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Bosch-Rué E, Zhang Q, Truskey GA, Olmos Buitrago J, M Bosch B, Pérez RA. Development of small tissue engineered blood vessels and their clinical and research applications. Biofabrication 2025; 17:032005. [PMID: 40341214 DOI: 10.1088/1758-5090/add626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 05/08/2025] [Indexed: 05/10/2025]
Abstract
Since the first tissue engineered blood vessel (TEBV) was developed, different approaches, biomaterial scaffolds and cell sources have been used to obtain an engineered vessel as much similar as native vessels in terms of structure, functionality and mechanical properties. At the same time, diverse needs to obtain a functional TEBV have emerged, such as for blood vessel replacement for cardiovascular diseases (CVDs) to be used as artery bypass, to vascularize tissue engineered constructs, or even to model vascular diseases or drug testing. In this review, after briefly describing the native structure and function of arteries, we will give an overview of different biomaterials, cells and methods that have been used during the last years for the development of small TEBV (1-6 mm diameter). The importance of perfusing the TEBV to acquire functionality and maturation will be also discussed. Finally, we will center the review on TEBV applications beyond their use as vascular graft for CVDs.
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Affiliation(s)
- Elia Bosch-Rué
- Bioengineering Institute of Technology (BIT), Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
- Bioengineering Department, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
| | - Qiao Zhang
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States of America
| | - George A Truskey
- Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States of America
| | - Jenifer Olmos Buitrago
- Bioengineering Institute of Technology (BIT), Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
- Bioengineering Department, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
| | - Begoña M Bosch
- Bioengineering Institute of Technology (BIT), Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
- Bioengineering Department, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
| | - Román A Pérez
- Bioengineering Institute of Technology (BIT), Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
- Bioengineering Department, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08195 Barcelona, Spain
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Liu S, Wang Y, Gao E, Lin H, Wang H. Enhancement of Fat Septa: Polycaprolactone (PCL) Microspheres Boost Collagen Production in Subcutaneous Adipose Tissue. Aesthet Surg J 2025; 45:514-524. [PMID: 39936547 DOI: 10.1093/asj/sjaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND The reduction in collagen content within the subcutaneous fat layer due to aging results in thinning and weakening of the fibrous septum, leading to an unstable fat pad. Studies on the mechanism of action of polycaprolactone (PCL) collagen stimulators in the adipose layer are lacking. OBJECTIVES This research aimed to explore the effectiveness of PCL-based filler in enhancing the fibrous septum within adipose tissue, thereby facilitating collagen and elastin synthesis in the adipose layer, while also comparing the disparities in the process between juvenile and aged individuals. METHODS A rat model was utilized to study subcutaneous fat implantation effects of PCL-based filler. Over 4 months, the impact on fibrous septum formation was evaluated with Masson's trichrome staining and immunostainings for Types I and III collagen, and a structural evaluation through scanning electron microscopy analysis. PCL-induced collagenization mechanisms were explored by quantitative polymerase chain reaction (qPCR). Elastin regeneration was examined with Elastica van Gieson (EVG) staining. RESULTS Histological analysis demonstrated that PCL-based filler effectively stimulated collagen fiber formation in subcutaneous adipose tissue in both juvenile and aged rats. Immunostainings indicated significant promotion of Types I and III collagen regeneration, primarily within the interstitial spaces among adipocytes, as well as its confirmation at the genetic level through qPCR analysis. EVG staining further unveiled the role of PCL in promoting elastin production while mitigating age-related decline. CONCLUSIONS PCL-based filler enhanced fat septum regeneration and deposition, demonstrating a robust, age-independent response. These findings suggest PCL-based fillers as promising therapeutic agents for rejuvenating subcutaneous adipose tissue and enhancing skin volume and elasticity in cosmetic and reconstructive contexts.
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Ji X, Wang X, Dong Q, Li W, Zhou N, Yue X, Zhao D, Yang X. CDCP1 knockdown suppresses PDGFRβ/AKT pathway-mediated vascular smooth muscle cell proliferation by inhibiting PDGFRβ endocytosis. PeerJ 2025; 13:e19114. [PMID: 40256729 PMCID: PMC12007496 DOI: 10.7717/peerj.19114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 02/13/2025] [Indexed: 04/22/2025] Open
Abstract
CUB domain-containing protein 1 (CDCP1) is a type of cell surface glycoprotein that has been identified as being capable of regulating cell anchorage, migration, proliferation, and differentiation. However, the contributions of CDCP1 in intimal hyperplasia, specifically regarding the proliferation and migration of vascular smooth muscle cells (VSMC), are unclear. In this study, we analyzed CDCP1 expression on intimal hyperplasia through a focal carotid stenosis model in vivo. In vitro, we cultured mouse VSMCs and stimulated them with 20 ng/mL platelet-derived growth factor BB (PDGF-BB) for 24 h. Western blot analysis was performed to detect the expression of CDCP1 in the cells. Next, we knocked down the expression of CDCP1 in VSMCs and assessed its effects on cell proliferation and migration using CCK8 assays, EDU+ assay, and wound healing experiments. We then performed RNA-Seq analysis on the CDCP1-knockdown VSMCs. Based on the sequencing results, we utilized western blotting to investigate the impact of CDCP1 knockdown on the AKT signaling pathway. Additionally, we validated the interactions between Platelet-derived growth factor receptor (PDGFR)β with NEDD4, clathrin, and Rab5 using immunofluorescence and co-immunoprecipitation assays. The results discovered that CDCP1 levels were activated in the intimal hyperplasia tissues in vivo. CDCP1 knockdown significantly attenuated mouse VSMC proliferation and migration induced by PDGF-BB in vitro. Based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the differentially expressed proteins obtained from RNA-sequencing, we found that the knockdown of CDCP1 is related to the "PI3K-AKT signaling pathway", "ubiquitin-mediated proteolysis", and "endocytosis" pathways. The subsequent experiments demonstrated that CDCP1 knockdown inhibited AKT signaling pathway. CDCP1 knockdown promoted the binding of PDGFRβ and NEDD4, and PDGFRβ ubiquitin. Moreover, CDCP1 knockdown attenuated the binding of PDGFRβ to clathrin and Rab5. These data reveal that the absence of CDCP1 may enhance the binding of PDGFR to NEDD4 and promote the ubiquitination of PDGFR, thereby regulating the AKT signaling pathway and intimal hyperplasia.
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MESH Headings
- Animals
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Cell Proliferation/genetics
- Mice
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Signal Transduction
- Endocytosis/genetics
- Myocytes, Smooth Muscle/metabolism
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cell Movement
- Gene Knockdown Techniques
- Becaplermin/pharmacology
- Male
- Cells, Cultured
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Mice, Inbred C57BL
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Affiliation(s)
- Xin Ji
- Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Ministry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei Province, China
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, Guangdong Province, China
| | - Xin Wang
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Qianqian Dong
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Wanqiu Li
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Ning Zhou
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, Guangdong Province, China
| | - Xiaole Yue
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Dandan Zhao
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xiaolong Yang
- Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, Hebei Collaborative Innovation Center for Eco-Environment, Ministry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei Province, China
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4
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Li Q, Yu S, Wang Y, Zhao H, Gao Z, Du H, Yang H, Shen L, Zhou H. Programmable embedded bioprinting for one-step manufacturing of arterial models with customized contractile and metabolic functions. Trends Biotechnol 2025; 43:918-945. [PMID: 39779422 DOI: 10.1016/j.tibtech.2024.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
Replicating the contractile function of arterial tissues in vitro requires precise control of cell alignment within 3D structures, a challenge that existing bioprinting techniques struggle to meet. In this study, we introduce the voxel-based embedded construction for tailored orientational replication (VECTOR) method, a voxel-based approach that controls cellular orientation and collective behavior within bioprinted filaments. By fine-tuning voxel vector magnitude and using an omnidirectional printing trajectory, we achieve structural mimicry at both the macroscale and the cellular alignment level. This dual-scale approach enhances vascular smooth muscle cell (VSMC) function by regulating contractile and synthetic pathways. The VECTOR method facilitates the construction of 3D arterial structures that closely replicate natural coronary architectures, significantly improving contractility and metabolic function. Moreover, the resulting multilayered arterial models (AMs) exhibit precise responses to pharmacological stimuli, similar to native arteries. This work highlights the critical role of structural mimicry in tissue functionality and advances the replication of complex tissues in vitro.
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Affiliation(s)
- Qi Li
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Engineering, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Shuyuan Yu
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Yuxuan Wang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Hui Zhao
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, People's Republic of China
| | - Ziqi Gao
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Huilong Du
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Luqi Shen
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, People's Republic of China.
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310058, People's Republic of China; School of Mechanical Engineering, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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5
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Florido MHC, Ziats NP. Endothelial dysfunction and cardiovascular diseases: The role of human induced pluripotent stem cells and tissue engineering. J Biomed Mater Res A 2024; 112:1286-1304. [PMID: 38230548 DOI: 10.1002/jbm.a.37669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/07/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024]
Abstract
Cardiovascular disease (CVD) remains to be the leading cause of death globally today and therefore the need for the development of novel therapies has become increasingly important in the cardiovascular field. The mechanism(s) behind the pathophysiology of CVD have been laboriously investigated in both stem cell and bioengineering laboratories. Scientific breakthroughs have paved the way to better mimic cell types of interest in recent years, with the ability to generate any cell type from reprogrammed human pluripotent stem cells. Mimicking the native extracellular matrix using both organic and inorganic biomaterials has allowed full organs to be recapitulated in vitro. In this paper, we will review techniques from both stem cell biology and bioengineering which have been fruitfully combined and have fueled advances in the cardiovascular disease field. We will provide a brief introduction to CVD, reviewing some of the recent studies as related to the role of endothelial cells and endothelial cell dysfunction. Recent advances and the techniques widely used in both bioengineering and stem cell biology will be discussed, providing a broad overview of the collaboration between these two fields and their overall impact on tissue engineering in the cardiovascular devices and implications for treatment of cardiovascular disease.
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Affiliation(s)
- Mary H C Florido
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Nicholas P Ziats
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Departments of Biomedical Engineering and Anatomy, Case Western Reserve University, Cleveland, Ohio, USA
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6
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Jiao YC, Wang YX, Liu WZ, Xu JW, Zhao YY, Yan CZ, Liu FC. Advances in the differentiation of pluripotent stem cells into vascular cells. World J Stem Cells 2024; 16:137-150. [PMID: 38455095 PMCID: PMC10915963 DOI: 10.4252/wjsc.v16.i2.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/20/2023] [Accepted: 01/16/2024] [Indexed: 02/26/2024] Open
Abstract
Blood vessels constitute a closed pipe system distributed throughout the body, transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys. Changes in blood vessels are related to many disorders like stroke, myocardial infarction, aneurysm, and diabetes, which are important causes of death worldwide. Translational research for new approaches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems. Although mice or rats have been widely used, applying data from animal studies to human-specific vascular physiology and pathology is difficult. The rise of induced pluripotent stem cells (iPSCs) provides a reliable in vitro resource for disease modeling, regenerative medicine, and drug discovery because they carry all human genetic information and have the ability to directionally differentiate into any type of human cells. This review summarizes the latest progress from the establishment of iPSCs, the strategies for differentiating iPSCs into vascular cells, and the in vivo transplantation of these vascular derivatives. It also introduces the application of these technologies in disease modeling, drug screening, and regenerative medicine. Additionally, the application of high-tech tools, such as omics analysis and high-throughput sequencing, in this field is reviewed.
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Affiliation(s)
- Yi-Chang Jiao
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Ying-Xin Wang
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Wen-Zhu Liu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jing-Wen Xu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yu-Ying Zhao
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Chuan-Zhu Yan
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao) of Shandong University, Qingdao 266103, Shandong Province, China
- Brain Science Research Institute, Shandong University, Jinan 250012, Shandong Province, China
| | - Fu-Chen Liu
- Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
- Brain Science Research Institute, Shandong University, Jinan 250012, Shandong Province, China.
