of Cl- efflux using Cl- channel inhibitors DIDS or DCPIB (10 mg/kg, i.m., every other day for 2 weeks) significantly enhanced blood flow recovery and new capillaries formation. In conclusion, decrease of [Cl-]i suppresses angiogenesis via inhibiting oxidase stress-mediated VEGFR2 signaling activation by preventing NADPH oxidase complex formation and promoting VEGFR2/PTP1B association, suggesting that modulation of [Cl-]i may be a novel therapeutic avenue for the treatment of angiogenic dysfunction-associated diseases.
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Affiliation(s)
- Kai Li
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ying-Ying Liu
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiao-Fei Lv
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhuo-Miao Lin
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ting-Ting Zhang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Fei-Ran Zhang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jia-Wei Guo
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yu Hong
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiu Liu
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiao-Chun Lin
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jia-Guo Zhou
- Program of Kidney and Cardiovascular Disease, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
- Department of Physiology, Key Laboratory of Cardiovascular disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
- Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Qian-Qian Wu
- Key Laboratory of Metabolic Cardiovascular Diseases Research of National Health Commission, Ningxia Medical University, Yinchuan, 750004, China
- Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, 750004, China
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China
| | - Si-Jia Liang
- Program of Kidney and Cardiovascular Disease, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China.
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Jin-Yan Shang
- Program of Kidney and Cardiovascular Disease, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, China.
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Garcia-Hernandez A, Leal-Orta E, Ramirez-Ricardo J, Cortes-Reynosa P, Thompson-Bonilla R, Salazar EP. Linoleic acid induces secretion of extracellular vesicles from MDA-MB-231 breast cancer cells that mediate cellular processes involved with angiogenesis in HUVECs. Prostaglandins Other Lipid Mediat 2021; 153:106519. [PMID: 33238201 DOI: 10.1016/j.prostaglandins.2020.106519] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 12/20/2022]
Abstract
Extracellular vesicles (EVs) are vesicles secreted by normal and malignant cells that are implicated in tumor progression. Linoleic acid (LA) is an essential polyunsaturated fatty acid that induces migration, invasion and an increase in phospholipase D activity in breast cancer cells. In this study, we determined whether stimulation of MDA-MB-231 breast cancer cells with LA induces the secretion of EVs, which can mediate cell processes related with angiogenesis in human umbilical vein endothelial cells (HUVECs). Our findings demonstrate that treatment of MDA-MB-231 cells with 90 μM LA for 48 h induce an increase in the number of EVs released. Moreover, EVs from MDA-MB-231 stimulated with 90 μM LA induce FAK and Src activation and migration via FAK and Src activity, whereas the secretion of these EVs is through FFAR1 and FFAR4 activation in HUVECs. The EVs from MDA-MB-231 cells treated with LA also increase proliferation, invasion, MMP-9 secretion, an increase of MMP-2 secretion and formation of new tubules in HUVECs. In summary, we demonstrate, for the first time, that treatment with LA induces the release of EVs from MDA-MB-231 cells that induce cellular processes involved with angiogenesis in HUVECs.
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Pan S, Zhao X, Shao C, Fu B, Huang Y, Zhang N, Dou X, Zhang Z, Qiu Y, Wang R, Jin M, Kong D. STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells. Cell Death Dis 2021; 12:38. [PMID: 33414420 PMCID: PMC7791041 DOI: 10.1038/s41419-020-03304-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 12/16/2022]
Abstract
Cancer cells secrete abundant exosomes, and the secretion can be promoted by an increase of intracellular Ca2+. Stromal interaction molecule 1 (STIM1) plays a key role in shaping Ca2+ signals. MicroRNAs (miRNAs) have been reported to be potential therapeutic targets for many diseases, including breast cancer. Recently, we investigated the effect of exosomes from STIM1-knockout breast cancer MDA-MB-231 cells (Exo-STIM1-KO), and from SKF96365-treated MDA-MB-231 cells (Exo-SKF) on angiogenesis in human umbilical vein endothelial cells (HUVECs) and nude mice. The exosomes Exo-STIM1-KO and Exo-SKF inhibited tube formation by HUVECs remarkably. The miR-145 was increased in SKF96365 treated or STIM1-knockout MDA-MB-231 cells, Exo-SKF and Exo-STIM1-KO, and HUVECs treated with Exo-SKF or Exo-STIM1-KO. Moreover, the expressions of insulin receptor substrate 1 (IRS1), which is the target of miR-145, and the downstream proteins such as Akt/mammalian target of rapamycin (mTOR), Raf/extracellular signal regulated-protein kinase (ERK), and p38 were markedly inhibited in HUVECs treated with Exo-SKF or Exo-STIM1-KO. Matrigel plug assay in vivo showed that tumor angiogenesis was suppressed in Exo-STIM1-KO, but promoted when miR-145 antagomir was added. Taken together, our findings suggest that STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells.
