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1
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Del Toro K, Licon-Munoz Y, Crabtree W, Oper T, Robbins C, Hines WC. Breast pericytes: a newly identified driver of tumor cell proliferation. Front Oncol 2024; 14:1455484. [PMID: 39741968 PMCID: PMC11685225 DOI: 10.3389/fonc.2024.1455484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/27/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction Effective treatment of breast cancer remains a formidable challenge, partly due to our limited understanding of the complex microenvironmental factors that contribute to disease pathology. Among these factors are tissue-resident perivascular cells, which play crucial roles in shaping vascular basement membranes, maintaining vessel integrity, and communicating with adjacent endothelial cells. Despite their essential functions, perivascular cells have been relatively overlooked. Identifying them by immunostaining has been challenging due to their low abundance, inherent heterogeneity, and shared marker expression with other cell types. These challenges have hindered efforts to purify pericytes and generate primary cell models for studying their biology. Methods Using a recently developed FACS method, we successfully identified and purified each cell type from breast tissues, allowing us to deep-sequence their transcriptomes and generate primary cell models of each cell type-including pericytes. Here, we used these data to analyze cell-type-specific gene expression in tumors, which revealed a strong association between pericyte-specific genes and breast cancer patient mortality. To explore this association, we defined the heterogeneity of breast pericytes using single-cell RNA sequencing and identified a broad marker for visualizing perivascular cells in breast tumors. Results Remarkably, we discovered perivascular cells dissociated from vessels and emerged as a dominant mesenchymal cell type in a subset of breast tumors that contrasted with their normal perivascular location. Moreover, when we purified pericytes from the breast and cultured them alongside breast tumor cells, we discovered that they induced rapid tumor cell growth significantly greater than isogenic fibroblast controls. Discussion These findings identify perivascular cells as a key microenvironmental factor in breast cancer, highlighting the critical need for further research to explore their biology and identify specific stimulatory mechanisms that could be targeted therapeutically.
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Affiliation(s)
| | | | | | | | | | - William C. Hines
- Department of Biochemistry and Molecular Biology, University of New Mexico School of
Medicine, 1 University of New Mexico MSC08 4670, Albuquerque, NM, United States
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Aplin AC, Aghazadeh Y, Mohn OG, Hull-Meichle RL. Role of the Pancreatic Islet Microvasculature in Health and Disease. J Histochem Cytochem 2024; 72:711-728. [PMID: 39601198 PMCID: PMC11600425 DOI: 10.1369/00221554241299862] [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: 12/10/2023] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
The pancreatic islet vasculature comprises microvascular endothelial cells surrounded by mural cells (pericytes). Both cell types support the islet by providing (1) a conduit for delivery and exchange of nutrients and hormones; (2) paracrine signals and extracellular matrix (ECM) components that support islet development, architecture, and endocrine function; and (3) a barrier against inflammation and immune cell infiltration. In type 2 diabetes, the islet vasculature becomes inflamed, showing loss of endothelial cells, detachment, and/or trans-differentiation of pericytes, vessel dilation, and excessive ECM deposition. While most work to date has focused either on endothelial cells or pericytes in isolation, it is very likely that the interaction between these cell types and disruption of that interaction in diabetes are critically important. In fact, dissociation of pericytes from endothelial cells is an early, key feature of microvascular disease in multiple tissues/disease states. Moreover, in beta-cell replacement therapy, co-transplantation with microvessels versus endothelial cells alone is substantially more effective in improving survival and function of the transplanted cells. Ongoing studies, including characterization of islet vascular cell signatures, will aid in the identification of new therapeutic targets aimed at improving islet function and benefiting people living with all forms of diabetes.
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Affiliation(s)
- Alfred C. Aplin
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Yasaman Aghazadeh
- Institut de Recherches Cliniques de Montreal (IRCM), Department of Medicine, University of Montreal, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Olivia G. Mohn
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Rebecca L. Hull-Meichle
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington; and Alberta Diabetes Institute and Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada
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3
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Kang Y, Na J, Karima G, Amirthalingam S, Hwang NS, Kim HD. Mesenchymal Stem Cell Spheroids: A Promising Tool for Vascularized Tissue Regeneration. Tissue Eng Regen Med 2024; 21:673-693. [PMID: 38578424 PMCID: PMC11187036 DOI: 10.1007/s13770-024-00636-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are undifferentiated cells that can differentiate into specific cell lineages when exposed to the right conditions. The ability of MSCs to differentiate into particular cells is considered very important in biological research and clinical applications. MSC spheroids are clusters of MSCs cultured in three dimensions, which play an important role in enhancing the proliferation and differentiation of MSCs. MSCs can also participate in vascular formation by differentiating into endothelial cells and secreting paracrine factors. Vascularization ability is essential in impaired tissue repair and function recovery. Therefore, the vascularization ability of MSCs, which enhances angiogenesis and accelerates tissue healing has made MSCs a promising tool for tissue regeneration. However, MSC spheroids are a relatively new research field, and more research is needed to understand their full potential. METHODS In this review, we highlight the importance of MSC spheroids' vascularization ability in tissue engineering and regenerative medicine while providing the current status of studies on the MSC spheroids' vascularization and suggesting potential future research directions for MSC spheroids. RESULTS Studies both in vivo and in vitro have demonstrated MSC spheroids' capacity to develop into endothelial cells and stimulate vasculogenesis. CONCLUSION MSC spheroids show potential to enhance vascularization ability in tissue regeneration. Yet, further research is required to comprehensively understand the relationship between MSC spheroids and vascularization mechanisms.
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Affiliation(s)
- Yoonjoo Kang
- Department of IT Convergence (Brain Korea Plus 21), Korea National University of Transportation, Chungju, 27469, Republic of Korea
| | - Jinwoo Na
- Department of Polymer Science and Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, 27469, Republic of Korea
| | - Gul Karima
- Department of Polymer Science and Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, 27469, Republic of Korea
| | - Sivashanmugam Amirthalingam
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea
- Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nathaniel S Hwang
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea
- Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hwan D Kim
- Department of IT Convergence (Brain Korea Plus 21), Korea National University of Transportation, Chungju, 27469, Republic of Korea.
- Department of Polymer Science and Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, 27469, Republic of Korea.
- Department of Biomedical Engineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea.
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Li H, Shang Y, Zeng J, Matsusaki M. Technology for the formation of engineered microvascular network models and their biomedical applications. NANO CONVERGENCE 2024; 11:10. [PMID: 38430377 PMCID: PMC10908775 DOI: 10.1186/s40580-024-00416-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/15/2024] [Indexed: 03/03/2024]
Abstract
Tissue engineering and regenerative medicine have made great progress in recent decades, as the fields of bioengineering, materials science, and stem cell biology have converged, allowing tissue engineers to replicate the structure and function of various levels of the vascular tree. Nonetheless, the lack of a fully functional vascular system to efficiently supply oxygen and nutrients has hindered the clinical application of bioengineered tissues for transplantation. To investigate vascular biology, drug transport, disease progression, and vascularization of engineered tissues for regenerative medicine, we have analyzed different approaches for designing microvascular networks to create models. This review discusses recent advances in the field of microvascular tissue engineering, explores potential future challenges, and offers methodological recommendations.
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Affiliation(s)
- He Li
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yucheng Shang
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Jinfeng Zeng
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Michiya Matsusaki
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Osaka University, Suita, Osaka, Japan.
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Ramsay E, Lajunen T, Bhattacharya M, Reinisalo M, Rilla K, Kidron H, Terasaki T, Urtti A. Selective drug delivery to the retinal cells: Biological barriers and avenues. J Control Release 2023; 361:1-19. [PMID: 37481214 DOI: 10.1016/j.jconrel.2023.07.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 06/09/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023]
Abstract
Retinal drug delivery is a challenging, but important task, because most retinal diseases are still without any proper therapy. Drug delivery to the retina is hampered by the anatomical and physiological barriers resulting in minimal bioavailability after topical ocular and systemic administrations. Intravitreal injections are current method-of-choice in retinal delivery, but these injections show short duration of action for small molecules and low target bioavailability for many protein, gene based drugs and nanomedicines. State-of-art delivery systems are based on prolonged retention, controlled drug release and physical features (e.g. size and charge). However, drug delivery to the retina is not cell-specific and these approaches do not facilitate intracellular delivery of modern biological drugs (e.g. intracellular proteins, RNA based medicines, gene editing). In this focused review we highlight biological factors and mechanisms that form the basis for the selective retinal drug delivery systems in the future. Therefore, we are presenting current knowledge related to retinal membrane transporters, receptors and targeting ligands in relation to nanomedicines, conjugates, extracellular vesicles, and melanin binding. These issues are discussed in the light of retinal structure and cell types as well as future prospects in the field. Unlike in some other fields of targeted drug delivery (e.g. cancer research), selective delivery technologies have been rarely studied, even though cell targeted delivery may be even more feasible after local administration into the eye.
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Affiliation(s)
- Eva Ramsay
- Drug Research Programme, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland
| | - Tatu Lajunen
- Drug Research Programme, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland
| | - Madhushree Bhattacharya
- Drug Research Programme, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland
| | - Mika Reinisalo
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland
| | - Kirsi Rilla
- School of Medicine, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland
| | - Heidi Kidron
- Drug Research Programme, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland
| | - Tetsuya Terasaki
- School of Pharmacy, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland
| | - Arto Urtti
- Drug Research Programme, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland.