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7
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Hamilton NJI, Tait A, Weil B, Daniels J. The Use of a Dehydrated Cellularized Collagen Matrix to Replace Fibrotic Vocal Fold Mucosa. Laryngoscope 2024; 134:882-893. [PMID: 37681762 DOI: 10.1002/lary.31034] [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: 05/09/2023] [Revised: 08/01/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023]
Abstract
OBJECTIVES Fibrosis of the vocal fold lamina propria reduces vocal cord vibration resulting in a chronically hoarse voice. We describe a novel approach using umbilical cord-derived mesenchymal stem cells in a dehydrated collagen matrix (cellogen) to reconstruct the delicate balance of extracellular matrix within the vocal fold lamina propria whilst limiting the host inflammatory response to the implant. METHODS Human umbilical cord-derived mesenchymal stem-cells were embedded in bovine type I collagen hydrogel and dehydrated using the RAFT™ 3D culture system. The extracellular matrix, cellular viability and composition, paracrine profile, and genomic profile were assessed and the scaffold engrafted onto the hind muscle of NUDE mice. RESULTS The cells retained stem-cell markers following fabrication and secreted collagen III, fibronectin, and glycosaminoglycans within the scaffold. Electron microscopy showed the scaffold consisted of single strands of protein with interspersed bundles of a similar size to native vocal fold lamina propria. The use of the dehydration step improved cell viability and upregulated the expression of genes important in wound healing and matrix organization compared with unmodified collagen hydrogel carriers. The cells were shown to secrete exosomes and cytokines and, following engraftment within an immunocompromised mouse model, appeared to modulate the host inflammatory response compared with controls. CONCLUSION This article provides a scalable cell-protein scaffold that with further modifications could provide a replacement for lost or damaged vocal fold mucosa. Further investigations are required to assess the mechanical properties of the scaffold and inhibit the differentiation of the umbilical cord-derived stem-cells following implantation. Laryngoscope, 134:882-893, 2024.
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Affiliation(s)
- Nick J I Hamilton
- Head & Neck Academic Centre, UCL Division of Surgery and Interventional Sciences, University College London, London, UK
- Royal National Ear Nose & Throat Hospital, University College London Hospitals NHS Trust, London, UK
| | - Angela Tait
- Centre for Cell, Gene & Tissue Therapy, Royal Free London NHS Foundation Trust, London, UK
| | - Ben Weil
- Centre for Cell, Gene & Tissue Therapy, Royal Free London NHS Foundation Trust, London, UK
| | - Julie Daniels
- Cells for Sight, Institute of Ophthalmology, University College London, London, UK
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8
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Werner MP, Kučikas V, Voß K, Abel D, Jockenhoevel S, van Zandvoort MAMJ, Schmitz-Rode T. Multiphoton Imaging of Maturation in Tissue Engineering. Tissue Eng Part C Methods 2024; 30:38-48. [PMID: 38115629 DOI: 10.1089/ten.tec.2023.0141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023] Open
Abstract
Donor cell-specific tissue-engineered (TE) implants are a promising therapy for personalized treatment of cardiovascular diseases, but current development protocols lack a stable longitudinal assessment of tissue development at subcellular resolution. As a first step toward such an assessment approach, in this study we establish a generalized labeling and imaging protocol to obtain quantified maturation parameters of TE constructs in three dimensions (3D) without the need of histological slicing, thus leaving the tissue intact. Focusing on intracellular matrix (ICM) and extracellular matrix (ECM) networks, multiphoton laser scanning microscopy (MPLSM) was used to investigate TE patches of different conditioning durations of up to 21 days. We show here that with a straightforward labeling procedure of whole-mount samples (so without slicing into thin histological sections), followed by an easy-to-use multiphoton imaging process, we obtained high-quality images of the tissue in 3D at various time points during development. The stacks of images could then be further analyzed to visualize and quantify the volume of cell coverage as well as the volume fraction and network of structural proteins. We showed that collagen and alpha-smooth muscle actin (α-SMA) volume fractions increased as normalized to full tissue volume and proportional to the cell count, with a converging trend to the final density of (4.0% ± 0.6%) and (7.6% ± 0.7%), respectively. The image analysis of ICM and ECM revealed a developing and widely branched interconnected matrix. We are currently working on the second step, that is, to integrate MPLSM endoscopy into a dynamic bioreactor system to monitor the maturation of intact TE constructs over time, thus without the need to take them out.
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Affiliation(s)
- Maximilian P Werner
- Department of Biohybrid & Medical Textiles (BioTex), Institute of Applied Medical Engineering (AME), Helmholtz Institute, RWTH Aachen University, Aachen, Germany
- Aachen-Maastricht-Institute for Biobased Materials (AMIBM), Maastricht University, Geleen, The Netherlands
| | - Vytautas Kučikas
- Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
| | - Kirsten Voß
- Institute of Automatic Control (IRT), RWTH Aachen University, Aachen, Germany
| | - Dirk Abel
- Institute of Automatic Control (IRT), RWTH Aachen University, Aachen, Germany
| | - Stefan Jockenhoevel
- Department of Biohybrid & Medical Textiles (BioTex), Institute of Applied Medical Engineering (AME), Helmholtz Institute, RWTH Aachen University, Aachen, Germany
- Aachen-Maastricht-Institute for Biobased Materials (AMIBM), Maastricht University, Geleen, The Netherlands
| | - Marc A M J van Zandvoort
- Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Department of Genetics and Cell Biology, Cardiovascular Research Institute Maastricht (CARIM), School for Oncology and Developmental Biology (GROW), Maastricht, The Netherlands
| | - Thomas Schmitz-Rode
- Department of Biohybrid & Medical Textiles (BioTex), Institute of Applied Medical Engineering (AME), Helmholtz Institute, RWTH Aachen University, Aachen, Germany
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9
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Meijer E, Giles R, van Dijk CGM, Maringanti R, Wissing TB, Appels Y, Chrifi I, Crielaard H, Verhaar MC, Smits AI, Cheng C. Effect of Mechanical Stimuli on the Phenotypic Plasticity of Induced Pluripotent Stem-Cell-Derived Vascular Smooth Muscle Cells in a 3D Hydrogel. ACS APPLIED BIO MATERIALS 2023; 6:5716-5729. [PMID: 38032545 PMCID: PMC10731661 DOI: 10.1021/acsabm.3c00840] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 12/01/2023]
Abstract
Introduction: Vascular smooth muscle cells (VSMCs) play a pivotal role in vascular homeostasis, with dysregulation leading to vascular complications. Human-induced pluripotent stem-cell (hiPSC)-derived VSMCs offer prospects for personalized disease modeling and regenerative strategies. Current research lacks comparative studies on the impact of three-dimensional (3D) substrate properties under cyclic strain on phenotypic adaptation in hiPSC-derived VSMCs. Here, we aim to investigate the impact of intrinsic substrate properties, such as the hydrogel's elastic modulus and cross-linking density in a 3D static and dynamic environment, on the phenotypical adaptation of human mural cells derived from hiPSC-derived organoids (ODMCs), compared to aortic VSMCs. Methods and results: ODMCs were cultured in two-dimensional (2D) conditions with synthetic or contractile differentiation medium or in 3D Gelatin Methacryloyl (GelMa) substrates with varying degrees of functionalization and percentages to modulate Young's modulus and cross-linking density. Cells in 3D substrates were exposed to cyclic, unidirectional strain. Phenotype characterization was conducted using specific markers through immunofluorescence and gene expression analysis. Under static 2D culture, ODMCs derived from hiPSCs exhibited a VSMC phenotype, expressing key mural markers, and demonstrated a level of phenotypic plasticity similar to primary human VSMCs. In static 3D culture, a substrate with a higher Young's modulus and cross-linking density promoted a contractile phenotype in ODMCs and VSMCs. Dynamic stimulation in the 3D substrate promoted a switch toward a contractile phenotype in both cell types. Conclusion: Our study demonstrates phenotypic plasticity of human ODMCs in response to 2D biological and 3D mechanical stimuli that equals that of primary human VSMCs. These findings may contribute to the advancement of tailored approaches for vascular disease modeling and regenerative strategies.
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Affiliation(s)
- Elana
M. Meijer
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
| | - Rachel Giles
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
| | - Christian G. M. van Dijk
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
| | - Ranganath Maringanti
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
- Experimental
Cardiology, Department of Cardiology, Thorax
Center Erasmus University Medical Center, Rotterdam 3000 CA, The Netherlands
| | - Tamar B. Wissing
- Department
of Biomedical Engineering, Eindhoven University
of Technology; Eindhoven 5612 AE, The Netherlands
- Institute
for Complex Molecular Systems (ICMS), Eindhoven
University of Technology; Eindhoven 5612 AE, The Netherlands
| | - Ymke Appels
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
| | - Ihsan Chrifi
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
- Experimental
Cardiology, Department of Cardiology, Thorax
Center Erasmus University Medical Center, Rotterdam 3000 CA, The Netherlands
| | - Hanneke Crielaard
- Department
of Biomedical Engineering, Erasmus Medical
Center, Rotterdam 3000 CA, The Netherlands
| | - Marianne C. Verhaar
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
| | - Anthal I.P.M. Smits
- Department
of Biomedical Engineering, Eindhoven University
of Technology; Eindhoven 5612 AE, The Netherlands
- Institute
for Complex Molecular Systems (ICMS), Eindhoven
University of Technology; Eindhoven 5612 AE, The Netherlands
| | - Caroline Cheng
- Department
of Nephrology and Hypertension, Division of Internal Medicine and
Dermatology, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands
- Regenerative
Medicine Center Utrecht, University Medical
Center Utrecht, Utrecht 3508 GA, The Netherlands
- Experimental
Cardiology, Department of Cardiology, Thorax
Center Erasmus University Medical Center, Rotterdam 3000 CA, The Netherlands
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10
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Vervenne T, Maes L, Van Hoof L, Rega F, Famaey N. Drivers of vascular growth and remodeling: A computational framework to promote benign adaptation in the Ross procedure. J Mech Behav Biomed Mater 2023; 148:106170. [PMID: 37852088 DOI: 10.1016/j.jmbbm.2023.106170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/04/2023] [Accepted: 10/09/2023] [Indexed: 10/20/2023]
Abstract
In the sixties, Dr Donald Ross designed a surgical solution for young patients with aortic valve disease by using the patients' own pulmonary valve. The Ross procedure is the only aortic valve replacement technique that can restore long-term survival and preserve quality of life. The main failure mode of the Ross procedure is wall dilatation, potentially leading to valve regurgitation and leakage. Dilatation occurs due to the inability of the pulmonary autograft to adapt to the sudden increase in loading when exposing to aortic pressures. Previous experimental data has shown that a permanent external support wrapped around the artery can prevent the acute dilatation of the arterial wall. However, the textile support leads to stress-shielding phenomena due to the loss of mechanical wall compliance. We present a pragmatic and modular computational framework of arterial growth and remodeling predicting the long-term outcomes of cardiovascular tissue adaptation, with and without textile wrapping. The model integrates mean, systolic and diastolic pressures and assumes the resulting wall stresses to drive the biological remodeling rules. Rather than a single mean pressure or stress deviation from the homeostatic state, we demonstrate that only pulsatile stresses can predict available experimental results. Therefore, we suggest that a biodegradable external support could induce benign remodeling in the Ross procedure. Indeed, a biodegradable textile wrapped around the autograft fulfills the trade-off between prevention of acute dilatation on the one hand and recovery of arterial wall compliance on the other hand. After further validation, the computational framework can set the basis for the development of an actual biodegradable external support for the Ross procedure with optimized polymer mechanical properties and degradation behavior.