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Affiliation(s)
- Shunli Pan
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Xiaoxia Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Chen Shao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Bingjie Fu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Yingying Huang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Ning Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Xiaojing Dou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Ran Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Meihua Jin
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China.
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China.
- School of Medicine, Tianjin Tianshi College, Tianyuan University, 301700, Tianjin, China.
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Tunçer S, Gurbanov R. A novel approach for the discrimination of culture medium from Vascular Endothelial Growth Factor (VEGF) overexpressing colorectal cancer cells. TURKISH JOURNAL OF BIOCHEMISTRY 2020. [DOI: 10.1515/tjb-2020-0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Objectives
The expression level of Vascular Endothelial Growth Factor (VEGF) is assumed as a prognostic marker for several tumor types, including colorectal cancer. Therefore, the determination of pre- and post-therapy levels of VEGF appears to have great value in the assessment of tumor prognosis. Enzyme-Linked Immunosorbent Assay (ELISA) is commonly used for the determination of serum or plasma VEGF levels, but the method is costly and time-consuming. In this study, we aimed to describe a rapid and cost-effective analysis method to discriminate VEGF overexpressing colorectal cancer-derived conditioned medium (CM).
Methods
Attenuated Total Reflection (ATR)-Fourier Transform Infrared (FTIR) spectroscopy, combined with Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA), was used to differentiate VEGF overexpressing colorectal cancer cell line CM from CM obtained from the corresponding control cells which express and secrete relatively lower amount of VEGF.
Results
Samples belong to VEGF overexpressing colorectal cancer cells were clearly distinguished from the control group with very high PC scores as PC1 + PC2 = 96%. Besides, a 100% accurate distinction between these two groups was achieved by the LDA analysis.
Conclusions
ATR-FTIR spectroscopy combined with pattern recognition techniques was able to discriminate CM of VEGF overexpressing colorectal cancer cells with high efficiency and accuracy.
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Affiliation(s)
- Sinem Tunçer
- Bilecik Seyh Edebali Universitesi , Vocational School of Health Services Department of Medical Laboratory Techniques , Pelitözü Mah. Fatih Sultan Mehmet Bulvarı No:27, Merkez , Bilecik , Turkey
- Bilecik Seyh Edebali Universitesi , Biotechnology Application and Research Center , Pelitözü Mah. Fatih Sultan Mehmet Bulvarı No:27, Merkez , Bilecik , Turkey
| | - Rafig Gurbanov
- Bilecik Seyh Edebali Universitesi , Department of Molecular Biology and Genetics , Bilecik , Turkey
- Bilecik Seyh Edebali Universitesi , Biotechnology Application and Research Center , Bilecik , Turkey
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50
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Wuu YR, Hu B, Okunola H, Paul AM, Blaber EA, Cheng-Campbell M, Beheshti A, Grabham P. LET-Dependent Low Dose and Synergistic Inhibition of Human Angiogenesis by Charged Particles: Validation of miRNAs that Drive Inhibition. iScience 2020; 23:101771. [PMID: 33376971 PMCID: PMC7756138 DOI: 10.1016/j.isci.2020.101771] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/19/2020] [Accepted: 10/31/2020] [Indexed: 12/17/2022] Open
Abstract
Space radiation inhibits angiogenesis by two mechanisms depending on the linear energy transfer (LET). Using human 3D micro-vessel models, blockage of the early motile stage of angiogenesis was determined to occur after exposure to low LET ions (<3 KeV/AMU), whereas inhibition of the later stages occurs after exposure to high LET ions (>8 KeV/AMU). Strikingly, the combined effect is synergistic, detectible as low as 0.06 Gy making mixed ion space radiation more potent. Candidates for bystander transmission are microRNAs (miRNAs), and analysis on miRNA-seq data from irradiated mice shows that angiogenesis would in theory be downregulated. Further analysis of three previously identified miRNAs showed downregulation of their targets associated with angiogenesis and confirmed their involvement in angiogenesis pathways and increased health risks associated with cardiovascular disease. Finally, synthetic molecules (antagomirs) designed to inhibit the predicted miRNAs were successfully used to reverse the inhibition of angiogenesis.
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Affiliation(s)
- Yen-Ruh Wuu
- Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Burong Hu
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hazeem Okunola
- Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, VC 11-243, 630 West 168 Street, New York, NY 10032, USA
| | - Amber M. Paul
- Universities Space Research Association, Columbia, MD 21046, USA
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Elizabeth A. Blaber
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
- Department of Bioengineering, Center for Biotechnology & InterdisciplinaryStudies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Margareth Cheng-Campbell
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
- Department of Bioengineering, Center for Biotechnology & InterdisciplinaryStudies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
| | - Afshin Beheshti
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Peter Grabham
- Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, VC 11-243, 630 West 168 Street, New York, NY 10032, USA
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