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6
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Grandi E, Navedo MF, Saucerman JJ, Bers DM, Chiamvimonvat N, Dixon RE, Dobrev D, Gomez AM, Harraz OF, Hegyi B, Jones DK, Krogh-Madsen T, Murfee WL, Nystoriak MA, Posnack NG, Ripplinger CM, Veeraraghavan R, Weinberg S. Diversity of cells and signals in the cardiovascular system. J Physiol 2023; 601:2547-2592. [PMID: 36744541 PMCID: PMC10313794 DOI: 10.1113/jp284011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/19/2023] [Indexed: 02/07/2023] Open
Abstract
This white paper is the outcome of the seventh UC Davis Cardiovascular Research Symposium on Systems Approach to Understanding Cardiovascular Disease and Arrhythmia. This biannual meeting aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2022 Symposium was 'Cell Diversity in the Cardiovascular System, cell-autonomous and cell-cell signalling'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies, and challenges in examining cell and signal diversity, co-ordination and interrelationships involved in cardiovascular function. This paper originates from the topics of formal presentations and informal discussions from the Symposium, which aimed to develop a holistic view of how the multiple cell types in the cardiovascular system integrate to influence cardiovascular function, disease progression and therapeutic strategies. The first section describes the major cell types (e.g. cardiomyocytes, vascular smooth muscle and endothelial cells, fibroblasts, neurons, immune cells, etc.) and the signals involved in cardiovascular function. The second section emphasizes the complexity at the subcellular, cellular and system levels in the context of cardiovascular development, ageing and disease. Finally, the third section surveys the technological innovations that allow the interrogation of this diversity and advancing our understanding of the integrated cardiovascular function and dysfunction.
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Affiliation(s)
- Eleonora Grandi
- Department of Pharmacology, University of California Davis, Davis, CA, USA
| | - Manuel F. Navedo
- Department of Pharmacology, University of California Davis, Davis, CA, USA
| | - Jeffrey J. Saucerman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Donald M. Bers
- Department of Pharmacology, University of California Davis, Davis, CA, USA
| | - Nipavan Chiamvimonvat
- Department of Pharmacology, University of California Davis, Davis, CA, USA
- Department of Internal Medicine, University of California Davis, Davis, CA, USA
| | - Rose E. Dixon
- Department of Physiology and Membrane Biology, University of California Davis, Davis, CA, USA
| | - Dobromir Dobrev
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
- Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Canada
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Ana M. Gomez
- Signaling and Cardiovascular Pathophysiology-UMR-S 1180, INSERM, Université Paris-Saclay, Orsay, France
| | - Osama F. Harraz
- Department of Pharmacology, Larner College of Medicine, and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT, USA
| | - Bence Hegyi
- Department of Pharmacology, University of California Davis, Davis, CA, USA
| | - David K. Jones
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Trine Krogh-Madsen
- Department of Physiology & Biophysics, Weill Cornell Medicine, New York, New York, USA
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Matthew A. Nystoriak
- Department of Medicine, Division of Environmental Medicine, Center for Cardiometabolic Science, University of Louisville, Louisville, KY, 40202, USA
| | - Nikki G. Posnack
- Department of Pediatrics, Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA
- Sheikh Zayed Institute for Pediatric and Surgical Innovation, Children’s National Heart Institute, Children’s National Hospital, Washington, DC, USA
| | | | - Rengasayee Veeraraghavan
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University – Wexner Medical Center, Columbus, OH, USA
| | - Seth Weinberg
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
- Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University – Wexner Medical Center, Columbus, OH, USA
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Wu JY, Yeager K, Tavakol DN, Morsink M, Wang B, Soni RK, Hung CT, Vunjak-Novakovic G. Directed differentiation of human iPSCs into mesenchymal lineages by optogenetic control of TGF-β signaling. Cell Rep 2023; 42:112509. [PMID: 37178118 PMCID: PMC10278972 DOI: 10.1016/j.celrep.2023.112509] [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: 06/24/2022] [Revised: 12/28/2022] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
In tissue development and homeostasis, transforming growth factor (TGF)-β signaling is finely coordinated by latent forms and matrix sequestration. Optogenetics can offer precise and dynamic control of cell signaling. We report the development of an optogenetic human induced pluripotent stem cell system for TGF-β signaling and demonstrate its utility in directing differentiation into the smooth muscle, tenogenic, and chondrogenic lineages. Light-activated TGF-β signaling resulted in expression of differentiation markers at levels close to those in soluble factor-treated cultures, with minimal phototoxicity. In a cartilage-bone model, light-patterned TGF-β gradients allowed the establishment of hyaline-like layer of cartilage tissue at the articular surface while attenuating with depth to enable hypertrophic induction at the osteochondral interface. By selectively activating TGF-β signaling in co-cultures of light-responsive and non-responsive cells, undifferentiated and differentiated cells were simultaneously maintained in a single culture with shared medium. This platform can enable patient-specific and spatiotemporally precise studies of cellular decision making.
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Affiliation(s)
- Josephine Y Wu
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Keith Yeager
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | | | - Margaretha Morsink
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Bryan Wang
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Rajesh Kumar Soni
- Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Clark T Hung
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
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Xia M, Jiao L, Wang XH, Tong M, Yao MD, Li XM, Yao J, Li D, Zhao PQ, Yan B. Single-cell RNA sequencing reveals a unique pericyte type associated with capillary dysfunction. Theranostics 2023; 13:2515-2530. [PMID: 37215579 PMCID: PMC10196835 DOI: 10.7150/thno.83532] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Background: Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However, the molecular profiles that govern the heterogeneity of pericytes have not been fully elucidated. Methods: Single-cell RNA sequencing was conducted on oxygen-induced proliferative retinopathy (OIR) model. Bioinformatics analysis was conducted to identify specific pericytes involved in capillary dysfunction. qRT-PCRs and western blots were conducted to detect Col1a1 expression pattern during capillary dysfunction. Matrigel co-culture assays, PI staining, and JC-1 staining was conducted to determine the role of Col1a1 in pericyte biology. IB4 and NG2 staining was conducted to determine the role of Col1a1 in capillary dysfunction. Results: We constructed an atlas of > 76,000 single-cell transcriptomes from 4 mouse retinas, which could be annotated to 10 distinct retinal cell types. Using the sub-clustering analysis, we further characterized retinal pericytes into 3 different subpopulations. Notably, GO and KEGG pathway analysis demonstrated that pericyte sub-population 2 was identified to be vulnerable to retinal capillary dysfunction. Based on the single-cell sequencing results, Col1a1 was identified as a marker gene of pericyte sub-population 2 and a promising therapeutic target for capillary dysfunction. Col1a1 was abundantly expressed in pericytes and its expression was obviously upregulated in OIR retinas. Col1a1 silencing could retard the recruitment of pericytes toward endothelial cells and aggravated hypoxia-induced pericyte apoptosis in vitro. Col1a1 silencing could reduce the size of neovascular area and avascular area in OIR retinas and suppressed pericyte-myofibroblast transition and endothelial-mesenchymal transition. Moreover, Col1a1 expression was up-regulated in the aqueous humor of the patients with proliferative diabetic retinopathy (PDR) or retinopathy of prematurity (ROP) and up-regulated in the proliferative membranes of PDR patients. Conclusions: These findings enhance the understanding of the complexity and heterogeneity of retinal cells and have important implications for future treatment of capillary dysfunction.
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Affiliation(s)
- Min Xia
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Lyu Jiao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Xiao-Han Wang
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Min Tong
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200030, China
| | - Mu-Di Yao
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200030, China
| | - Xiu-Miao Li
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Jin Yao
- The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Dan Li
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200030, China
| | - Pei-Quan Zhao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Biao Yan
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200030, China
- NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200030, China
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9
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Val-Bernal JF, Hermana S, Aller L. Acquired Elastotic Hemangioma-like Change of the Vulva Associated With Lichen Sclerosus. Int J Gynecol Pathol 2022; 41:636-641. [PMID: 34593702 DOI: 10.1097/pgp.0000000000000829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Acquired elastotic hemangioma (AEH) is a rare variant of hemangioma that usually presents as an asymptomatic, solitary, slow-growing red plaque on a sun-exposed site of an adult. Ultraviolet radiation can contribute to the pathogenesis of this hemangioma. Lichen sclerosus (LS), a scarring disease, may present a prominent accumulation of elastic fibers in the reticular dermis reflecting a reparative process. Vulvar elastosis, a novel diagnostic entity with fibers similar to solar elastosis, is more common in women 45 yr and older and is related to aging and/or hormonal changes. We herein report for the first time a case of AEH-like change located in the vulva, a sun-protected area, associated with genital LS. An 81-yr-old woman presented with a painful vulvar lesion of 1-yr duration. Clinical examination revealed vulvar LS and 1 cm-flat, erythematous, well-defined plaque with increased consistency located on the left labium minus. Histopathology showed a non-neoplastic proliferation of WT1-positive, small vascular channels surrounded and intertwined by intense elastosis in the reticular dermis. Alpha-smooth muscle actin positive pericytes encircled the vascular channels. The lesion can be understood as a reparative process within an LS with the appearance of epidermal hyperplasia, proliferation of small vascular channels, and hyperplastic elastosis. There is a close link between epidermal hyperplasia and angiogenesis in the formation of this reparative lesion. Recognition of this lesion is crucial to avoid confusion with other significant processes especially Kaposi sarcoma and well-differentiated angiosarcoma.
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Lampejo AO, Jo M, Murfee WL, Breslin JW. The Microvascular-Lymphatic Interface and Tissue Homeostasis: Critical Questions That Challenge Current Understanding. J Vasc Res 2022; 59:327-342. [PMID: 36315992 PMCID: PMC9780194 DOI: 10.1159/000525787] [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: 03/22/2022] [Accepted: 06/20/2022] [Indexed: 11/07/2022] Open
Abstract
Lymphatic and blood microvascular networks play critical roles in the clearance of excess fluid from local tissue spaces. Given the importance of these dynamics in inflammation, tumor metastasis, and lymphedema, understanding the coordinated function and remodeling between lymphatic and blood vessels in adult tissues is necessary. Knowledge gaps exist because the functions of these two systems are typically considered separately. The objective of this review was to highlight the coordinated functional relationships between blood and lymphatic vessels in adult microvascular networks. Structural, functional, temporal, and spatial relationships will be framed in the context of maintaining tissue homeostasis, vessel permeability, and system remodeling. The integration across systems will emphasize the influence of the local environment on cellular and molecular dynamics involved in fluid flow from blood capillaries to initial lymphatic vessels in microvascular networks.