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Affiliation(s)
- Thibault Vervenne
- Biomechanics Section, Mechanical Engineering Department, KU Leuven, Celestijnenlaan 300, Leuven, 3001, Belgium.
| | - Lauranne Maes
- Biomechanics Section, Mechanical Engineering Department, KU Leuven, Celestijnenlaan 300, Leuven, 3001, Belgium
| | - Lucas Van Hoof
- Cardiac Surgery, Department of Cardiovascular Sciences, KU Leuven, UZ Herestraat 49, Leuven, 3000, Belgium
| | - Filip Rega
- Cardiac Surgery, Department of Cardiovascular Sciences, KU Leuven, UZ Herestraat 49, Leuven, 3000, Belgium
| | - Nele Famaey
- Biomechanics Section, Mechanical Engineering Department, KU Leuven, Celestijnenlaan 300, Leuven, 3001, Belgium
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11
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Kizub IV. Induced pluripotent stem cells for cardiovascular therapeutics: Progress and perspectives. REGULATORY MECHANISMS IN BIOSYSTEMS 2023; 14:451-468. [DOI: 10.15421/10.15421/022366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
The discovery of methods for reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) opens up prospects of developing personalized cell-based therapy options for a variety of human diseases as well as disease modeling and new drug discovery. Like embryonic stem cells, iPSCs can give rise to various cell types of the human body and are amenable to genetic correction. This allows usage of iPSCs in the development of modern therapies for many virtually incurable human diseases. The review summarizes progress in iPSC research in the context of application in the cardiovascular field including modeling cardiovascular disease, drug study, tissue engineering, and perspectives for personalized cardiovascular medicine.
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12
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Ji J, Xu H, Li C, Luo J. Small-Caliber Tissue-Engineered Vascular Grafts Based on Human-Induced Pluripotent Stem Cells: Progress and Challenges. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:441-455. [PMID: 36884294 DOI: 10.1089/ten.teb.2023.0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Small-caliber tissue-engineered vascular grafts (TEVGs, luminal diameter <6 mm) are promising therapies for coronary or peripheral artery bypassing surgeries or emergency treatments of vascular trauma, and a robust seed cell source is required for scalable manufacturing of small-caliber TEVGs with robust mechanical strength and bioactive endothelium in future. Human-induced pluripotent stem cells (hiPSCs) could serve as a robust cell source to derive functional vascular seed cells and potentially lead to generation of immunocompatible engineered vascular tissues. Up to date, this rising field of small-caliber hiPSC-derived TEVG (hiPSC-TEVG) research has received increasing attention and achieved significant progress. Implantable, small-caliber, hiPSC-TEVGs have been generated. These hiPSC-TEVGs displayed rupture pressure and suture retention strength approaching to those of human native saphenous veins, with vessel wall decellularized and luminal surface endothelialized with monolayer of hiPSC-endothelial cells. Meanwhile, a series of challenges remain in this field, including functional maturity of hiPSC-derived vascular cells, poor elastogenesis, suboptimal efficiency of obtaining hiPSC-derived seed cells, and relative low ready availability of hiPSC-TEVGs, which are waiting to be addressed. This review is conceived to introduce representative achievements and challenges in small-caliber TEVG generation using hiPSCs, and encapsulate the potential solution and future directions.
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Affiliation(s)
- Junyi Ji
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Hongju Xu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chen Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Jiesi Luo
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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13
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Laboyrie SL, de Vries MR, Bijkerk R, Rotmans JI. Building a Scaffold for Arteriovenous Fistula Maturation: Unravelling the Role of the Extracellular Matrix. Int J Mol Sci 2023; 24:10825. [PMID: 37446003 DOI: 10.3390/ijms241310825] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Vascular access is the lifeline for patients receiving haemodialysis as kidney replacement therapy. As a surgically created arteriovenous fistula (AVF) provides a high-flow conduit suitable for cannulation, it remains the vascular access of choice. In order to use an AVF successfully, the luminal diameter and the vessel wall of the venous outflow tract have to increase. This process is referred to as AVF maturation. AVF non-maturation is an important limitation of AVFs that contributes to their poor primary patency rates. To date, there is no clear overview of the overall role of the extracellular matrix (ECM) in AVF maturation. The ECM is essential for vascular functioning, as it provides structural and mechanical strength and communicates with vascular cells to regulate their differentiation and proliferation. Thus, the ECM is involved in multiple processes that regulate AVF maturation, and it is essential to study its anatomy and vascular response to AVF surgery to define therapeutic targets to improve AVF maturation. In this review, we discuss the composition of both the arterial and venous ECM and its incorporation in the three vessel layers: the tunica intima, media, and adventitia. Furthermore, we examine the effect of chronic kidney failure on the vasculature, the timing of ECM remodelling post-AVF surgery, and current ECM interventions to improve AVF maturation. Lastly, the suitability of ECM interventions as a therapeutic target for AVF maturation will be discussed.
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Affiliation(s)
- Suzanne L Laboyrie
- Department of Internal Medicine, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands
| | - Margreet R de Vries
- Department of Surgery and the Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Vascular Surgery, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands
| | - Roel Bijkerk
- Department of Internal Medicine, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands
| | - Joris I Rotmans
- Department of Internal Medicine, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands
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14
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Li C, Wang Z, Yang H, Hong H, Li C, Xu R, Wu Y, Zhang F, Qian J, Chen L, Tu S, Ge J. The Association Between Angiographically Derived Radial Wall Strain and the Risk of Acute Myocardial Infarction. JACC Cardiovasc Interv 2023; 16:1039-1049. [PMID: 37164601 DOI: 10.1016/j.jcin.2023.02.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/26/2023] [Accepted: 02/14/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND The radial wall strain (RWS) is a novel angiography-based method to assess the biomechanical property of the coronary artery and whether it can predict future acute myocardial infarction (AMI) events remains to be elucidated. OBJECTIVES This study aimed to investigate the association between angiography-derived RWS and future AMI events in mild to intermediate lesions. METHODS We performed a matched case-control analysis nested in a retrospective cohort of patients who had received prior angiography (the index procedure) at least 1 month before and were hospitalized again for repeat angiography. Patients with at least 1 de novo mild to intermediate lesion identified at the index procedure and eligible for RWS analysis were enrolled. The study identified cases with target lesion-related AMI diagnosed at the repeat angiography, matching each case to 3 control subjects without AMI. RESULTS Altogether 44 patients with lesion-related AMI and 132 matched controls were enrolled. The median diameter stenosis of the overall interrogated lesions was 34.0%. The baseline maximum RWS (RWSmax), which was defined as the highest RWS in the stenotic segment, was significantly higher in lesions responsible for AMI than those that remained quiescent (median 13% vs 10%; P < 0.001). RWSmax was predictive of lesion-related AMI, with an area under the curve of 0.83 (95% CI: 0.76-0.90; P < 0.001) and an optimal cutoff >12%. RWSmax >12% was found to be independently associated with subsequent AMI events with a risk ratio of 7.25 (95% CI: 3.94-13.37; P < 0.001). CONCLUSIONS Among angiographically mild to intermediate lesions, a high-strain pattern identified by angiography-derived RWS was associated with an increased risk of AMI events.
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Affiliation(s)
- Chenguang Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Zhiqing Wang
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China; Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Yang
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Huihong Hong
- Department of Cardiology, the First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China
| | - Chunming Li
- Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Rende Xu
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Yizhe Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Feng Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Juying Qian
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Lianglong Chen
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shengxian Tu
- Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, National Clinical Research Center for Interventional Medicine, Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China.
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15
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Raskov H, Gaggar S, Tajik A, Orhan A, Gögenur I. The Matrix Reloaded-The Role of the Extracellular Matrix in Cancer. Cancers (Basel) 2023; 15:2057. [PMID: 37046716 PMCID: PMC10093330 DOI: 10.3390/cancers15072057] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in response to environmental cues, and it controls a plethora of cellular functions, including metabolism, cell polarity, migration, and proliferation, to sustain and support oncogenesis. The biophysical and biochemical properties of the ECM, such as its structural arrangement and being a reservoir for bioactive molecules, control several intra- and intercellular signalling pathways and induce cytoskeletal changes that alter cell shapes, behaviour, and viability. Desmoplasia is a major component of solid tumours. The abnormal deposition and composition of the tumour matrix lead to biochemical and biomechanical alterations that determine disease development and resistance to treatment. This review summarises the complex roles of ECM in cancer and highlights the possible therapeutic targets and how to potentially remodel the dysregulated ECM in the future. Furthering our understanding of the ECM in cancer is important as the modification of the ECM will probably become an important tool in the characterisation of individual tumours and personalised treatment options.
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Affiliation(s)
- Hans Raskov
- Center for Surgical Science, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark
| | - Shruti Gaggar
- Center for Surgical Science, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark
| | - Asma Tajik
- Center for Surgical Science, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark
| | - Adile Orhan
- Center for Surgical Science, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Department of Clinical Oncology, Zealand University Hospital, 4000 Roskilde, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Zealand University Hospital, Lykkebækvej 1, 4600 Køge, Denmark
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
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16
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Adipose and Bone Marrow Derived-Mesenchymal Stromal Cells Express Similar Tenogenic Expression Levels when Subjected to Mechanical Uniaxial Stretching In Vitro. Stem Cells Int 2023; 2023:4907230. [PMID: 36756494 PMCID: PMC9902123 DOI: 10.1155/2023/4907230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 05/12/2022] [Accepted: 09/03/2022] [Indexed: 01/31/2023] Open
Abstract
The present study was conducted to determine whether adipose derived mesenchymal stromal cells (AD-MSCs) or bone marrow derived-MSCs (BM-MSCs) would provide superior tenogenic expressions when subjected to cyclical tensile loading. The results for this would indicate the best choice of MSCs source to be used for cell-based tendon repair strategies. Both AD-MSCs and BM-MSCs were obtained from ten adult donors (N = 10) and cultured in vitro. At passaged-2, cells from both groups were subjected to cyclical stretching at 1 Hz and 8% of strain. Cellular morphology, orientation, proliferation rate, protein, and gene expression levels were compared at 0, 24, and 48 hours of stretching. In both groups, mechanical stretching results in similar morphological changes, and the redirection of cell alignment is perpendicular to the direction of stretching. Loading at 8% strain did not significantly increase proliferation rates but caused an increase in total collagen expression and tenogenic gene expression levels. In both groups, these levels demonstrated no significant differences suggesting that in a similar loading environment, both cell types possess similar tenogenic potential. In conclusion, AD-MSCs and BM-MSCs both demonstrate similar tenogenic phenotypic and gene expression levels when subjected to cyclic tensile loading at 1 Hz and 8% strain, thus, suggesting that the use of either cell source may be suitable for tendon repair.
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17
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Sivaraman S, Ravishankar P, Rao RR. Differentiation and Engineering of Human Stem Cells for Smooth Muscle Generation. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:1-9. [PMID: 35491587 DOI: 10.1089/ten.teb.2022.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Cardiovascular diseases are responsible for 31% of global deaths and are considered the main cause of death and disability worldwide. Stem cells from various sources have become attractive options for a range of cell-based therapies for smooth muscle tissue regeneration. However, for efficient myogenic differentiation, the stem cell characteristics, cell culture conditions, and their respective microenvironments need to be carefully assessed. This review covers the various approaches involved in the regeneration of vascular smooth muscles by conditioning human stem cells. This article delves into the different sources of stem cells used in the generation of myogenic tissues, the role of soluble growth factors, use of scaffolding techniques, biomolecular cues, relevance of mechanical stimulation, and key transcription factors involved, aimed at inducing myogenic differentiation. Impact statement The review article's main goal is to discuss the recent advances in the field of smooth muscle tissue regeneration. We look at various cell sources, growth factors, scaffolds, mechanical stimuli, and factors involved in smooth muscle formation. These stem cell-based approaches for vascular muscle formation will provide various options for cell-based therapies with long-term beneficial effects on patients.