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Affiliation(s)
- Arinola O. Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Michiko Jo
- Division of Presymptomatic Disease, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Walter L. Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
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11
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Gaussian curvature-driven direction of cell fate toward osteogenesis with triply periodic minimal surface scaffolds. Proc Natl Acad Sci U S A 2022; 119:e2206684119. [PMID: 36191194 PMCID: PMC9564829 DOI: 10.1073/pnas.2206684119] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Leaf photosynthesis, coral mineralization, and trabecular bone growth depend on triply periodic minimal surfaces (TPMSs) with hyperboloidal structure on every surface point with varying Gaussian curvatures. However, translation of this structure into tissue-engineered bone grafts is challenging. This article reports the design and fabrication of high-resolution three-dimensional TPMS scaffolds embodying biomimicking hyperboloidal topography with different Gaussian curvatures, composed of body inherent β-tricalcium phosphate, by stereolithography-based three-dimensional printing and sintering. The TPMS bone scaffolds show high porosity and interconnectivity. Notably, compared with conventional scaffolds, they can reduce stress concentration, leading to increased mechanical strength. They are also found to support the attachment, proliferation, osteogenic differentiation, and angiogenic paracrine function of human mesenchymal stem cells (hMSCs). Through transcriptomic analysis, we theorize that the hyperboloid structure induces cytoskeleton reorganization of hMSCs, expressing elongated morphology on the convex direction and strengthening the cytoskeletal contraction. The clinical therapeutic efficacy of the TPMS scaffolds assessed by rabbit femur defect and mouse subcutaneous implantation models demonstrate that the TPMS scaffolds augment new bone formation and neovascularization. In comparison with conventional scaffolds, our TPMS scaffolds successfully guide the cell fate toward osteogenesis through cell-level directional curvatures and demonstrate drastic yet quantifiable improvements in bone regeneration.
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12
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Rocker AJ, Cavasin M, Johnson NR, Shandas R, Park D. Sulfonated Thermoresponsive Injectable Gel for Sequential Release of Therapeutic Proteins to Protect Cardiac Function after Myocardial Infarction. ACS Biomater Sci Eng 2022; 8:3883-3898. [PMID: 35950643 DOI: 10.1021/acsbiomaterials.2c00616] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Myocardial infarction causes cardiomyocyte death and persistent inflammatory responses, which generate adverse pathological remodeling. Delivering therapeutic proteins from injectable materials in a controlled-release manner may present an effective biomedical approach for treating this disease. A thermoresponsive injectable gel composed of chitosan, conjugated with poly(N-isopropylacrylamide) and sulfonate groups, was developed for spatiotemporal protein delivery to protect cardiac function after myocardial infarction. The thermoresponsive gel delivered vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and platelet-derived growth factor (PDGF) in a sequential and sustained manner in vitro. An acute myocardial infarction mouse model was used to evaluate polymer biocompatibility and to determine therapeutic effects from the delivery system on cardiac function. Immunohistochemistry showed biocompatibility of the hydrogel, while the controlled delivery of the proteins reduced macrophage infiltration and increased vascularization. Echocardiography showed an improvement in ejection fraction and fractional shortening after injecting the thermal gel and proteins. A factorial design of experimental study was implemented to optimize the delivery system for the best combination and doses of proteins for further increasing stable vascularization and reducing inflammation using a subcutaneous injection mouse model. The results showed that VEGF, IL-10, and FGF-2 demonstrated significant contributions toward promoting long-term vascularization, while PDGF's effect was minimal.
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Affiliation(s)
- Adam J Rocker
- Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Maria Cavasin
- Department of Medicine, Division of Cardiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Noah R Johnson
- Department of Neurology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Robin Shandas
- Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Daewon Park
- Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States
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13
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Matsuo R, Kishibe M, Horiuchi K, Kano K, Tatsukawa T, Hayasaka T, Kabara M, Iinuma S, Eguchi R, Igawa S, Hasebe N, Ishida-Yamamoto A, Kawabe JI. Ninjurin1 deletion in neuron-glial antigen 2-positive pericytes prevents microvessel maturation and delays wound healing. JID INNOVATIONS 2022; 2:100141. [PMID: 36262667 PMCID: PMC9573932 DOI: 10.1016/j.xjidi.2022.100141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/20/2022] [Accepted: 05/28/2022] [Indexed: 11/24/2022] Open
Abstract
The formation of mature vasculature through angiogenesis is essential for adequate wound healing, such that blood-borne cells, nutrients, and oxygen can be delivered to the remodeling skin area. Neovessel maturation is highly dependent on the coordinated functions of vascular endothelial cells and perivascular cells, namely pericytes (PCs). However, the underlying mechanism for vascular maturation has not been completely elucidated, and its role in wound healing remains unclear. In this study, we investigated the role of Ninjurin-1 (Ninj1), a new molecule mediating vascular maturation, in wound healing using an inducible PC-specific Ninj1 deletion mouse model. Ninj1 expression increased temporarily in NG2-positive PCs in response to skin injury. When tamoxifen treatment induced a decreased Ninj1 expression in PCs, the neovessels in the regenerating wound margins were structurally and functionally immature, but the total number of microvessels was unaltered. This phenotypic change is associated with a reduction in PC-associated microvessels. Wound healing was significantly delayed in the NG2-specific Ninj1 deletion mouse model. Finally, we showed that Ninj1 is a crucial molecule that mediates vascular maturation in injured skin tissue through the interaction of vascular endothelial cells and PCs, thereby inducing adequate and prompt wound healing.
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Affiliation(s)
- Risa Matsuo
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Mari Kishibe
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Kiwamu Horiuchi
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Division of Cardiovascular, Respiratory and Neurology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kohei Kano
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Division of Cardiovascular, Respiratory and Neurology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takamitsu Tatsukawa
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Department of Vascular Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Taiki Hayasaka
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Division of Cardiovascular, Respiratory and Neurology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Maki Kabara
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
| | - Shin Iinuma
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Ryoji Eguchi
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
| | - Satomi Igawa
- Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan
| | - Naoyuki Hasebe
- Division of Cardiovascular, Respiratory and Neurology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
- Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
| | | | - Jun-ichi Kawabe
- Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan
- Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
- Correspondence: Jun-ichi Kawabe, Department of Biochemistry, Asahikawa Medical University, Asahikawa, 2-1-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan.
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14
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Lampejo AO, Hu NW, Lucas D, Lomel BM, Nguyen CM, Dominguez CC, Ren B, Huang Y, Murfee WL. A Challenge for Engineering Biomimetic Microvascular Models: How do we Incorporate the Physiology? Front Bioeng Biotechnol 2022; 10:912073. [PMID: 35795159 PMCID: PMC9252339 DOI: 10.3389/fbioe.2022.912073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
The gap between in vitro and in vivo assays has inspired biomimetic model development. Tissue engineered models that attempt to mimic the complexity of microvascular networks have emerged as tools for investigating cell-cell and cell-environment interactions that may be not easily viewed in vivo. A key challenge in model development, however, is determining how to recreate the multi-cell/system functional complexity of a real network environment that integrates endothelial cells, smooth muscle cells, vascular pericytes, lymphatics, nerves, fluid flow, extracellular matrix, and inflammatory cells. The objective of this mini-review is to overview the recent evolution of popular biomimetic modeling approaches for investigating microvascular dynamics. A specific focus will highlight the engineering design requirements needed to match physiological function and the potential for top-down tissue culture methods that maintain complexity. Overall, examples of physiological validation, basic science discoveries, and therapeutic evaluation studies will emphasize the value of tissue culture models and biomimetic model development approaches that fill the gap between in vitro and in vivo assays and guide how vascular biologists and physiologists might think about the microcirculation.
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Affiliation(s)
- Arinola O. Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Nien-Wen Hu
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Daniela Lucas
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Banks M. Lomel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Christian M. Nguyen
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Carmen C. Dominguez
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Bing Ren
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, United States
| | - Yong Huang
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, United States
| | - Walter L. Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
- *Correspondence: Walter L. Murfee,
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15
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Dolan R, Lampejo AO, Santini-González J, Hodges NA, Phelps EA, Murfee WL. A Novel ex vivo Method for Investigating Vascularization of Transplanted Islets. J Vasc Res 2022; 59:229-238. [PMID: 35462373 PMCID: PMC9308658 DOI: 10.1159/000523925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 03/01/2022] [Indexed: 11/19/2022] Open
Abstract
Revascularization of transplanted pancreatic islets is critical for survival and treatment of type 1 diabetes. Questions concerning how islets influence local microvascular networks and how networks form connections with islets remain understudied and motivate the need for new models that mimic the complexity of real tissue. Recently, our laboratory established the rat mesentery culture model as a tool to investigate cell dynamics involved in microvascular growth. An advantage is the ability to observe blood vessels, lymphatics, and immune cells. The objective of this study was to establish the rat mesentery tissue culture model as a useful tool to investigate islet tissue integration. DiI-labeled islets were seeded onto adult rat mesentery tissues and cultured for up to 3 days. Live lectin labeling enabled time-lapse observation of vessel growth. During culture, DiI-positive islets remained intact. Radial lectin-positive capillary sprouts with DiI labeling were observed to form from islets and connect to host networks. Lectin-positive vessels from host networks were also seen growing toward islets. PECAM and NG2 labeling confirmed that vessels sprouting from islets contained endothelial cells and pericytes. Our results introduce the rat mesentery culture model as a platform for investigating dynamics associated with the initial revascularization of transplanted islets.