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Affiliation(s)
- Srikanth Sivaraman
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, USA
| | - Prashanth Ravishankar
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, USA
| | - Raj R Rao
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas, USA
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18
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Jara ZP, Harford T, Singh KD, Desnoyer R, Kumar A, Srinivasan D, Karnik SS. Distinct Mechanisms of β-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality. Hypertension 2023; 80:385-402. [PMID: 36440576 PMCID: PMC9852074 DOI: 10.1161/hypertensionaha.122.19232] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 11/04/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Aortic aneurysm (AA) is a "silent killer" human disease with no effective treatment. Although the therapeutic potential of various pharmacological agents have been evaluated, there are no reports of β-arrestin-biased AT1R (angiotensin-II type-1 receptor) agonist (TRV027) used to prevent the progression of AA. METHODS We tested the hypothesis that TRV027 infusion in AngII (angiotensin II)-induced mouse model of AA prevents AA. High-fat-diet-fed ApoE (apolipoprotein E gene)-null mice were infused with AngII to induce AA and co-infused with TRV027 and a clinically used AT1R blocker Olmesartan to prevent AA. Aortas explanted from different ligand infusion groups were compared with assess different grades of AA or lack of AA. RESULTS AngII produced AA in ≈67% male mice with significant mortality associated with AA rupture. We observed ≈13% mortality due to aortic arch dissection without aneurysm in male mice. AngII-induced AA and mortality was prevented by co-infusion of TRV027 or Olmesartan, but through different mechanisms. In TRV027 co-infused mice aortic wall thickness, elastin content, new DNA, and protein synthesis were higher than untreated and Olmesartan co-infused mice. Co-infusion with both TRV027 and Olmesartan prevented endoplasmic reticulum stress, fibrosis, and vasomotor hyper responsiveness. CONCLUSIONS TRV027-engaged AT1R prevented AA and associated mortality by distinct molecular mechanisms compared with the AT1R blocker, Olmesartan. Developing novel β-arrestin-biased AT1R ligands may yield promising drugs to combat AA.
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Affiliation(s)
- Zaira Palomino Jara
- Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic
| | - Terri Harford
- Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic
| | | | - Russell Desnoyer
- Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic
| | - Avinash Kumar
- Pathobiology Department, Lerner Research Institute, Cleveland Clinic
| | | | - Sadashiva S. Karnik
- Cardiovascular and Metabolic Sciences Department, Lerner Research Institute, Cleveland Clinic
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19
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Angiography-derived radial wall strain predicts coronary lesion progression in non-culprit intermediate stenosis. J Geriatr Cardiol 2022; 19:937-948. [PMID: 36632201 PMCID: PMC9807399 DOI: 10.11909/j.issn.1671-5411.2022.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Intermediate coronary lesions (ICLs) are highly prevalent but ported mixed prognosis. Radial strain has been associated with plaque vulnerability, yet its role in predicting lesion progression is largely unknown. The purpose of this study was to determine the predictive value of angiography-derived radial wall strain (RWS) for progression of untreated non-culprit ICLs. METHODS Post-hoc analysis was conducted in a study cohort including 603 consecutive patients with 808 ICLs identified at index procedure with angiographic follow-up of up to two years. RWS analysis was performed on selected angiographic frames with minimal foreshortening and vessel overlap. Lesion progression was defined as ≥ 20% increase in percent diameter stenosis. RESULTS Lesion progression occurred in 49 ICLs (6.1%) with a median follow-up period of 16.8 months. Maximal RWS (RWSmax), frequently located at the proximal and throat plaque regions, distinguished progressive ICLs from silent ones. The largest area under the curve value of 0.75 (95% CI: 0.67-0.82, P < 0.001) was reached at the optimal RWSmax cutoff value of > 12.6%. According to this threshold, 178 ICLs were classified as having a high strain pattern. Exposure to a high strain amplitude with RWSmax > 12.6% was independently associated with an increased risk of lesion progression (adjusted HR = 6.82, 95% CI: 3.67-12.66, P < 0.001). CONCLUSIONS Assessment of RWS from coronary angiography is feasible and provides independent prognostic value in patients with untreated ICLs.
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20
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Liu Q, Liu Z, Gu H, Ge Y, Wu X, Zuo F, Du Q, Lei Y, Wang Z, Lin H. Comparative study of differentiating human pluripotent stem cells into vascular smooth muscle cells in hydrogel-based culture methods. Regen Ther 2022; 22:39-49. [PMID: 36618488 PMCID: PMC9798140 DOI: 10.1016/j.reth.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs), which provides structural integrity and regulates the diameter of vasculature, are of great potential for modeling vascular-associated diseases and tissue engineering. Here, we presented a detailed comparison of differentiating human pluripotent stem cells (hPSCs) into VSMCs (hPSCs-VSMCs) in four different culture methods, including 2-dimensional (2D) culture, 3-dimensional (3D) PNIPAAm-PEG hydrogel culture, 3-dimensional (3D) alginate hydrogel culture, and transferring 3-dimensional alginate hydrogel culture to 2-dimensional (2D) culture. Both hydrogel-based culture methods could mimic in vivo microenvironment to protect cells from shear force, and avoid cells agglomeration, resulting in the extremely high culture efficiency (e.g., high viability, high purity and high yield) compared with 2D culture. We demonstrated hPSC-VSMCs produced from hydrogel-based culture methods had better contractile phenotypes and the potential of vasculature formation. The transcriptome analysis showed the hPSC-VSMCs derived from hydrogel-based culture methods displayed more upregulated genes in vasculature development, angiogenesis and blood vessel development, extracellular matrix compared with 2D culture. Taken together, hPSC-VSMCs produced from hydrogel-based culture system could be applied in various biomedical fields, and further indicated the suitable development of alginate hydrogel for industrial production by taking all aspects into consideration.
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Affiliation(s)
- Qing Liu
- Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100006, China
| | - Zhen Liu
- Department of Neurosurgery, Beijing Shunyi District Hospital, Beijing, 101300, China
| | - Hongyu Gu
- Department of Thoracic Surgery Ward 3, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital, Southern Medical University, Qiqihar, 161005, China
| | - Yuxia Ge
- Department of Neurology, The Second Hospital of Harbin, Harbin, 150056, China
| | - Xuesheng Wu
- Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Fuxing Zuo
- Department of Neurosurgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qian Du
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Yuguo Lei
- Department of Biomedical Engineering, Huck Life Science Institute, Pennsylvania State University, University Park, PA, 16802, USA,Corresponding author.
| | - Zhanqi Wang
- Department of Vascular Surgery, Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, 100029, China,Corresponding author.
| | - Haishuang Lin
- Department of Neurology, The Second Hospital of Harbin, Harbin, 150056, China,Corresponding author.
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21
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Ding X, Zhang W, Xu P, Feng W, Tang X, Yang X, Wang L, Li L, Huang Y, Ji J, Chen D, Liu H, Fan Y. The Regulatory Effect of Braided Silk Fiber Skeletons with Differential Porosities on In Vivo Vascular Tissue Regeneration and Long-Term Patency. RESEARCH (WASHINGTON, D.C.) 2022; 2022:9825237. [PMID: 36474603 PMCID: PMC9703915 DOI: 10.34133/2022/9825237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/11/2022] [Indexed: 06/21/2024]
Abstract
The development of small-diameter vascular grafts that can meet the long-term patency required for implementation in clinical practice presents a key challenge to the research field. Although techniques such as the braiding of scaffolds can offer a tunable platform for fabricating vascular grafts, the effects of braided silk fiber skeletons on the porosity, remodeling, and patency in vivo have not been thoroughly investigated. Here, we used finite element analysis of simulated deformation and compliance to design vascular grafts comprised of braided silk fiber skeletons with three different degrees of porosity. Following the synthesis of low-, medium-, and high-porosity silk fiber skeletons, we coated them with hemocompatible sulfated silk fibroin sponges and then evaluated the mechanical and biological functions of the resultant silk tubes with different porosities. Our data showed that high-porosity grafts exhibited higher elastic moduli and compliance but lower suture retention strength, which contrasted with low-porosity grafts. Medium-porosity grafts offered a favorable balance of mechanical properties. Short-term in vivo implantation in rats indicated that porosity served as an effective means to regulate blood leakage, cell infiltration, and neointima formation. High-porosity grafts were susceptible to blood leakage, while low-porosity grafts hindered graft cellularization and tended to induce intimal hyperplasia. Medium-porosity grafts closely mimicked the biomechanical behaviors of native blood vessels and facilitated vascular smooth muscle layer regeneration and polarization of infiltrated macrophages to the M2 phenotype. Due to their superior performance and lack of occlusion, the medium-porosity vascular grafts were evaluated in long-term (24-months) in vivo implantation. The medium-porosity grafts regenerated the vascular smooth muscle cell layers and collagen extracellular matrix, which were circumferentially aligned and resembled the native artery. Furthermore, the formed neoarteries pulsed synchronously with the adjacent native artery and demonstrated contractile function. Overall, our study underscores the importance of braided silk fiber skeleton porosity on long-term vascular graft performance and will help to guide the design of next-generation vascular grafts.
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Affiliation(s)
- Xili Ding
- School of Engineering Medicine, Beihang University, Beijing 100083, China
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Weirong Zhang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Peng Xu
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Wentao Feng
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Xiaokai Tang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Xianda Yang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Lizhen Wang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Linhao Li
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Yan Huang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Jing Ji
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Diansheng Chen
- eRobot Institute, School of Mechanical Engineering and Automation, Beihang University, Beijing 100083, China
| | - Haifeng Liu
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Yubo Fan
- School of Engineering Medicine, Beihang University, Beijing 100083, China
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
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22
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Wen SM, Wen WC, Chao PHG. Zyxin and actin structure confer anisotropic YAP mechanotransduction. Acta Biomater 2022; 152:313-320. [PMID: 36089236 DOI: 10.1016/j.actbio.2022.08.079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 08/24/2022] [Accepted: 08/31/2022] [Indexed: 11/01/2022]
Abstract
Tissues and the embedded cells experience anisotropic deformations due to their functions and anatomical locations. The resident cells, such as tenocytes and muscle cells, are often restricted by their extracellular matrix and organize parallel to their major loading direction, yet most studies on cellular responses to strains use isotropic substrates without predetermined organizations. To understand how confined cells sense and respond to anisotropic loading, we combine cell patterning and uniaxial stretch to have precise geometric control. Dynamic stretch parallel to the long axis of the cell activates YAP nuclear translocation, but not when stretched in the perpendicular direction. Looking at the initial cytoskeleton response, parallel stretch leads to actin breakage and repair within the first minute, mediated by zyxin, the focal adhesion protein. In addition, this zyxin-mediated repair response is controlled by focal adhesion kinase (FAK) and leads to YAP signaling. As these factors are intimately involved in a wide range of mechanical regulation, our findings point to new roles of zyxin and YAP in anisotropic mechanotransduction, and may provide additional perspectives in cellular adaptive responses and tissue homeostasis. STATEMENT OF SIGNIFICANCE: Structure and deformation of tissues control gene expression, migration, and proliferation of the resident cells. In an effort to understand the underlying mechanisms, we find that the transcription cofactor YAP respond to mechanical stretch in a direction-dependent manner. We demonstrate that parallel stretch induces actin cytoskeleton damage, focal adhesion kinase (FAK) activation, and zyxin relocation, which are involved in the anisotropic YAP signaling. Our findings provide additional perspectives in the interactions of tissue structure and cell mechanotransduction.
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Affiliation(s)
- Shin-Min Wen
- Department of Biomedical Engineering, School of Medicine and School of Engineering National Taiwan University
| | - Wen-Cih Wen
- Department of Biomedical Engineering, School of Medicine and School of Engineering National Taiwan University
| | - Pen-Hsiu Grace Chao
- Department of Biomedical Engineering, School of Medicine and School of Engineering National Taiwan University.
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23
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van Asten JGM, Ristori T, Nolan DR, Lally C, Baaijens FPT, Sahlgren CM, Loerakker S. Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension. J Mech Behav Biomed Mater 2022; 133:105325. [PMID: 35839633 PMCID: PMC7613661 DOI: 10.1016/j.jmbbm.2022.105325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/03/2022] [Accepted: 06/18/2022] [Indexed: 11/29/2022]
Abstract
Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.