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Affiliation(s)
- Robert Dolan
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Arinola O Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Jorge Santini-González
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Nicholas A Hodges
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Edward A Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
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16
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Zhou SY, Guo ZN, Zhang DH, Qu Y, Jin H. The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets. Front Mol Neurosci 2022; 15:866700. [PMID: 35493333 PMCID: PMC9043812 DOI: 10.3389/fnmol.2022.866700] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/18/2022] [Indexed: 12/25/2022] Open
Abstract
Ischemic stroke (IS) is a cerebrovascular disease causing high rates of disability and fatality. In recent years, the concept of the neurovascular unit (NVU) has been accepted by an increasing number of researchers and is expected to become a new paradigm for exploring the pathogenesis and treatment of IS. NVUs are composed of neurons, endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix. As an important part of the NVU, pericytes provide support for other cellular components and perform a variety of functions, including participating in the maintenance of the normal physiological function of the blood–brain barrier, regulating blood flow, and playing a role in inflammation, angiogenesis, and neurogenesis. Therefore, treatment strategies targeting pericyte functions, regulating pericyte epigenetics, and transplanting pericytes warrant exploration. In this review, we describe the reactions of pericytes after IS, summarize the potential therapeutic targets and strategies targeting pericytes for IS, and provide new treatment ideas for ischemic stroke.
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Affiliation(s)
- Sheng-Yu Zhou
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Zhen-Ni Guo
- Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Dian-Hui Zhang
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Yang Qu
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
| | - Hang Jin
- Department of Neurology, Stroke Center, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Hang Jin,
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17
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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18
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Zhu S, Chen M, Ying Y, Wu Q, Huang Z, Ni W, Wang X, Xu H, Bennett S, Xiao J, Xu J. Versatile subtypes of pericytes and their roles in spinal cord injury repair, bone development and repair. Bone Res 2022; 10:30. [PMID: 35296645 PMCID: PMC8927336 DOI: 10.1038/s41413-022-00203-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/16/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
Vascular regeneration is a challenging topic in tissue repair. As one of the important components of the neurovascular unit (NVU), pericytes play an essential role in the maintenance of the vascular network of the spinal cord. To date, subtypes of pericytes have been identified by various markers, namely the PDGFR-β, Desmin, CD146, and NG2, each of which is involved with spinal cord injury (SCI) repair. In addition, pericytes may act as a stem cell source that is important for bone development and regeneration, whilst specific subtypes of pericyte could facilitate bone fracture and defect repair. One of the major challenges of pericyte biology is to determine the specific markers that would clearly distinguish the different subtypes of pericytes, and to develop efficient approaches to isolate and propagate pericytes. In this review, we discuss the biology and roles of pericytes, their markers for identification, and cell differentiation capacity with a focus on the potential application in the treatment of SCI and bone diseases in orthopedics.
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Affiliation(s)
- Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,Molecular Pharmacology Research Centre, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia
| | - Min Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yibo Ying
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Qiuji Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Zhiyang Huang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Wenfei Ni
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Huazi Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Samuel Bennett
- Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia
| | - Jian Xiao
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,Molecular Pharmacology Research Centre, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Jiake Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. .,Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
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19
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Ayoub NM, Jaradat SK, Al-Shami KM, Alkhalifa AE. Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches. Front Pharmacol 2022; 13:838133. [PMID: 35281942 PMCID: PMC8913593 DOI: 10.3389/fphar.2022.838133] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.
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Affiliation(s)
- Nehad M. Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
- *Correspondence: Nehad M. Ayoub,
| | - Sara K. Jaradat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
| | - Kamal M. Al-Shami
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Amer E. Alkhalifa
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
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20
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Rahimnejad M, Nasrollahi Boroujeni N, Jahangiri S, Rabiee N, Rabiee M, Makvandi P, Akhavan O, Varma RS. Prevascularized Micro-/Nano-Sized Spheroid/Bead Aggregates for Vascular Tissue Engineering. NANO-MICRO LETTERS 2021; 13:182. [PMID: 34409511 PMCID: PMC8374027 DOI: 10.1007/s40820-021-00697-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 07/13/2021] [Indexed: 05/02/2023]
Abstract
Efficient strategies to promote microvascularization in vascular tissue engineering, a central priority in regenerative medicine, are still scarce; nano- and micro-sized aggregates and spheres or beads harboring primitive microvascular beds are promising methods in vascular tissue engineering. Capillaries are the smallest type and in numerous blood vessels, which are distributed densely in cardiovascular system. To mimic this microvascular network, specific cell components and proangiogenic factors are required. Herein, advanced biofabrication methods in microvascular engineering, including extrusion-based and droplet-based bioprinting, Kenzan, and biogripper approaches, are deliberated with emphasis on the newest works in prevascular nano- and micro-sized aggregates and microspheres/microbeads.
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Affiliation(s)
- Maedeh Rahimnejad
- Biomedical Engineering Institute, School of Medicine, Université de Montréal, Montreal, Canada
- Research Centre, Centre Hospitalier de L'Université de Montréal (CRCHUM), Montreal, Canada
| | | | - Sepideh Jahangiri
- Research Centre, Centre Hospitalier de L'Université de Montréal (CRCHUM), Montreal, Canada
- Department of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, Canada
| | - Navid Rabiee
- Department of Physics, Sharif University of Technology, P.O. Box 11155-9161, Tehran, Iran.
| | - Mohammad Rabiee
- Biomaterial Group, Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Pooyan Makvandi
- Centre for Materials Interfaces, Istituto Italiano Di Tecnologia, viale Rinaldo Piaggio 34, 56 025, Pontedera, Pisa, Italy
| | - Omid Akhavan
- Department of Physics, Sharif University of Technology, P.O. Box 11155-9161, Tehran, Iran.
| | - Rajender S Varma
- Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute, Palacky University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
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21
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Martin P, Gurevich DB. Macrophage regulation of angiogenesis in health and disease. Semin Cell Dev Biol 2021; 119:101-110. [PMID: 34330619 DOI: 10.1016/j.semcdb.2021.06.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/24/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022]
Abstract
Macrophages are primarily known as phagocytic innate immune cells, but are, in fact, highly dynamic multi-taskers that interact with many different tissue types and have regulatory roles in development, homeostasis, tissue repair, and disease. In all of these scenarios angiogenesis is pivotal and macrophages appear to play a key role in guiding both blood vessel sprouting and remodelling wherever that occurs. Recent studies have explored these processes in a diverse range of models utilising the complementary strengths of rodent, fish and tissue culture studies to unravel the mechanisms underlying these interactions and regulatory functions. Here we discuss how macrophages regulate angiogenesis and its resolution as embryonic tissues grow, as well as their parallel and different functions in repairing wounds and in pathologies, with a focus on chronic wounds and cancer.
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Affiliation(s)
- Paul Martin
- School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK; School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK
| | - David Baruch Gurevich
- Department of Biology & Biochemistry, Faculty of Science, University of Bath, Claverton Down, Bath BA2 7AY, UK.
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22
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Hannan RT, Miller AE, Hung RC, Sano C, Peirce SM, Barker TH. Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition. Matrix Biol Plus 2021; 10:100056. [PMID: 34195593 PMCID: PMC8233458 DOI: 10.1016/j.mbplus.2020.100056] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Of the many origins of pulmonary myofibroblasts, microvascular pericytes are a known source. Prior literature has established the ability of pericytes to transition into myofibroblasts, but provide limited insight into molecular cues that drive this process during lung injury repair and fibrosis. Fibronectin and RGD-binding integrins have long been considered pro-fibrotic factors in myofibroblast biology, and here we test the hypothesis that these known myofibroblast cues coordinate pericyte-to-myofibroblast transitions. Specifically, we hypothesized that αvβ3 integrin engagement on fibronectin induces pericyte transition into myofibroblastic phenotypes in the murine bleomycin lung injury model. Myosin Heavy Chain 11 (Myh11)-CreERT2 lineage tracing in transgenic mice allows identification of cells of pericyte origin and provides a robust tool for isolating pericytes from tissues for further evaluation. We used this murine model to track and characterize pericyte behaviors during tissue repair. The majority of Myh11 lineage-positive cells are positive for the pericyte surface markers, PDGFRβ (55%) and CD146 (69%), and display typical pericyte morphology with spatial apposition to microvascular networks. After intratracheal bleomycin treatment of mice, Myh11 lineage-positive cells showed significantly increased contractile and secretory markers, as well as αv integrin expression. According to RNASeq measurements, many disease and tissue-remodeling genesets were upregulated in Myh11 lineage-positive cells in response to bleomycin-induced lung injury. In vitro, blocking αvβ3 binding through cycloRGDfK prevented expression of the myofibroblastic marker αSMA relative to controls. In response to RGD-containing provisional matrix proteins present in lung injury, pericytes may alter their integrin profile.
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Affiliation(s)
- Riley T. Hannan
- Department of Pathology, University of Virginia, 415 Lane Road, Charlottesville, VA, United States
| | - Andrew E. Miller
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United States
| | - Ruei-Chun Hung
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United States
| | - Catherine Sano
- Department of Chemical Engineering, University of Virginia, 102 Engineer's Way, Charlottesville, VA, United States
| | - Shayn M. Peirce
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United States
| | - Thomas H. Barker
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA, United States
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23
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Rosanto YB, Hasan CY, Rahardjo R, Pangestiningsih TW. Effect of snail mucus on angiogenesis during wound healing. F1000Res 2021; 10:181. [PMID: 38912381 PMCID: PMC11190653 DOI: 10.12688/f1000research.51297.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/07/2021] [Indexed: 06/25/2024] Open
Abstract
Background: Angiogenesis is the process through which new blood vessels are formed from existing ones. This process plays an important role in supplying the oxygen and nutrients needed for cellular metabolism and eliminating cell debris during wound healing. Snail mucus can bind to several factors that stimulate angiogenesis, including vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor. The aim of this study is to observe changes in angiogenesis during the healing of wounds topically applied with snail mucus. Methods: Punch biopsy was performed on the back of male Wistar rats to obtain four wounds, and different concentrations of snail mucus were applied to each of these wounds. The animals were sacrificed on days 2, 4, and 7 to observe the extent of angiogenesis during wound healing by microscopy. Results: Two-way ANOVA showed differences in number of blood vessels formed (p = 0.00) and day of observation (p = 0.00) between groups. Post hoc Tukey's HSD test showed that 24% snail mucus treatment does not significantly affect wound healing (p = 0.488); by contrast, treatment with 48% and 96% snail mucus demonstrated significant effects on angiogenesis (p = 0.01). Spearman's test showed interactive effects between snail mucus concentration and day of observation on the extent of angiogenesis (p = 0.001, R = 0.946). Conclusion: Topical application of snail mucus gel can increase angiogenesis during wound healing in Wistar rat skin.
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Affiliation(s)
- Yosaphat Bayu Rosanto
- Oral and Maxillofacial Surgery, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia, 55281, Indonesia
| | - Cahya Yustisia Hasan
- Oral and Maxillofacial Surgery, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia, 55281, Indonesia
| | - Rahardjo Rahardjo
- Oral and Maxillofacial Surgery, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia, 55281, Indonesia
| | - Tri Wahyu Pangestiningsih
- Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia, 55281, Indonesia
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24
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Payne LB, Darden J, Suarez-Martinez AD, Zhao H, Hendricks A, Hartland C, Chong D, Kushner EJ, Murfee WL, Chappell JC. Pericyte migration and proliferation are tightly synchronized to endothelial cell sprouting dynamics. Integr Biol (Camb) 2021; 13:31-43. [PMID: 33515222 DOI: 10.1093/intbio/zyaa027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/13/2020] [Accepted: 12/26/2020] [Indexed: 01/17/2023]
Abstract
Pericytes are critical for microvascular stability and maintenance, among other important physiological functions, yet their involvement in vessel formation processes remains poorly understood. To gain insight into pericyte behaviors during vascular remodeling, we developed two complementary tissue explant models utilizing 'double reporter' animals with fluorescently-labeled pericytes and endothelial cells (via Ng2:DsRed and Flk-1:eGFP genes, respectively). Time-lapse confocal imaging of active vessel remodeling within adult connective tissues and embryonic skin revealed a subset of pericytes detaching and migrating away from the vessel wall. Vessel-associated pericytes displayed rapid filopodial sampling near sprouting endothelial cells that emerged from parent vessels to form nascent branches. Pericytes near angiogenic sprouts were also more migratory, initiating persistent and directional movement along newly forming vessels. Pericyte cell divisions coincided more frequently with elongating endothelial sprouts, rather than sprout initiation sites, an observation confirmed with in vivo data from the developing mouse brain. Taken together, these data suggest that (i) pericyte detachment from the vessel wall may represent an important physiological process to enhance endothelial cell plasticity during vascular remodeling, and (ii) pericyte migration and proliferation are highly synchronized with endothelial cell behaviors during the coordinated expansion of a vascular network.
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Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA
| | - Jordan Darden
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Ariana D Suarez-Martinez
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Huaning Zhao
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Alissa Hendricks
- Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Caitlin Hartland
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA
| | - Diana Chong
- Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Erich J Kushner
- Department of Biological Sciences, University of Denver, Denver, CO 80208 USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - John C Chappell
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.,Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
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25
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Jones VM, Suarez-Martinez AD, Hodges NA, Murfee WL, Llull R, Katz AJ. A clinical perspective on adipose-derived cell therapy for enhancing microvascular health and function: Implications and applications for reconstructive surgery. Microcirculation 2020; 28:e12672. [PMID: 33174272 DOI: 10.1111/micc.12672] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/18/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022]
Abstract
Restoration of form and function requires apposition of tissues in the form of flaps to reconstitute local perfusion. Successful reconstruction relies on flap survival and its integration with the recipient bed. The flap's precariously perfused hypoxic areas undergo adaptive microvascular changes both internally and in connection with the recipient bed. A cell-mediated, coordinated response to hypoxia drives these adaptive processes, restoring a tissue's normoxic homeostasis via de novo vasculogenesis, sprouting angiogenesis, and stabilizing arterialization. As cells exert prolonged and coordinated effects on site, their use as biological agents merit translational consideration of sourcing angio-competent cells and delivering them to territories enduring microcirculatory acclimatization. Angio-competent cells abound in adipose tissue: a reliable, accessible, and expendable source of adipose-derived cells (ADC). When subject to enzymatic digestion and centrifugation, adipose tissue separates its various ADC: A subset of buoyant oil-dense adipocytes (the tissue's parenchymal component) accumulates on a supra-natant layer, whereas the mesenchymal component remains in the infra-natant sediment, containing the tissue's stromal vascular fraction (SVF), where angio-component cells abound. The SVF can be further manipulated, selected, or culture expanded into more specific stromal subsets (herein defined as adipose stromal cells, ASC). While promising clinical applications for ADC await clinical proof and regulatory authorization, basic science investigation is needed to elucidate the specific ADC mechanisms that influence microvascular growth, remodeling, and function following flap surgery. The objective of this article is to share the clinical perspectives of reconstructive plastic surgeons regarding the use of ADC-based therapies to help with flap tissue integration, revascularization, and wound healing. Specifically, the focus will be on considering the potential for ADC as therapeutic agents and how their clinical application motivates basic science opportunities.
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Affiliation(s)
- V Morgan Jones
- Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ariana D Suarez-Martinez
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Nicholas A Hodges
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Ramon Llull
- Department of Plastic Surgery, Hospital Quiron Salud PalmaPlanas, Palma, Spain
| | - Adam J Katz
- Department of Plastic and Reconstructive Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA
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26
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Li J, Burgess DJ. Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment. Acta Pharm Sin B 2020; 10:2110-2124. [PMID: 33304781 PMCID: PMC7714990 DOI: 10.1016/j.apsb.2020.05.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/15/2020] [Accepted: 05/21/2020] [Indexed: 12/17/2022] Open
Abstract
The complex tumor microenvironment is a most important factor in cancer development. The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells, pericytes, and cancer-associated fibroblasts. Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components. In addition to the biological microenvironment, the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance. Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells, B cells, macrophages, and dendritic cells. In this review, the main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy.
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Affiliation(s)
- Jin Li
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA
| | - Diane J. Burgess
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA
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27
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Fleischer S, Tavakol DN, Vunjak-Novakovic G. From arteries to capillaries: approaches to engineering human vasculature. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1910811. [PMID: 33708027 PMCID: PMC7942836 DOI: 10.1002/adfm.201910811] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Indexed: 05/02/2023]
Abstract
From micro-scaled capillaries to millimeter-sized arteries and veins, human vasculature spans multiple scales and cell types. The convergence of bioengineering, materials science, and stem cell biology has enabled tissue engineers to recreate the structure and function of different hierarchical levels of the vascular tree. Engineering large-scale vessels has been pursued over the past thirty years to replace or bypass damaged arteries, arterioles, and venules, and their routine application in the clinic may become a reality in the near future. Strategies to engineer meso- and microvasculature have been extensively explored to generate models to study vascular biology, drug transport, and disease progression, as well as for vascularizing engineered tissues for regenerative medicine. However, bioengineering of large-scale tissues and whole organs for transplantation, have failed to result in clinical translation due to the lack of proper integrated vasculature for effective oxygen and nutrient delivery. The development of strategies to generate multi-scale vascular networks and their direct anastomosis to host vasculature would greatly benefit this formidable goal. In this review, we discuss design considerations and technologies for engineering millimeter-, meso-, and micro-scale vessels. We further provide examples of recent state-of-the-art strategies to engineer multi-scale vasculature. Finally, we identify key challenges limiting the translation of vascularized tissues and offer our perspective on future directions for exploration.
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Affiliation(s)
| | | | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University
- Department of Medicine, Columbia University
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28
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Tao Z, Liu Y, Yang H, Feng Y, Li H, Shi Q, Li S, Cheng J, Lu X. Customizing a Tridomain TRAIL Variant to Achieve Active Tumor Homing and Endogenous Albumin-Controlled Release of the Molecular Machine In Vivo. Biomacromolecules 2020; 21:4017-4029. [PMID: 32804484 DOI: 10.1021/acs.biomac.0c00785] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive antitumor drug candidate for precision cancer therapy due to its superior selective cytotoxicity in a variety of tumor cells. However, the clinical application of TRAIL in cancer therapy has been limited by its poor tumor-homing capacities and short half-life. Herein, we designed a tridomain TRAIL variant, Z-ABD-TRAIL, by sequentially fusing the platelet-derived growth factor receptor beta (PDGFRβ)-specific affibody ZPDGFRβ and an albumin-binding domain (ABD) to the N-terminus of TRAIL. The fusion protein Z-ABD-TRAIL was produced as a soluble protein with high yield in Escherichia coli (E. coli). The ZPDGFRβ domain provided Z-ABD-TRAIL with PDGFRβ-binding properties and thus promoted its tumor homing via the engagement of PDGFRβ-expressing pericytes on tumor microvessels. ABD-mediated binding of Z-ABD-TRAIL to albumin in the blood endowed TRAIL with long-lasting (>72 h for Z-ABD-TRAIL vs <0.5 h for TRAIL) abilities to kill tumor cells. Although the in vitro cytotoxicity of Z-ABD-TRAIL in tumor cells was similar to that of the parent TRAIL, the in vivo tumor uptake, apoptosis-inducing ability, and antitumor effect of Z-ABD-TRAIL were much greater than those of TRAIL, indicating that ZPDGFRβ-mediated tumor homing and ABD-introduced albumin binding significantly improved the pharmacodynamics of TRAIL. In addition, repeated injection of high-dose Z-ABD-TRAIL showed no obvious acute toxicity in mice. These results demonstrate that the newly designed tridomain Z-ABD-TRAIL is a promising agent for precision cancer therapy.
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Affiliation(s)
- Ze Tao
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuehua Liu
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hao Yang
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanru Feng
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Heng Li
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiuxiao Shi
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shengfu Li
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jingqiu Cheng
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.,Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaofeng Lu
- Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.,Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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29
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Abstract
Purpose of review Pericytes are essential components of capillaries in many tissues and organs, contributing to vessel stability and integrity, with additional contributions to microvascular function still being discovered. We review current and foundational studies identifying pericyte differentiation mechanics and their roles in the earliest stages of vessel formation. Recent findings Recent advances in pericyte-focused tools and models have illuminated critical aspects of pericyte biology including their roles in vascular development.Pericytes likely collaborate with endothelial cells undergoing vasculogenesis, initiating direct interactions during sprouting and intussusceptive angiogenesis. Pericytes also provide important regulation of vascular growth including mechanisms underlying vessel pruning, rarefaction, and subsequent regrowth.