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Affiliation(s)
- Jordy G M van Asten
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Tommaso Ristori
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - David R Nolan
- School of Engineering and Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
| | - Caitríona Lally
- School of Engineering and Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
| | - Frank P T Baaijens
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Cecilia M Sahlgren
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands; Faculty of Science and Engineering, Biosciences, Åbo Akademi, Turku, Finland
| | - Sandra Loerakker
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
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24
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Fang L, Mei J, Yao B, Liu J, Liu P, Wang X, Zhou J, Lin Z. Hypoxia facilitates proliferation of smooth muscle cells derived from pluripotent stem cells for vascular tissue engineering. J Tissue Eng Regen Med 2022; 16:744-756. [PMID: 35633489 DOI: 10.1002/term.3324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 11/07/2022]
Abstract
Tissue-engineered blood vessels (TEBVs) show significant therapeutic potential for replacing diseased blood vessels. Vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (hiPSCs) via embryoid body (EB)-based differentiation, are promising seed cells to construct TEBVs. However, obtaining sufficient high-quality hiPSC-VSMCs remains challenging. Stem cells are located in a niche characterized by hypoxia. Hence, we explored molecular and cellular functions at different induction stages from the EB formation commencement to the end of directed differentiation under normoxic and hypoxic conditions, respectively. Hypoxia enhanced the formation, adhesion and amplification rates of EBs. During directed differentiation, hiPSC-VSMCs exhibited increased cell viability under hypoxic conditions. Moreover, seeding hypoxia-pretreated cells on biodegradable scaffolds, facilitated collagen I and elastin secretion, which has significant application value for TEBV development. Hence, we proposed that hypoxic treatment during differentiation effectively induces proliferative hiPSC-VSMCs, expanding high-quality seed cell sources for TEBV construction.
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Affiliation(s)
- Lijun Fang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Jingyi Mei
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, China
| | - Boqian Yao
- Songshan Lake Central Hospital of Dongguan City, Dongguan, Guangdong, China
| | - Jiang Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.,Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guanzhou, China
| | - Peng Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, China
| | - Xichun Wang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Jiahui Zhou
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China
| | - Zhanyi Lin
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.,Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, Guangdong, China.,School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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25
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Abstract
Elastin is a long-lived extracellular matrix protein that is organized into elastic fibers that provide elasticity to the arterial wall, allowing stretch and recoil with each cardiac cycle. By forming lamellar units with smooth muscle cells, elastic fibers transduce tissue-level mechanics to cell-level changes through mechanobiological signaling. Altered amounts or assembly of elastic fibers leads to changes in arterial structure and mechanical behavior that compromise cardiovascular function. In particular, genetic mutations in the elastin gene (ELN) that reduce elastin protein levels are associated with focal arterial stenosis, or narrowing of the arterial lumen, such as that seen in supravalvular aortic stenosis and Williams-Beuren syndrome. Global reduction of Eln levels in mice allows investigation of the tissue- and cell-level arterial mechanical changes and associated alterations in smooth muscle cell phenotype that may contribute to stenosis formation. A loxP-floxed Eln allele in mice highlights cell type- and developmental origin-specific mechanobiological effects of reduced elastin amounts. Eln production is required in distinct cell types for elastic layer formation in different parts of the mouse vasculature. Eln deletion in smooth muscle cells from different developmental origins in the ascending aorta leads to characteristic patterns of vascular stenosis and neointima. Dissecting the mechanobiological signaling associated with local Eln depletion and subsequent smooth muscle cell response may help develop new therapeutic interventions for elastin-related diseases.
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Affiliation(s)
- Chien-Jung Lin
- 1Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri,2Cardiovascular Division, Department of Medicine, Washington University, St. Louis, Missouri
| | - Austin J. Cocciolone
- 3Department of Biomedical Engineering, Washington University, St. Louis, Missouri
| | - Jessica E. Wagenseil
- 4Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, Missouri
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26
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Fell CA, Brooks-Richards TL, Woodruff M, Allenby MC. Soft pneumatic actuators for mimicking multi-axial femoropopliteal artery mechanobiology. Biofabrication 2022; 14. [PMID: 35378520 DOI: 10.1088/1758-5090/ac63ef] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/04/2022] [Indexed: 11/12/2022]
Abstract
Tissue biomanufacturing aims to produce lab-grown stem cell grafts and biomimetic drug testing platforms but remains limited in its ability to recapitulate native tissue mechanics. The emerging field of soft robotics aims to emulate dynamic physiological locomotion, representing an ideal approach to recapitulate physiologically complex mechanical stimuli and enhance patient-specific tissue maturation. The kneecap's femoropopliteal artery (FPA) represents a highly flexible tissue across multiple axes during blood flow, walking, standing, and crouching positions, and these complex biomechanics are implicated in the FPA's frequent presentation of peripheral artery disease. We developed a soft pneumatically actuated (SPA) cell culture platform to investigate how patient-specific FPA mechanics affect lab-grown arterial tissues. Silicone hyperelastomers were screened for flexibility and biocompatibility, then additively manufactured into SPAs using a simulation-based design workflow to mimic normal and diseased FPA extensions in radial, angular, and longitudinal dimensions. SPA culture platforms were seeded with mesenchymal stem cells, connected to a pneumatic controller, and provided with 24-hour multi-axial exercise schedules to demonstrate the effect of dynamic conditioning on cell alignment, collagen production, and muscle differentiation without additional growth factors. Soft robotic bioreactors are promising platforms for recapitulating patient-, disease-, and lifestyle-specific mechanobiology for understanding disease, treatment simulations, and lab-grown tissue grafts.
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Affiliation(s)
- Cody A Fell
- School of Mechanical, Medical and Process Engineering; Centre for Biomedical Technologies, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Queensland, 4001, AUSTRALIA
| | - Trent L Brooks-Richards
- School of Mechanical, Medical and Process Engineering; Centre for Biomedical Technologies, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Queensland, 4001, AUSTRALIA
| | - Mia Woodruff
- School of Mechanical, Medical and Process Engineering; Centre for Biomedical Technologies, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland, 4001, AUSTRALIA
| | - Mark Colin Allenby
- School of Chemical Engineering, The University of Queensland, Andrew N. Liveris Building, St Lucia, Queensland, 4072, AUSTRALIA
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27
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Liu S, Lin Z. Vascular Smooth Muscle Cells Mechanosensitive Regulators and Vascular Remodeling. J Vasc Res 2021; 59:90-113. [PMID: 34937033 DOI: 10.1159/000519845] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 09/23/2021] [Indexed: 11/19/2022] Open
Abstract
Blood vessels are subjected to mechanical loads of pressure and flow, inducing smooth muscle circumferential and endothelial shear stresses. The perception and response of vascular tissue and living cells to these stresses and the microenvironment they are exposed to are critical to their function and survival. These mechanical stimuli not only cause morphological changes in cells and vessel walls but also can interfere with biochemical homeostasis, leading to vascular remodeling and dysfunction. However, the mechanisms underlying how these stimuli affect tissue and cellular function, including mechanical stimulation-induced biochemical signaling and mechanical transduction that relies on cytoskeletal integrity, are unclear. This review focuses on signaling pathways that regulate multiple biochemical processes in vascular mesangial smooth muscle cells in response to circumferential stress and are involved in mechanosensitive regulatory molecules in response to mechanotransduction, including ion channels, membrane receptors, integrins, cytoskeletal proteins, nuclear structures, and cascades. Mechanoactivation of these signaling pathways is closely associated with vascular remodeling in physiological or pathophysiological states.
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Affiliation(s)
- Shangmin Liu
- Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, China, .,Medical Research Center, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, China,
| | - Zhanyi Lin
- Ji Hua Institute of Biomedical Engineering Technology, Ji Hua Laboratory, Foshan, China.,Institute of Geriatric Medicine, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, China
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28
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Yang D, Wei GY, Li M, Peng MS, Sun Y, Zhang YL, Lu C, Qing KX, Cai HB. Cyclic tensile strain facilitates proliferation and migration of human aortic smooth muscle cells and reduces their apoptosis via miRNA-187-3p. Bioengineered 2021; 12:11439-11450. [PMID: 34895047 PMCID: PMC8810176 DOI: 10.1080/21655979.2021.2009321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The cardiovascular is a system that contains extremely complex mechanical factors, in which the circulatory flow of blood has rich mechanical laws. Many studies have revealed that mechanical factors play a very important role in the process of revascularization. Hence, it is essential to investigate the mechanical factors in the process of revascularization in depth. A cyclic tensile strain (CTS) was applied to human aortic smooth muscle cells (HASMCs) at a frequency of 1 Hz and amplitudes of 5%, 10% and 15%, respectively. SmallRNA-seq was used to identify differentially expressed miRNAs (DE-miRNAs) responding to CTS in HASMCs. Starbase database predicted the target genes of DE-miRNAs. Metascape was applied for GO and KEGG pathway enrichment analysis and protein–protein interaction network construction. The proliferation and migration of CTS-treated HASMCs were significantly enhanced, and apoptosis were significantly reduced compared to the control group. SmallRNA-seq results demonstrated that 55, 16 and 16 DE-miRNAs were present in 5%, 10% and 15% CTS-treated HASMCs, respectively. Compared to controls, with miR-26a-2-3p and miR-187-3p being the intersection of these DE-miRNAs. Starbase database identified 189 common target genes for miR-26a-2-3p and miR-187-3p. Common target genes are mainly enriched in the basolateral plasma membrane and endocytosis. Further, in vitro experiments exhibited that CTS upregulated miR-187-3p expression, and miR-187-3p enhanced the proliferation and migration of HASMCs and reduced their apoptosis. It is suggested that miR-187-3p may be an important target for CTS participate in the process of cardiovascular disease. ![]() ![]()
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Affiliation(s)
- Di Yang
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Guang-Yuan Wei
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Min Li
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ming-Sheng Peng
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuan Sun
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yan-Liang Zhang
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chuang Lu
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Kai-Xiong Qing
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hong-Bo Cai
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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29
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Kazemi T, Mohammadpour AA, Matin MM, Mahdavi-Shahri N, Dehghani H, Kazemi Riabi SH. Decellularized bovine aorta as a promising 3D elastin scaffold for vascular tissue engineering applications. Regen Med 2021; 16:1037-1050. [PMID: 34852636 DOI: 10.2217/rme-2021-0062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To evaluate the suitability of using aorta elastin scaffold, in combination with human adipose-derived mesenchymal stem cells (hAd-MSCs), as an approach for cardiovascular tissue engineering. Materials & Methods: Human adipose-derived MSCs were seeded on elastin samples of decellularized bovine aorta. The samples were cultured in vitro to investigate the inductive effects of this scaffold on the cells. The results were evaluated using histological, and immunohistochemical methods, as well as MTT assay, DNA content, reverse transcription-PCR and scanning electron microscopy. Results: Histological staining and DNA content confirmed the efficacy of decellularization procedure (82% DNA removal). MTT assay showed the construct's ability to support cell viability and proliferation. Cell differentiation was confirmed by reverse transcription-PCR and positive immunohistochemistry for alfa smooth muscle actin and von Willebrand. Conclusion: The prepared aortic elastin samples act as a potential scaffold, in combination with MSCs, for applications in cardiovascular tissue engineering. Further experiments in animal models are required to confirm this.
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Affiliation(s)
- Tahmineh Kazemi
- Department of Basic Sciences, Faculty of Veterinary Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad A Mohammadpour
- Department of Basic Sciences, Faculty of Veterinary Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics & Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran; Stem Cell & Regenerative Medicine Research Group; Iranian Academic Center for Education, Culture & Research (ACECR) Khorasan Razavi Branch, Mashhad, Iran
| | - Nasser Mahdavi-Shahri
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Novel Diagnostics & Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hesam Dehghani
- Department of Basic Sciences, Faculty of Veterinary Science, Ferdowsi University of Mashhad, Mashhad, Iran; Embryonic & Stem Cell Biology & Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Seyed H Kazemi Riabi
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
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30
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Fukuie M, Yamabe T, Hoshi D, Hashitomi T, Nomura Y, Sugawara J. Effect of Aquatic Exercise Training on Aortic Hemodynamics in Middle-Aged and Elderly Adults. Front Cardiovasc Med 2021; 8:770519. [PMID: 34796221 PMCID: PMC8592941 DOI: 10.3389/fcvm.2021.770519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Aquatic exercise is an attractive form of exercise that utilizes the various properties of water to improve physical health, including arterial stiffness. However, it is unclear whether regular head-out aquatic exercise affects aortic hemodynamics, the emerging risk factors for future cardiovascular disease. The purpose of this study was to investigate whether head-out aquatic exercise training improves aortic hemodynamics in middle-aged and elderly people. In addition, to shed light on the underlying mechanisms, we determined the contribution of change in arterial stiffness to the hypothesized changes in aortic hemodynamics. Twenty-three middle-aged and elderly subjects (62 ± 9 years) underwent a weekly aquatic exercise course for 15 weeks. Aortic hemodynamics were evaluated by pulse wave analysis via the general transfer function method. Using a polar coordinate description, companion metrics of aortic pulse pressure (PPC = √{(systolic blood pressure)2 + (diastolic blood pressure)2}) and augmentation index (AIxC = √{(augmentation pressure)2 + (pulse pressure)2}) were calculated as measures of arterial load. Brachial-ankle (baPWV, reflecting stiffness of the abdominal aorta and leg artery) and heart-ankle (haPWV, reflecting stiffness of the whole aortic and leg artery) pulse wave velocities were also measured. The rate of participation in the aquatic training program was 83.5 ± 13.0%. Aortic systolic blood pressure, pulse pressure, PPC, AIxC, baPWV, and haPWV decreased after the training (P < 0.05 for all), whereas augmentation index remained unchanged. Changes in aortic SBP were correlated with changes in haPWV (r = 0.613, P = 0.002) but not baPWV (r = 0.296, P = 0.170). These findings suggest that head-out aquatic exercise training may improve aortic hemodynamics in middle-aged and elderly people, with the particular benefits for reducing aortic SBP which is associated with proximal aortic stiffness.