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Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA
| | - Maruf Hoque
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Blacksburg, VA 24061, USA
| | - Clifton Houk
- Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.,Previous Affiliations
| | - Jordan Darden
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Blacksburg, VA 24061, USA.,Previous Affiliations
| | - John C Chappell
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.,Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA
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30
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Zheng Z, Chopp M, Chen J. Multifaceted roles of pericytes in central nervous system homeostasis and disease. J Cereb Blood Flow Metab 2020; 40:1381-1401. [PMID: 32208803 PMCID: PMC7308511 DOI: 10.1177/0271678x20911331] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pericytes, the mural cells surrounding microcirculation, are gaining increasing attention for their roles in health and disease of the central nervous system (CNS). As an essential part of the neurovascular unit (NVU), pericytes are actively engaged in interactions with neighboring cells and work in synergy with them to maintain homeostasis of the CNS, such as maintaining the blood-brain barrier (BBB), regulating cerebral blood flow (CBF) and the glymphatic system as well as mediating immune responses. However, the dysfunction of pericytes may contribute to the progression of various pathologies. In this review, we discuss: (1) origin of pericytes and different pericyte markers; (2) interactions of pericytes with endothelial cells (ECs), astrocytes, microglia, oligodendrocytes, and neurons; (3) physiological roles of pericytes in the CNS; (4) effects of pericytes in different CNS diseases; (5) relationship of pericytes with extracellular vesicles (EVs) and microRNAs (miRs); (6) recent advances in pericytes studies and future perspective.
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Affiliation(s)
- Zhitong Zheng
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.,Department of Physics, Oakland University, Rochester, MI, USA
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
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31
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Coronary vessel formation in development and disease: mechanisms and insights for therapy. Nat Rev Cardiol 2020; 17:790-806. [PMID: 32587347 DOI: 10.1038/s41569-020-0400-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2020] [Indexed: 12/20/2022]
Abstract
The formation of new blood vessels after myocardial infarction (MI) is essential for the survival of existing and regenerated cardiac tissue. However, the extent of endogenous revascularization after MI is insufficient, and MI can often result in ventricular remodelling, progression to heart failure and premature death. The neutral results of numerous clinical trials that have evaluated the efficacy of angiogenic therapy to revascularize the infarcted heart reflect our poor understanding of the processes required to form a functional coronary vasculature. In this Review, we describe the latest advances in our understanding of the processes involved in coronary vessel formation, with mechanistic insights taken from developmental studies. Coronary vessels originate from multiple cellular sources during development and form through a number of distinct and carefully orchestrated processes. The ectopic reactivation of developmental programmes has been proposed as a new paradigm for regenerative medicine, therefore, a complete understanding of these processes is crucial. Furthermore, knowledge of how these processes differ between the embryonic and adult heart, and how they might be more closely recapitulated after injury are critical for our understanding of regenerative biology, and might facilitate the identification of tractable molecular targets to therapeutically promote neovascularization and regeneration of the infarcted heart.
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32
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Hou Z, Neng L, Zhang J, Cai J, Wang X, Zhang Y, Lopez IA, Shi X. Acoustic Trauma Causes Cochlear Pericyte-to-Myofibroblast-Like Cell Transformation and Vascular Degeneration, and Transplantation of New Pericytes Prevents Vascular Atrophy. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1943-1959. [PMID: 32562655 DOI: 10.1016/j.ajpath.2020.05.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/19/2020] [Accepted: 05/26/2020] [Indexed: 12/20/2022]
Abstract
Acoustic trauma disrupts cochlear blood flow and damages sensory hair cells. Damage and regression of capillaries after acoustic trauma have long been observed, but the underlying mechanism of pathology has not been understood. We show herein that loud sound causes change of phenotype from neural/glial antigen 2 positive/α-smooth muscle actin negative to neural/glial antigen 2 positive/α-smooth muscle actin positive in some pericytes (PCs) on strial capillaries that is strongly associated with up-regulation of transforming growth factor-β1. The acoustic trauma also reduced capillary density and increased deposition of matrix proteins, particularly in the vicinity of transformed PCs. In a newly established in vitro three-dimensional endothelial cell (EC) and PC co-culture model, transformed PCs induced thicker capillary-like branches in ECs and increased collagen IV and laminin expression. Transplantation of exogenous PCs derived from neonatal day 10 mouse cochleae to acoustic traumatized cochleae, however, significantly attenuated the decreased vascular density in the stria. Transplantation of PCs pretransfected with adeno-associated virus 1-vascular endothelial growth factor-A165 under control of a hypoxia-response element markedly promotes vascular volume and blood flow, increased proliferation of PCs and ECs, and attenuated loud sound-caused loss in endocochlear potential and hearing. Our results indicate that loud sound-triggered PC transformation contributes to capillary wall thickening and regression, and young PC transplantation effectively rehabilitates the vascular regression and improves hearing.
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Affiliation(s)
- Zhiqiang Hou
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon
| | - Lingling Neng
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon
| | - Jinhui Zhang
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon
| | - Jing Cai
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon
| | - Xiaohan Wang
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon; Center for Life Sciences, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Yunpei Zhang
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon
| | - Ivan A Lopez
- Cellular and Molecular Biology of the Inner Ear Laboratory, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Xiaorui Shi
- Department of Otolaryngology/Head & Neck Surgery, Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon.
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33
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Azimi MS, Motherwell JM, Dutreil M, Fishel RL, Nice M, Hodges NA, Bunnell BA, Katz A, Murfee WL. A novel tissue culture model for evaluating the effect of aging on stem cell fate in adult microvascular networks. GeroScience 2020; 42:515-526. [PMID: 32206968 PMCID: PMC7205973 DOI: 10.1007/s11357-020-00178-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 03/04/2020] [Indexed: 12/18/2022] Open
Abstract
In vitro models of angiogenesis are valuable tools for understanding the underlying mechanisms of pathological conditions and for the preclinical evaluation of therapies. Our laboratory developed the rat mesentery culture model as a new tool for investigating mechanistic cell-cell interactions at specific locations across intact blood and lymphatic microvascular networks ex vivo. The objective of this study was to report a method for evaluating the effect of aging on human stem cell differentiation into pericytes during angiogenesis in cultured microvascular networks. DiI labeled exogenous stem cells were seeded onto harvested adult Wistar rat mesenteric tissues and cultured in alpha-MEM + 1% serum for up to 5 days according to four experimental groups: (1) adult human adipose-derived stem cells (hASCs), (2) aged hASCs, (3) adult human bone marrow-derived stem cells (hBMSCs), and (4) aged hBMSCs. Angiogenesis per experimental group was supported by observation of increased vessel density and capillary sprouting. For each tissue per experimental group, a subset of cells was observed in typical pericyte location wrapped along blood vessels. Stem cell differentiation into pericytes was supported by the adoption of elongated pericyte morphology along endothelial cells and positive NG2 labeling. The percentage of cells in pericyte locations was not significantly different across the experimental groups, suggesting that aged mesenchymal stem cells are able to retain their differentiation capacity. Our results showcase an application of the rat mesentery culture model for aging research and the evaluation of stem cell fate within intact microvascular networks.
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Affiliation(s)
- Mohammad S Azimi
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Jessica M Motherwell
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Maria Dutreil
- Tulane Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Ryan L Fishel
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Matthew Nice
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Nicholas A Hodges
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Bruce A Bunnell
- Tulane Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Adam Katz
- Depart of Surgery, University of Florida School of Medicine, Gainesville, FL, 32611, USA
| | - Walter L Murfee
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA.
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Payne LB, Zhao H, James CC, Darden J, McGuire D, Taylor S, Smyth JW, Chappell JC. The pericyte microenvironment during vascular development. Microcirculation 2019; 26:e12554. [PMID: 31066166 PMCID: PMC6834874 DOI: 10.1111/micc.12554] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/22/2022]
Abstract
Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.
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Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
| | - Huaning Zhao
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
| | - Carissa C. James
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Jordan Darden
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - David McGuire
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Sarah Taylor
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
| | - James W. Smyth
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biological Sciences, College of Science, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
| | - John C. Chappell
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
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Hsu T, Nguyen-Tran HH, Trojanowska M. Active roles of dysfunctional vascular endothelium in fibrosis and cancer. J Biomed Sci 2019; 26:86. [PMID: 31656195 PMCID: PMC6816223 DOI: 10.1186/s12929-019-0580-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 10/09/2019] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammation is the underlying pathological condition that results in fibrotic diseases. More recently, many forms of cancer have also been linked to chronic tissue inflammation. While stromal immune cells and myofibroblasts have been recognized as major contributors of cytokines and growth factors that foster the formation of fibrotic tissue, the endothelium has traditionally been regarded as a passive player in the pathogenic process, or even as a barrier since it provides a physical divide between the circulating immune cells and the inflamed tissues. Recent findings, however, have indicated that endothelial cells in fact play a crucial role in the inflammatory response. Endothelial cells can be activated by cytokine signaling and express inflammatory markers, which can sustain or exacerbate the inflammatory process. For example, the activated endothelium can recruit and activate leukocytes, thus perpetuating tissue inflammation, while sustained stimulation of endothelial cells may lead to endothelial-to-mesenchymal transition that contributes to fibrosis. Since chronic inflammation has now been recognized as a significant contributing factor to tumorigenesis, it has also emerged that activation of endothelium also occurs in the tumor microenvironment. This review summarizes recent findings characterizing the molecular and cellular changes in the vascular endothelium that contribute to tissue fibrosis, and potentially to cancer formation.
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Affiliation(s)
- Tien Hsu
- Department of Biomedical Sciences and Engineering, National Central University, 300 Jhongda Rd, Taoyuan City, Taiwan, Republic of China. .,Center for Chronic Disease Research, National Central University, 300 Jhongda Rd, Taoyuan City, Taiwan, Republic of China.
| | - Hieu-Huy Nguyen-Tran
- Department of Biomedical Sciences and Engineering, National Central University, 300 Jhongda Rd, Taoyuan City, Taiwan, Republic of China
| | - Maria Trojanowska
- Arthritis Center, Boston University School of Medicine, 75 E. Newton St. Evans Building, Boston, MA, 02118, USA
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Da Silva AC, Jammal MP, Crispim PCA, Murta EFC, Nomelini RS. The Role of Stroma in Ovarian Cancer. Immunol Invest 2019; 49:406-424. [PMID: 32264761 DOI: 10.1080/08820139.2019.1658770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Ovarian cancer is one of the gynecological malignancies responsible for thousands of deaths in women worldwide. Malignant solid tumors are formed by malignant cells and stroma that influence each other, where different types of cells in the stromal environment can be recruited by malignant cells to promote tumor growth and facilitate metastasis. The chronic inflammatory response is increasingly accepted in its relation to the pathophysiology of the onset and development of tumors, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma and DNA damage agents may increase the risk to develop a neoplasm.Methods: A search for the following keywords was performed in the PubMed database; "Ovarian cancer", "stroma", "tumor-associated macrophages", "cancer-associated fibroblasts", "cytokines", "angiogenesis", "epithelial-mesenchymal transition", and "extracellular matrix".Results: The articles identified were published in English between 1971 and 2018. A total of 154 articles were selected for further analysis. Conclusion: We consider ovarian cancer as a heterogeneous disease, not only in the sense that different histological or molecular subtypes may be behind the same clinical result, but also that multiple cell types besides cancer cells, like other non-cellular components, need to be mobilized and coordinated to support tumor survival, growth, invasion and progression.
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Affiliation(s)
- Ana Carolinne Da Silva
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Millena Prata Jammal
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Paula Carolina Arvelos Crispim
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Eddie Fernando Candido Murta
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Rosekeila Simões Nomelini
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
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Abstract
Ageing is the main risk factor for the development of cardiovascular diseases. A central mechanism by which ageing promotes vascular pathologies is compromising endothelial health. The age-related attenuation of endothelium-dependent dilator responses (endothelial dysfunction) associated with impairment of angiogenic processes and the subsequent pathological remodelling of the microcirculation contribute to compromised tissue perfusion and exacerbate functional decline in older individuals. This Review focuses on cellular, molecular, and functional changes that occur in the endothelium during ageing. We explore the links between oxidative and nitrative stress and the conserved molecular pathways affecting endothelial dysfunction and impaired angiogenesis during ageing. We also speculate on how these pathological processes could be therapeutically targeted. An improved understanding of endothelial biology in older patients is crucial for all cardiologists because maintenance of a competently functioning endothelium is critical for adequate tissue perfusion and long-term cardiac health.
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Chen DY, Sun NH, Lu YP, Hong LJ, Cui TT, Wang CK, Chen XH, Wang SS, Feng LL, Shi WX, Fukunaga K, Chen Z, Lu YM, Han F. GPR124 facilitates pericyte polarization and migration by regulating the formation of filopodia during ischemic injury. Theranostics 2019; 9:5937-5955. [PMID: 31534530 PMCID: PMC6735362 DOI: 10.7150/thno.34168] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 07/28/2019] [Indexed: 12/31/2022] Open
Abstract
Prolonged occlusion of multiple microvessels causes microvascular injury. G protein-coupled receptor 124 (GPR124) has been reported to be required for maintaining central nervous system (CNS) angiogenesis and blood-brain barrier integrity. However, the molecular mechanisms by which GPR124 regulates pericytes during ischemia have remained elusive. Methods: A microsphere embolism-induced ischemia model was used to evaluate the expression of GPR124 following microsphere embolism. Immunocytochemistry and stochastic optical reconstruction microscopy imaging were used to assess the expression and distribution of GPR124 in human brain vascular pericytes (HBVPs) and after the treatment with 3-morpholino-sydnonimine (SIN-1) or oxygen-glucose deprivation (OGD). The effect of GPR124 knockdown or overexpression on HBVP migration was analyzed in vitro using wound healing assays and a microfluidic device. GPR124 loss-of-function studies were performed in HBVPs and HEK293 cells using CRISPR-Cas9-mediated gene deletion. Time-lapse imaging was used to assess dynamic changes in the formation of filopodia in an individual cell. Finally, to explore the functional domains required for GPR124 activity, deletion mutants were constructed for each of the N-terminal domains. Results: GPR124 expression was increased in pericytes following microsphere embolism. Morphological analysis showed localization of GPR124 to focal adhesions where GPR124 bound directly to the actin binding protein vinculin and upregulated Cdc42. SIN-1 or OGD treatment redistributed GPR124 to the leading edges of HBVPs where GPR124 signaling was required for pericyte filopodia formation and directional migration. Partial deletion of GPR124 domains decreased SIN-1-induced filopodia formation and cell migration. Conclusion: Taken together, our results provide the first evidence for a role of GPR124 in pericyte migration under ischemic conditions and suggest that GPR124 was essential for Cdc42 activation and filopodia formation.
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Abstract
This review chapter describes the current knowledge about the nature of pericytes in the gut, their interaction with endothelial cells in blood vessels, and their pathophysiological functions in the setting of chronic liver disease. In particular, it focuses on the role of these vascular cell types and related molecular signaling pathways in pathological angiogenesis associated with liver disease and in the establishment of the gut-vascular barrier and the potential implications in liver disease through the gut-liver axis.
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Motherwell JM, Rozenblum M, Katakam PV, Murfee WL. Bioreactor System to Perfuse Mesentery Microvascular Networks and Study Flow Effects During Angiogenesis. Tissue Eng Part C Methods 2019; 25:447-458. [PMID: 31280703 PMCID: PMC6686705 DOI: 10.1089/ten.tec.2019.0119] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/02/2019] [Indexed: 02/03/2023] Open
Abstract
IMPACT STATEMENT Microvascular remodeling, or angiogenesis, plays a central role in multiple pathological conditions, including cancer, diabetes, and ischemia. Tissue-engineered in vitro models have emerged as tools to elucidate the mechanisms that drive the angiogenic process. However, a major challenge with model development is recapitulating the physiological complexity of real microvascular networks, including incorporation of the entire vascular tree and hemodynamics. This study establishes a bioreactor system that incorporates real microvascular networks with physiological flow as a novel ex vivo tissue culture model, thereby providing a platform to evaluate angiogenesis in a physiologically relevant environment.
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Affiliation(s)
- Jessica M. Motherwell
- Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Maximillian Rozenblum
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Prasad V.G. Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Walter L. Murfee
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida
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41
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Corliss BA, Mathews C, Doty R, Rohde G, Peirce SM. Methods to label, image, and analyze the complex structural architectures of microvascular networks. Microcirculation 2019; 26:e12520. [PMID: 30548558 PMCID: PMC6561846 DOI: 10.1111/micc.12520] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 10/31/2018] [Accepted: 11/26/2018] [Indexed: 12/30/2022]
Abstract
Microvascular networks play key roles in oxygen transport and nutrient delivery to meet the varied and dynamic metabolic needs of different tissues throughout the body, and their spatial architectures of interconnected blood vessel segments are highly complex. Moreover, functional adaptations of the microcirculation enabled by structural adaptations in microvascular network architecture are required for development, wound healing, and often invoked in disease conditions, including the top eight causes of death in the Unites States. Effective characterization of microvascular network architectures is not only limited by the available techniques to visualize microvessels but also reliant on the available quantitative metrics that accurately delineate between spatial patterns in altered networks. In this review, we survey models used for studying the microvasculature, methods to label and image microvessels, and the metrics and software packages used to quantify microvascular networks. These programs have provided researchers with invaluable tools, yet we estimate that they have collectively attained low adoption rates, possibly due to limitations with basic validation, segmentation performance, and nonstandard sets of quantification metrics. To address these existing constraints, we discuss opportunities to improve effectiveness, rigor, and reproducibility of microvascular network quantification to better serve the current and future needs of microvascular research.
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Affiliation(s)
- Bruce A. Corliss
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginia
| | - Corbin Mathews
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginia
| | - Richard Doty
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginia
| | - Gustavo Rohde
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginia
| | - Shayn M. Peirce
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginia
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Wagner DR, Karnik S, Gunderson ZJ, Nielsen JJ, Fennimore A, Promer HJ, Lowery JW, Loghmani MT, Low PS, McKinley TO, Kacena MA, Clauss M, Li J. Dysfunctional stem and progenitor cells impair fracture healing with age. World J Stem Cells 2019; 11:281-296. [PMID: 31293713 PMCID: PMC6600851 DOI: 10.4252/wjsc.v11.i6.281] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
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Affiliation(s)
- Diane R Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Sonali Karnik
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Zachary J Gunderson
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jeffery J Nielsen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States
| | - Alanna Fennimore
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Hunter J Promer
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - M Terry Loghmani
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Philip S Low
- Department of Chemistry, Purdue University, West Lafayette, IN 47907 United States
| | - Todd O McKinley
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, United States
| | - Matthias Clauss
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jiliang Li
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
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Senchukova MA, Makarova EV, Kalinin EA, Tkachev VV. Modern ideas about the origin, features of morphology, prognostic and predictive significance of tumor vessels. RUSSIAN JOURNAL OF BIOTHERAPY 2019; 18:6-15. [DOI: 10.17650/1726-9784-2019-18-1-6-15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The review presents modern ideas about the origin of tumor vessels and the features of their morphology. The various approaches to the classification of tumor vessel types and to the assessment of their clinical and prognostic significance are described. Also, the main problems associated with the use of angiogenesis blockers in the treatment of malignancies and their possible solutions are reflected in the review.