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Affiliation(s)
- Marina Fukuie
- Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.,Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Takayuki Yamabe
- Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.,Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Daisuke Hoshi
- Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.,Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Tatsuya Hashitomi
- Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.,Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | | | - Jun Sugawara
- Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.,Faculty of Health and Sports Sciences, University of Tsukuba, Tsukuba, Japan
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Walters B, Turner PA, Rolauffs B, Hart ML, Stegemann JP. Controlled Growth Factor Delivery and Cyclic Stretch Induces a Smooth Muscle Cell-like Phenotype in Adipose-Derived Stem Cells. Cells 2021; 10:cells10113123. [PMID: 34831345 PMCID: PMC8624888 DOI: 10.3390/cells10113123] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/29/2021] [Accepted: 11/09/2021] [Indexed: 01/02/2023] Open
Abstract
Adipose-derived stem cells (ASCs) are an abundant and easily accessible multipotent stem cell source with potential application in smooth muscle regeneration strategies. In 3D collagen hydrogels, we investigated whether sustained release of growth factors (GF) PDGF-AB and TGF-β1 from GF-loaded microspheres could induce a smooth muscle cell (SMC) phenotype in ASCs, and if the addition of uniaxial cyclic stretch could enhance the differentiation level. This study demonstrated that the combination of cyclic stretch and GF release over time from loaded microspheres potentiated the differentiation of ASCs, as quantified by protein expression of early to late SMC differentiation markers (SMA, TGLN and smooth muscle MHC). The delivery of GFs via microspheres produced large ASCs with a spindle-shaped, elongated SMC-like morphology. Cyclic strain produced the largest, longest, and most spindle-shaped cells regardless of the presence or absence of growth factors or the growth factor delivery method. Protein expression and cell morphology data confirmed that the sustained release of GFs from GF-loaded microspheres can be used to promote the differentiation of ASCs into SMCs and that the addition of uniaxial cyclic stretch significantly enhances the differentiation level, as quantified by intermediate and late SMC markers and a SMC-like elongated cell morphology.
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Affiliation(s)
- Brandan Walters
- Department of Biomedical Engineering, University of Michigan, 1107 Carl A. Gerstacker Building, 2200 Bonisteel Blvd, Ann Arbor, MI 48109, USA; (B.W.); (P.A.T.)
| | - Paul A. Turner
- Department of Biomedical Engineering, University of Michigan, 1107 Carl A. Gerstacker Building, 2200 Bonisteel Blvd, Ann Arbor, MI 48109, USA; (B.W.); (P.A.T.)
| | - Bernd Rolauffs
- G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Engesserstraße 4, 79108 Freiburg, Germany;
| | - Melanie L. Hart
- G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Engesserstraße 4, 79108 Freiburg, Germany;
- Correspondence: (M.L.H.); (J.P.S.); Tel.: +49-(761)-270-26102 (M.L.H.); +001-(734)-764-8313 (J.P.S.)
| | - Jan P. Stegemann
- Department of Biomedical Engineering, University of Michigan, 1107 Carl A. Gerstacker Building, 2200 Bonisteel Blvd, Ann Arbor, MI 48109, USA; (B.W.); (P.A.T.)
- Correspondence: (M.L.H.); (J.P.S.); Tel.: +49-(761)-270-26102 (M.L.H.); +001-(734)-764-8313 (J.P.S.)
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González-Pérez M, Camasão DB, Mantovani D, Alonso M, Rodríguez-Cabello JC. Biocasting of an elastin-like recombinamer and collagen bi-layered model of the tunica adventitia and external elastic lamina of the vascular wall. Biomater Sci 2021; 9:3860-3874. [PMID: 33890956 DOI: 10.1039/d0bm02197k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The development of techniques for fabricating vascular wall models will foster the development of preventive and therapeutic therapies for treating cardiovascular diseases. However, the physical and biological complexity of vascular tissue represents a major challenge, especially for the design and the production of off-the-shelf biomimetic vascular replicas. Herein, we report the development of a biocasting technique that can be used to replicate the tunica adventitia and the external elastic lamina of the vascular wall. Type I collagen embedded with neonatal human dermal fibroblast (HDFn) and an elastic click cross-linkable, cell-adhesive and protease-sensitive elastin-like recombinamer (ELR) hydrogel were investigated as readily accessible and tunable layers to the envisaged model. Mechanical characterization confirmed that the viscous and elastic attributes predominated in the collagen and ELR layers, respectively. In vitro maturation confirmed that the collagen and ELR provided a favorable environment for the HDFn viability, while histology revealed the wavy and homogenous morphology of the ELR and collagen layer respectively, the cell polarization towards the cell-attachment sites encoded on the ELR, and the enhanced expression of glycosaminoglycan-rich extracellular matrix and differentiation of the embedded HDFn into myofibroblasts. As a complementary assay, 30% by weight of the collagen layer was substituted with the ELR. This model proved the possibility to tune the composition and confirm the versatile character of the technology developed, while revealing no significant differences with respect to the original construct. On-demand modification of the model dimensions, number and composition of the layers, as well as the type and density of the seeded cells, can be further envisioned, thus suggesting that this bi-layered model may be a promising platform for the fabrication of biomimetic vascular wall models.
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Affiliation(s)
- Miguel González-Pérez
- BIOFORGE (Group for Advanced Materials and Nanobiotechnology), University of Valladolid, CIBER-BBN, 47011 Valladolid, Spain.
| | - Dimitria Bonizol Camasão
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met-Materials Engineering, Research Center of CHU de Québec, Division of Regenerative Medicine, Laval University, Québec, QC, Canada G1V 0A6
| | - Diego Mantovani
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met-Materials Engineering, Research Center of CHU de Québec, Division of Regenerative Medicine, Laval University, Québec, QC, Canada G1V 0A6
| | - Matilde Alonso
- BIOFORGE (Group for Advanced Materials and Nanobiotechnology), University of Valladolid, CIBER-BBN, 47011 Valladolid, Spain.
| | - José Carlos Rodríguez-Cabello
- BIOFORGE (Group for Advanced Materials and Nanobiotechnology), University of Valladolid, CIBER-BBN, 47011 Valladolid, Spain.
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Disease-Relevant Single Cell Photonic Signatures Identify S100β Stem Cells and their Myogenic Progeny in Vascular Lesions. Stem Cell Rev Rep 2021; 17:1713-1740. [PMID: 33730327 PMCID: PMC8446106 DOI: 10.1007/s12015-021-10125-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2021] [Indexed: 10/31/2022]
Abstract
A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening and lesion formation. While medial SMCs contribute to vascular lesions, the involvement of resident vascular stem cells (vSCs) remains unclear. We evaluated single cell photonics as a discriminator of cell phenotype in vitro before the presence of vSC within vascular lesions was assessed ex vivo using supervised machine learning and further validated using lineage tracing analysis. Using a novel lab-on-a-Disk(Load) platform, label-free single cell photonic emissions from normal and injured vessels ex vivo were interrogated and compared to freshly isolated aortic SMCs, cultured Movas SMCs, macrophages, B-cells, S100β+ mVSc, bone marrow derived mesenchymal stem cells (MSC) and their respective myogenic progeny across five broadband light wavelengths (λ465 - λ670 ± 20 nm). We found that profiles were of sufficient coverage, specificity, and quality to clearly distinguish medial SMCs from different vascular beds (carotid vs aorta), discriminate normal carotid medial SMCs from lesional SMC-like cells ex vivo following flow restriction, and identify SMC differentiation of a series of multipotent stem cells following treatment with transforming growth factor beta 1 (TGF- β1), the Notch ligand Jagged1, and Sonic Hedgehog using multivariate analysis, in part, due to photonic emissions from enhanced collagen III and elastin expression. Supervised machine learning supported genetic lineage tracing analysis of S100β+ vSCs and identified the presence of S100β+vSC-derived myogenic progeny within vascular lesions. We conclude disease-relevant photonic signatures may have predictive value for vascular disease.
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Zbinden JC, Blum KM, Berman AG, Ramachandra AB, Szafron JM, Kerr KE, Anderson JL, Sangha GS, Earl CC, Nigh NR, Mirhaidari GJM, Reinhardt JW, Chang Y, Yi T, Smalley R, Gabriele PD, Harris JJ, Humphrey JD, Goergen CJ, Breuer CK. Effects of Braiding Parameters on Tissue Engineered Vascular Graft Development. Adv Healthc Mater 2020; 9:e2001093. [PMID: 33063452 DOI: 10.1002/adhm.202001093] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/17/2020] [Indexed: 01/06/2023]
Abstract
Tissue engineered vascular grafts (TEVGs) using scaffolds fabricated from braided poly(glycolic acid) (PGA) fibers coated with poly(glycerol sebacate) (PGS) are developed. The approach relies on in vivo tissue engineering by which neotissue forms solely within the body after a scaffold has been implanted. Herein, the impact of altering scaffold braid design and scaffold coating on neotissue formation is investigated. Several combinations of braiding parameters are manufactured and evaluated in a Beige mouse model in the infrarenal abdominal aorta. Animals are followed with 4D ultrasound analysis, and 12 week explanted vessels are evaluated for biaxial mechanical properties as well as histological composition. Results show that scaffold parameters (i.e., braiding angle, braiding density, and presence of a PGS coating) have interdependent effects on the resulting graft performance, namely, alteration of these parameters influences levels of inflammation, extracellular matrix production, graft dilation, neovessel distensibility, and overall survival. Coupling carefully designed in vivo experimentation with regression analysis, critical relationships between the scaffold design and the resulting neotissue that enable induction of favorable cellular and extracellular composition in a controlled manner are uncovered. Such an approach provides a potential for fabricating scaffolds with a broad range of features and the potential to manufacture optimized TEVGs.
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Affiliation(s)
- Jacob C. Zbinden
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - Kevin M. Blum
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - Alycia G. Berman
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Abhay B. Ramachandra
- Department of Biomedical Engineering, Yale University 55 Prospect Street New Haven CT 06520 USA
| | - Jason M. Szafron
- Department of Biomedical Engineering, Yale University 55 Prospect Street New Haven CT 06520 USA
| | - Katherine E. Kerr
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Jennifer L. Anderson
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Gurneet S. Sangha
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Conner C. Earl
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Noah R. Nigh
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Gabriel J. M. Mirhaidari
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - James W. Reinhardt
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - Yu‐Chun Chang
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - Tai Yi
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
| | - Ryan Smalley
- Secant Group, LLC 551 East Church Ave Telford PA 18969 USA
| | | | | | - Jay D. Humphrey
- Department of Biomedical Engineering, Yale University 55 Prospect Street New Haven CT 06520 USA
| | - Craig J. Goergen
- Weldon School of Biomedical Engineering, Purdue University 206 S Martin Jischke Drive West Lafayette IN 47907 USA
| | - Christopher K. Breuer
- Nationwide Children's Hospital, Abagail Wexner Research Institute 575 Children's Crossroad Columbus OH 43215 USA
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Shi X, He L, Zhang SM, Luo J. Human iPS Cell-derived Tissue Engineered Vascular Graft: Recent Advances and Future Directions. Stem Cell Rev Rep 2020; 17:862-877. [PMID: 33230612 DOI: 10.1007/s12015-020-10091-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2020] [Indexed: 12/19/2022]
Abstract
Tissue engineered vascular grafts (TEVGs) generated from human primary cells represent a promising vascular interventional therapy. However, generation and application of these TEVGs may be significantly hindered by the limited accessibility, finite expandability, donor-donor functional variation and immune-incompatibility of primary seed cells from donors. Alternatively, human induced pluripotent stem cells (hiPSCs) offer an infinite source to obtain functional vascular cells in large quantity and comparable quality for TEVG construction. To date, TEVGs (hiPSC-TEVGs) with significant mechanical strength and implantability have been generated using hiPSC-derived seed cells. Despite being in its incipient stage, this emerging field of hiPSC-TEVG research has achieved significant progress and presented promising future potential. Meanwhile, a series of challenges pertaining hiPSC differentiation, vascular tissue engineering technologies and future production and application await to be addressed. Herein, we have composed this review to introduce progress in TEVG generation using hiPSCs, summarize the current major challenges, and encapsulate the future directions of research on hiPSC-based TEVGs. Graphical abstract.
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Affiliation(s)
- Xiangyu Shi
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.,Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine , Yale School of Medicine, 300 George Street, Room 752, New Haven, CT, 06511, USA
| | - Lile He
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Shang-Min Zhang
- Department of Pathology, Yale School of Medicine, 06520, New Haven, CT, USA
| | - Jiesi Luo
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine , Yale School of Medicine, 300 George Street, Room 752, New Haven, CT, 06511, USA. .,Yale Stem Cell Center, 06520, New Haven, CT, USA.
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36
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Van de Walle AB, McFetridge PS. Flow with variable pulse frequencies accelerates vascular recellularization and remodeling of a human bioscaffold. J Biomed Mater Res A 2020; 109:92-103. [PMID: 32441862 DOI: 10.1002/jbm.a.37009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 03/30/2020] [Accepted: 04/04/2020] [Indexed: 11/07/2022]
Abstract
Despite significant advances in vascular tissue engineering, the ideal graft has not yet been developed and autologous vessels remain the gold standard substitutes for small diameter bypass procedures. Here, we explore the use of a flow field with variable pulse frequencies over the regeneration of an ex vivo-derived human scaffold as vascular graft. Briefly, human umbilical veins were decellularized and used as scaffold for cellular repopulation with human smooth muscle cells (SMC) and endothelial cells (EC). Over graft development, the variable flow, which mimics the real-time cardiac output of an individual performing daily activities (e.g., resting vs. exercising), was implemented and compared to the commonly used constant pulse frequency. Results show marked differences on SMC and EC function, with changes at the molecular level reflecting on tissue scales. First, variable frequencies significantly increased SMC proliferation rate and glycosaminoglycan production. These results can be tied with the SMC gene expression that indicates a synthetic phenotype, with a significant downregulation of myosin heavy chain. Additionally and quite remarkably, the variable flow frequencies motivated the re-endothelialization of the grafts, with a quiescent-like structure observed after 10 days of conditioning, contrasting with the low surface coverage and unaligned EC observed under constant frequency (CF). Besides, the overall biomechanics of the generated grafts (conditioned with both pulsed and CFs) evidence a significant remodeling after 55 days of culture, depicted by high burst pressure and Young's modulus. These last results demonstrate the positive recellularization and remodeling of a human-derived scaffold toward an arterial vessel.
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Affiliation(s)
- Aurore B Van de Walle
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA.,Laboratoire Matière et Systèmes, Complexes MSC, UMR 7057, CNRS, University Paris Diderot, Paris Cedex 13, France
| | - Peter S McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
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Mallis P, Papapanagiotou A, Katsimpoulas M, Kostakis A, Siasos G, Kassi E, Stavropoulos-Giokas C, Michalopoulos E. Efficient differentiation of vascular smooth muscle cells from Wharton's Jelly mesenchymal stromal cells using human platelet lysate: A potential cell source for small blood vessel engineering. World J Stem Cells 2020; 12:203-221. [PMID: 32266052 PMCID: PMC7118289 DOI: 10.4252/wjsc.v12.i3.203] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/17/2020] [Accepted: 01/31/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The development of fully functional small diameter vascular grafts requires both a properly defined vessel conduit and tissue-specific cellular populations. Mesenchymal stromal cells (MSCs) derived from the Wharton's Jelly (WJ) tissue can be used as a source for obtaining vascular smooth muscle cells (VSMCs), while the human umbilical arteries (hUAs) can serve as a scaffold for blood vessel engineering. AIM To develop VSMCs from WJ-MSCs utilizing umbilical cord blood platelet lysate. METHODS WJ-MSCs were isolated and expanded until passage (P) 4. WJ-MSCs were properly defined according to the criteria of the International Society for Cell and Gene Therapy. Then, these cells were differentiated into VSMCs with the use of platelet lysate from umbilical cord blood in combination with ascorbic acid, followed by evaluation at the gene and protein levels. Specifically, gene expression profile analysis of VSMCs for ACTA2, MYH11, TGLN, MYOCD, SOX9, NANOG homeobox, OCT4 and GAPDH, was performed. In addition, immunofluorescence against ACTA2 and MYH11 in combination with DAPI staining was also performed in VSMCs. HUAs were decellularized and served as scaffolds for possible repopulation by VSMCs. Histological and biochemical analyses were performed in repopulated hUAs. RESULTS WJ-MSCs exhibited fibroblastic morphology, successfully differentiating into "osteocytes", "adipocytes" and "chondrocytes", and were characterized by positive expression (> 90%) of CD90, CD73 and CD105. In addition, WJ-MSCs were successfully differentiated into VSMCs with the proposed differentiation protocol. VSMCs successfully expressed ACTA2, MYH11, MYOCD, TGLN and SOX9. Immunofluorescence results indicated the expression of ACTA2 and MYH11 in VSMCs. In order to determine the functionality of VSMCs, hUAs were isolated and decellularized. Based on histological analysis, decellularized hUAs were free of any cellular or nuclear materials, while their extracellular matrix retained intact. Then, repopulation of decellularized hUAs with VSMCs was performed for 3 wk. Decellularized hUAs were repopulated efficiently by the VSMCs. Biochemical analysis revealed the increase of total hydroyproline and sGAG contents in repopulated hUAs with VSMCs. Specifically, total hydroxyproline and sGAG content after the 1st, 2nd and 3rd wk was 71 ± 10, 74 ± 9 and 86 ± 8 μg hydroxyproline/mg of dry tissue weight and 2 ± 1, 3 ± 1 and 3 ± 1 μg sGAG/mg of dry tissue weight, respectively. Statistically significant differences were observed between all study groups (P < 0.05). CONCLUSION VSMCs were successfully obtained from WJ-MSCs with the proposed differentiation protocol. Furthermore, hUAs were efficiently repopulated by VSMCs. Differentiated VSMCs from WJ-MSCs could provide an alternative source of cells for vascular tissue engineering.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece.
| | - Aggeliki Papapanagiotou
- Department of Biological Chemistry, Medical School, National and Kapodistrian Univesity of Athens, Athens 15772, Greece
| | - Michalis Katsimpoulas
- Center of Experimental Surgery, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Alkiviadis Kostakis
- Center of Experimental Surgery, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Gerasimos Siasos
- Department of Biological Chemistry, Medical School, National and Kapodistrian Univesity of Athens, Athens 15772, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian Univesity of Athens, Athens 15772, Greece
| | | | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
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Jiang Y, Lian XL. Heart regeneration with human pluripotent stem cells: Prospects and challenges. Bioact Mater 2020; 5:74-81. [PMID: 31989061 PMCID: PMC6965207 DOI: 10.1016/j.bioactmat.2020.01.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 12/16/2019] [Accepted: 01/02/2020] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular disease, ranging from congenital heart disease to adult myocardial infarction, is the leading cause of death worldwide. In pursuit of reliable cardiovascular regenerative medicine, human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer plenty of potential cell-based applications. HPSCs are capable of proliferating indefinitely in an undifferentiated state, and are also pluripotent, being able to differentiate into virtually any somatic cell types given specific stepwise cues, thus representing an unlimited source to generate functional cardiovascular cells for heart regeneration. Here we recapitulated current advances in developing efficient protocols to generate hPSC-derived cardiovascular cell lineages, including cardiomyocytes, endothelial cells, and epicardial cells. We also discussed applications of hPSC-derived cells in combination with compatible bioactive materials, promising trials of cell transplantation in animal models of myocardial infarction, and potential hurdles to bring us closer to the ultimate goal of cell-based heart repair.
HPSCs hold tremendous therapeutic potential for treating CVDs. HPSCs could differentiate into multiple cardiovascular cell lineages. Transplantation of hPSC-derived cardiovascular cells and biomaterials shows promising results, but challenges still remain.
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Affiliation(s)
- Yuqian Jiang
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.,Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Xiaojun Lance Lian
- Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.,Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA.,Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA
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Cong X, Zhang SM, Batty L, Luo J. Application of Human Induced Pluripotent Stem Cells in Generating Tissue-Engineered Blood Vessels as Vascular Grafts. Stem Cells Dev 2019; 28:1581-1594. [PMID: 31663439 DOI: 10.1089/scd.2019.0234] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In pace with the advancement of tissue engineering during recent decades, tissue-engineered blood vessels (TEBVs) have been generated using primary seed cells, and their impressive success in clinical trials have demonstrated the great potential of these TEBVs as implantable vascular grafts in human regenerative medicine. However, the production, therapeutic efficacy, and readiness in emergencies of current TEBVs could be hindered by the accessibility, expandability, and donor-donor variation of patient-specific primary seed cells. Alternatively, using human induced pluripotent stem cells (hiPSCs) to derive seed vascular cells for vascular tissue engineering could fundamentally address this current dilemma in TEBV production. As an emerging research field with a promising future, the generation of hiPSC-based TEBVs has been reported recently with significant progress. Simultaneously, to further promote hiPSC-based TEBVs into vascular grafts for clinical use, several challenges related to the safety, readiness, and structural integrity of vascular tissue need to be addressed. Herein, this review will focus on the evolution and role of hiPSCs in vascular tissue engineering technology and summarize the current progress, challenges, and future directions of research on hiPSC-based TEBVs.
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Affiliation(s)
- Xiaoqiang Cong
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cardiology, Bethune First Hospital of Jilin University, ChangChun, China
| | - Shang-Min Zhang
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Luke Batty
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut
| | - Jiesi Luo
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Yale Stem Cell Center, School of Medicine, Yale University, New Haven, Connecticut
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Comparative study of variations in mechanical stress and strain of human blood vessels: mechanical reference for vascular cell mechano-biology. Biomech Model Mechanobiol 2019; 19:519-531. [PMID: 31494790 DOI: 10.1007/s10237-019-01226-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 08/31/2019] [Indexed: 10/26/2022]
Abstract
The diseases of human blood vessels are closely associated with local mechanical variations. A better understanding of the quantitative correlation in mechanical environment between the current mechano-biological studies and vascular physiological or pathological conditions in vivo is crucial for evaluating numerous existing results and exploring new factors for disease discovery. In this study, six representative human blood vessels with known experimental measurements were selected, and their stress and strain variations in vessel walls under different blood pressures were analyzed based on nonlinear elastic theory. The results suggest that conventional mechano-biological experiments seeking the different biological expressions of cells at high/low mechanical loadings are ambiguous as references for studying vascular diseases, because distinct "site-specific" characteristics appear in different vessels. The present results demonstrate that the inner surface of the vessel wall does not always suffer the most severe stretch under high blood pressures comparing to the outer surface. Higher tension on the outer surface of aortas supports the hypothesis of the outside-in inflammation dominated by aortic adventitial fibroblasts. These results indicate that cellular studies at different mechanical niches should be "disease-specific" as well. The present results demonstrate considerable stress gradients across the wall thickness, which indicate micro-scale mechanical variations existing around the vascular cells, and imply that the physiological or pathological changes are not static processes confined within isolated regions, but are coupled with dynamic cell behaviors such as migration. The results suggest that the stress gradients, as well as the mechanical stresses and strains, are key factors constituting the mechanical niches, which may shed new light on "factor-specific" experiments of vascular cell mechano-biology.