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Affiliation(s)
- M. A. Senchukova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
| | - E. V. Makarova
- Orenburg State Medical University of the Ministry of Health of the Russian Federation; Orenburg Regional Clinical Oncology Dispensary
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Cai H, Shi Q, Tang Y, Chen L, Chen Y, Tao Z, Yang H, Xie F, Wu X, Liu N, Yang Y, Wu H, Tian R, Lu X, Li L. Positron Emission Tomography Imaging of Platelet-Derived Growth Factor Receptor β in Colorectal Tumor Xenograft Using Zirconium-89 Labeled Dimeric Affibody Molecule. Mol Pharm 2019; 16:1950-1957. [PMID: 30986347 DOI: 10.1021/acs.molpharmaceut.8b01317] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Huawei Cai
- Laboratory of Clinical Nuclear Medicine, Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiuxiao Shi
- Key Lab of Transplant Engineering and Immunology, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu Tang
- Key Lab of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, China
| | - Lihong Chen
- Department of Biochemistry & Molecular Biology, West China School of Basic Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yue Chen
- Departments of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ze Tao
- Key Lab of Transplant Engineering and Immunology, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hao Yang
- Key Lab of Transplant Engineering and Immunology, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fang Xie
- PET Center, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiaoai Wu
- Laboratory of Clinical Nuclear Medicine, Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Nan Liu
- Departments of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yuanyou Yang
- Department of Biochemistry & Molecular Biology, West China School of Basic Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Haoxing Wu
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Rong Tian
- Laboratory of Clinical Nuclear Medicine, Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaofeng Lu
- Key Lab of Transplant Engineering and Immunology, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lin Li
- Laboratory of Clinical Nuclear Medicine, Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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Zhao H, Chappell JC. Microvascular bioengineering: a focus on pericytes. J Biol Eng 2019; 13:26. [PMID: 30984287 PMCID: PMC6444752 DOI: 10.1186/s13036-019-0158-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 03/15/2019] [Indexed: 12/26/2022] Open
Abstract
Capillaries within the microcirculation are essential for oxygen delivery and nutrient/waste exchange, among other critical functions. Microvascular bioengineering approaches have sought to recapitulate many key features of these capillary networks, with an increasing appreciation for the necessity of incorporating vascular pericytes. Here, we briefly review established and more recent insights into important aspects of pericyte identification and function within the microvasculature. We then consider the importance of including vascular pericytes in various bioengineered microvessel platforms including 3D culturing and microfluidic systems. We also discuss how vascular pericytes are a vital component in the construction of computational models that simulate microcirculation phenomena including angiogenesis, microvascular biomechanics, and kinetics of exchange across the vessel wall. In reviewing these topics, we highlight the notion that incorporating pericytes into microvascular bioengineering applications will increase their utility and accelerate the translation of basic discoveries to clinical solutions for vascular-related pathologies.
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Affiliation(s)
- Huaning Zhao
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, 2 Riverside Circle, Roanoke, VA 24016 USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061 USA
| | - John C Chappell
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, 2 Riverside Circle, Roanoke, VA 24016 USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061 USA.,3Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016 USA
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46
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Alcendor DJ. Human Vascular Pericytes and Cytomegalovirus Pathobiology. Int J Mol Sci 2019; 20:E1456. [PMID: 30909422 PMCID: PMC6471229 DOI: 10.3390/ijms20061456] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 03/01/2019] [Accepted: 03/20/2019] [Indexed: 12/11/2022] Open
Abstract
Pericytes are multipotent cells of the vascular system with cytoplasmic extensions proximal to endothelial cells that occur along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes are essential for proper microvascular formation, development, stabilization, and maintenance. Pericytes are essential for the regulation of paracellular flow between cells, transendothelial fluid transport, angiogenesis, and vascular immunosurveillance. They also influence the chemical composition of the surrounding microenvironment to protect endothelial cells from potential harm. Dysregulation or loss of pericyte function can result in microvascular instability and pathological consequences. Human pericytes have been shown to be targets for human cytomegalovirus (HCMV) infection and lytic replication that likely contribute to vascular inflammation. This review focuses on human vascular pericytes and their permissiveness for HCMV infection. It also discusses their implication in pathogenesis in the blood⁻brain barrier (BBB), the inner blood⁻retinal barrier (IBRB), the placenta⁻blood barrier, and the renal glomerulus as well as their potential role in subclinical vascular disease.
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Affiliation(s)
- Donald J Alcendor
- Center for AIDS Health Disparities Research, Department of Microbiology, Immunology, and Physiology, School of Medicine, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Hubbard Hospital, 5th Floor, Rm. 5025, Nashville, TN 37208, USA.
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47
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Lee LL, Chintalgattu V. Pericytes in the Heart. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:187-210. [PMID: 30937870 DOI: 10.1007/978-3-030-11093-2_11] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mural cells known as pericytes envelop the endothelial layer of microvessels throughout the body and have been described to have tissue-specific functions. Cardiac pericytes are abundantly found in the heart, but they are relatively understudied. Currently, their importance is emerging in cardiovascular homeostasis and dysfunction due to their pleiotropism. They are known to play key roles in vascular tone and vascular integrity as well as angiogenesis. However, their dysfunctional presence and/or absence is critical in the mechanisms that lead to cardiac pathologies such as myocardial infarction, fibrosis, and thrombosis. Moreover, they are targeted as a therapeutic potential due to their mesenchymal properties that could allow them to repair and regenerate a damaged heart. They are also sought after as a cell-based therapy based on their healing potential in preclinical studies of animal models of myocardial infarction. Therefore, recognizing the importance of cardiac pericytes and understanding their biology will lead to new therapeutic concepts.
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Affiliation(s)
- Linda L Lee
- Department of CardioMetabolic Disorders, Amgen Research and Discovery, Amgen Inc., South San Francisco, CA, USA
| | - Vishnu Chintalgattu
- Department of CardioMetabolic Disorders, Amgen Research and Discovery, Amgen Inc., South San Francisco, CA, USA.
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Fernandes C, Suares D, Yergeri MC. Tumor Microenvironment Targeted Nanotherapy. Front Pharmacol 2018; 9:1230. [PMID: 30429787 PMCID: PMC6220447 DOI: 10.3389/fphar.2018.01230] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022] Open
Abstract
Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect promotes nano-chemotherapeutics extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of nano-chemotherapeutics and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of nano-chemotherapeutics in non-tumor-stroma cells damages the non-tumor cells, and interferes with tumor-stroma crosstalk. This can lead not only to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a vital role in regulating nano-chemotherapeutics distribution and their biological effects. In this review, the barriers in tumor microenvironment, its consequential effects on nano-chemotherapeutics, considerations to improve nano-chemotherapeutics delivery and combinatory strategies to overcome acquired resistance induced by tumor microenvironment have been summarized. The various strategies viz., nanotechnology based approach as well as ligand-mediated, redox-responsive, and enzyme-mediated based combinatorial nanoapproaches have been discussed in this review.
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Affiliation(s)
| | | | - Mayur C Yergeri
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's Narsee Monjee Institute of Management Studies - NMIMS, Mumbai, India
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Darden J, Payne LB, Zhao H, Chappell JC. Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation. Angiogenesis 2018; 22:167-183. [PMID: 30238211 DOI: 10.1007/s10456-018-9648-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022]
Abstract
Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericytes indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-β (Pdgfrβ) expression. In contrast, PDGFRβ protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRβ and a truncated PDGFRβ isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRβ dynamics, without substantial involvement of pericyte Notch signaling during these early stages.
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Affiliation(s)
- Jordan Darden
- Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.,Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA
| | - Laura Beth Payne
- Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA
| | - Huaning Zhao
- Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA
| | - John C Chappell
- Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA. .,Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. .,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. .,Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.
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Elabd C, Ichim TE, Miller K, Anneling A, Grinstein V, Vargas V, Silva FJ. Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs. J Transl Med 2018; 16:222. [PMID: 30097061 PMCID: PMC6086019 DOI: 10.1186/s12967-018-1601-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 08/04/2018] [Indexed: 02/07/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) represent an attractive avenue for cellular therapies targeting degenerative diseases. MSC in vitro expansion is required in order to obtain therapeutic numbers during the manufacturing process. It is known that culture conditions impact cellular properties and behavior after in vivo transplantation. In this study, we aimed at evaluating the benefit of hypoxic culturing of human bone marrow derived mesenchymal stem cells on cell fitness and whole genome expression and discussed its implication on cellular therapies targeting orthopedic diseases such as chronic lower back pain. Methods Human bone marrow mesenchymal stem cells (hBMMSCs) were isolated from fresh human anticoagulated whole bone marrow and were cultured side by side in atmospheric (20% O2) and hypoxic (5% O2) oxygen partial pressure for up to 3 passages. Stem cell fitness was assessed by clonogenic assay, cell surface marker expression and differentiation potential. Whole genome expression was performed by mRNA sequencing. Data from clonogenic assays, cell surface marker by flow cytometry and gene expression by quantitative PCR were analyzed by two-tailed paired Student’s t-test. Data from mRNA sequencing were aligned to hg19 using Tophat-2.0.13 and analyzed using Cufflinks-2.1.1. Results Hypoxic culturing of hBMMSCs had positive effects on cell fitness, as evidenced by an increased clonogenicity and improved differentiation potential towards adipocyte and chondrocyte lineages. No difference in osteoblast differentiation or in cell surface markers were observed. Only a small subset of genes (34) were identified by mRNA sequencing to be significantly dysregulated by hypoxia. When clustered by biological function, these genes were associated with chondrogenesis and cartilage metabolism, inflammation and immunomodulation, cellular survival, migration and proliferation, vasculogenesis and angiogenesis. Conclusions Hypoxic culturing positively impacted hBMMSCs fitness and transcriptome, potentially improving inherent properties of these cells that are critical for the development of successful cellular therapies. Hypoxic culturing should be considered for the in vitro expansion of hBMMSCs during manufacturing of cellular therapies targeting orthopedic disorders such as lower back pain.
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Affiliation(s)
- C Elabd
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA
| | - T E Ichim
- Immune Advisors, LLC, La Jolla, CA, 92037, USA
| | - K Miller
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA
| | - A Anneling
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA
| | - V Grinstein
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA
| | - V Vargas
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA
| | - F J Silva
- BioRestorative Therapies, Inc., 40 Marcus Drive, Suite 1, Melville, NY, 11747, USA.
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