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Jiang YF, Guo LL, Zhang LW, Chu YX, Zhu GL, Lu Y, Zhang L, Lu QS, Jing ZP. Local upregulation of interleukin-1 beta in aortic dissecting aneurysm: correlation with matrix metalloproteinase-2, 9 expression and biomechanical decrease. Interact Cardiovasc Thorac Surg 2019; 28:344-352. [PMID: 30169834 DOI: 10.1093/icvts/ivy256] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/02/2018] [Accepted: 07/11/2018] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Our goal was to examine whether interleukin-1 beta (IL-1β) originates locally and its possible relationship with matrix metalloproteinases (MMPs), apoptosis, elastin fibres and biomechanics in aortic dissecting aneurysms (DAs). METHODS Aortic DAs were induced in 24 rats with β-aminopropionitrile (BAPN); another 12 rats without BAPN were designated as controls. Then IL-1β levels were measured both in the circulation and in local aortic specimens. The expression of MMP-2 and MMP-9 and Victoria blue and TUNEL staining were also detected. Biomechanical parameters such as the elasticity modulus were used to detect the biomechanical changes in the aortic wall. The correlation of IL-1β, MMP-2, MMP-9, apoptosis and biomechanical properties was analysed. RESULTS Seventeen rats (17/24, 71%) in the BAPN-treated group died of DA rupture. IL-1β levels were dramatically increased in the DA specimens but not in the circulation. Victoria blue staining confirmed the formation of the DA and the reduction of elastin content after induction by BAPN. The extent of apoptosis in the aortic media was dramatically higher in rats with BAPN-induced DA than that in the control group and that in rats treated with BAPN but without DA. MMP-2 and MMP-9 levels were significantly increased in BAPN-treated rats compared to the controls, but no statistical significance was found between rats with and without DA. There were significant differences in biomechanical parameters, such as the elasticity modulus. Among the 3 groups, IL-1β was positively correlated with MMP-2 and MMP-9 levels and with the elasticity modulus but not with apoptosis. CONCLUSIONS Local IL-1β might participate in the formation of aortic DA through the upregulation of MMP-2 and MMP-9 and the breakage of elastin fibres, which finally weakens the biomechanical properties of the aortic wall.
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Affiliation(s)
- Yun-Fei Jiang
- Department of Vascular Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Ling-Ling Guo
- Department of Biological Therapies for Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Li-Wei Zhang
- Department of Cardio-Thoracic Surgery, The People's Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Yong-Xin Chu
- Department of Vascular Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Guang-Lang Zhu
- Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ye Lu
- Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Lei Zhang
- Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qing-Sheng Lu
- Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zai-Ping Jing
- Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
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Bicuspid Aortic Valve Alters Aortic Protein Expression Profile in Neonatal Coarctation Patients. J Clin Med 2019; 8:jcm8040517. [PMID: 30995723 PMCID: PMC6518196 DOI: 10.3390/jcm8040517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/02/2019] [Accepted: 04/12/2019] [Indexed: 01/22/2023] Open
Abstract
Coarctation of the aorta is a form of left ventricular outflow tract obstruction in paediatric patients that can be presented with either bicuspid (BAV) or normal tricuspid (TAV) aortic valve. The congenital BAV is associated with hemodynamic changes and can therefore trigger different molecular remodelling in the coarctation area. This study investigated the proteomic and phosphoproteomic changes associated with BAV for the first time in neonatal coarctation patients. Aortic tissue was collected just proximal to the coarctation site from 23 neonates (BAV; n = 10, TAV; n = 13) that were matched for age (age range 4-22 days). Tissue from half of the patients was frozen and used for proteomic and phosphoproteomic analysis whilst the remaining tissue was formalin fixed and used for analysis of elastin content using Elastic Van-Gieson (EVG) staining. A total of 1796 protein and 75 phosphoprotein accession numbers were detected, of which 34 proteins and one phosphoprotein (SSH3) were differentially expressed in BAV patients compared to TAV patients. Ingenuity Pathway Analysis identified the formation of elastin fibres as a significantly enriched function (p = 1.12 × 10-4) due to the upregulation of EMILIN-1 and the downregulation of TNXB. Analysis of paraffin sections stained with EVG demonstrated increased elastin content in BAV patients. The proteomic/phosphoproteomic analysis also suggested changes in inositol signalling pathways and reduced expression of the antioxidant SOD3. This work demonstrates for the first time that coarcted aortic tissue in neonatal BAV patients has an altered proteome/phosphoproteome consistent with observed structural vascular changes when compared to TAV patients.
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Lin H, Du Q, Li Q, Wang O, Wang Z, Liu K, Akert L, Zhang C, Chung S, Duan B, Lei Y. Differentiating human pluripotent stem cells into vascular smooth muscle cells in three dimensional thermoreversible hydrogels. Biomater Sci 2019; 7:347-361. [PMID: 30483691 DOI: 10.1039/c8bm01128a] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Vascular smooth muscle cells (VSMCs) are of great value and are needed in large quantities for tissue engineering, drug screening, disease modeling and cell-based therapies. However, getting high quantity VSMCs remains a challenge. Here, we report a method for the scalable manufacturing of VSMCs from human pluripotent stem cells (hPSCs). hPSCs are expanded and differentiated into VSMCs in a three dimensional (3D) thermoreversible hydrogel. The hydrogel not only acts as a 3D scaffold for cells to grow, but also protects cells from hydrodynamic stresses in the culture vessel and prevents cells from excessive aggregation. Together, the hydrogel creates a cell-friendly microenvironment, leading to high culture efficiency. We show that VSMCs can be generated in 10 days with high viability (>90%), high purity (>80%) and high yield (∼2.0 × 107 cells per mL hydrogel) in the hydrogel scaffold. The generated VSMCs have normal functions. Genome-wide gene expression analysis shows VSMCs made in the hydrogel (i.e. 3D-VSMCs) have higher expression of genes related to vasculature development and glycolysis compared to VSMCs made in the conventional 2D cultures (i.e. 2D-VSMCs), while 2D-VSMCs have higher expression of genes related to cell proliferation. This simple, defined and efficient method is scalable for manufacturing hPSC-VSMCs for various biomedical applications.
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Affiliation(s)
- Haishuang Lin
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Nebraska, USA.
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Fukushi M, Kinoshita K, Yamada M, Yajima Y, Utoh R, Seki M. Formation of pressurizable hydrogel-based vascular tissue models by selective gelation in composite PDMS channels. RSC Adv 2019; 9:9136-9144. [PMID: 35517655 PMCID: PMC9062067 DOI: 10.1039/c9ra00257j] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/08/2019] [Indexed: 12/31/2022] Open
Abstract
Vascular tissue models created in vitro are of great utility in the biomedical research field, but versatile, facile strategies are still under development. In this study, we proposed a new approach to prepare vascular tissue models in PDMS-based composite channel structures embedded with barium salt powders. When a cell-containing hydrogel precursor solution was continuously pumped in the channel, the precursor solution in the vicinity of the channel wall was selectively gelled because of the barium ions as the gelation agent supplied to the flow. Based on this concept, we were able to prepare vascular tissue models, with diameters of 1–2 mm and with tunable morphologies, composed of smooth muscle cells in the hydrogel matrix and endothelial cells on the lumen. Perfusion culture was successfully performed under a pressurized condition of ∼120 mmHg. The presented platform is potentially useful for creating vascular tissue models that reproduce the physical and morphological characteristics similar to those of vascular tissues in vivo. A new approach for the preparation of vascular tissue models in PDMS-based composite channel structures embedded with barium salt powders.![]()
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Affiliation(s)
- Mayu Fukushi
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
| | - Keita Kinoshita
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
| | - Masumi Yamada
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
| | - Yuya Yajima
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
| | - Rie Utoh
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
| | - Minoru Seki
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University 1-33 Yayoi-cho, Inage-ku 263-8522 Japan +81-43-290-3398
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Ellis MW, Luo J, Qyang Y. Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering. Cell Mol Life Sci 2019; 76:893-901. [PMID: 30460472 PMCID: PMC6433159 DOI: 10.1007/s00018-018-2969-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/17/2018] [Accepted: 11/06/2018] [Indexed: 12/26/2022]
Abstract
Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development.
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Affiliation(s)
- Matthew W Ellis
- Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, Yale Cardiovascular Research Center, New Haven, CT, 06511, USA
- Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, 06519, USA
| | - Jiesi Luo
- Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, Yale Cardiovascular Research Center, New Haven, CT, 06511, USA
- Yale Stem Cell Center, New Haven, CT, 06520, USA
| | - Yibing Qyang
- Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, Yale Cardiovascular Research Center, New Haven, CT, 06511, USA.
- Yale Stem Cell Center, New Haven, CT, 06520, USA.
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA.
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Cochrane A, Albers HJ, Passier R, Mummery CL, van den Berg A, Orlova VV, van der Meer AD. Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology. Adv Drug Deliv Rev 2019; 140:68-77. [PMID: 29944904 DOI: 10.1016/j.addr.2018.06.007] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/11/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023]
Abstract
The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in 'microfluidic chips' (also known as 'organ-on-chip' technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.
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Lin H, Qiu X, Du Q, Li Q, Wang O, Akert L, Wang Z, Anderson D, Liu K, Gu L, Zhang C, Lei Y. Engineered Microenvironment for Manufacturing Human Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells. Stem Cell Reports 2019; 12:84-97. [PMID: 30527760 PMCID: PMC6335449 DOI: 10.1016/j.stemcr.2018.11.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/18/2022] Open
Abstract
Human pluripotent stem cell-derived vascular smooth muscle cells (hPSC-VSMCs) are of great value for disease modeling, drug screening, cell therapies, and tissue engineering. However, producing a high quantity of hPSC-VSMCs with current cell culture technologies remains very challenging. Here, we report a scalable method for manufacturing hPSC-VSMCs in alginate hydrogel microtubes (i.e., AlgTubes), which protect cells from hydrodynamic stresses and limit cell mass to <400 μm to ensure efficient mass transport. The tubes provide cells a friendly microenvironment, leading to extremely high culture efficiency. We have shown that hPSC-VSMCs can be generated in 10 days with high viability, high purity, and high yield (∼5.0 × 108 cells/mL). Phenotype and gene expression showed that VSMCs made in AlgTubes and VSMCs made in 2D cultures were similar overall. However, AlgTube-VSMCs had higher expression of genes related to vasculature development and angiogenesis, and 2D-VSMCs had higher expression of genes related to cell death and biosynthetic processes.
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Affiliation(s)
- Haishuang Lin
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Xuefeng Qiu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qian Du
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Qiang Li
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; Biomedical Engineering Program, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Ou Wang
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; Biomedical Engineering Program, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Leonard Akert
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Zhanqi Wang
- Department of Vascular Surgery, Beijing Anzhen Hospital of Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing 100029, China
| | - Dirk Anderson
- Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Kan Liu
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Linxia Gu
- Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Chi Zhang
- Department of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Yuguo Lei
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; Biomedical Engineering Program, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Lévesque L, Loy C, Lainé A, Drouin B, Chevallier P, Mantovani D. Incrementing the Frequency of Dynamic Strain on SMC-Cellularised Collagen-Based Scaffolds Affects Extracellular Matrix Remodeling and Mechanical Properties. ACS Biomater Sci Eng 2018; 4:3759-3767. [PMID: 33429603 DOI: 10.1021/acsbiomaterials.7b00395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Notwithstanding the efforts injected in vascular tissue engineering in the past 30 years, the clinical translation of engineered artery constructs is far from being successful. One common approach to improve artery regeneration is the use of cyclic mechanical stimuli to guide cellular remodeling. However, there is a lack of information on the effect of cyclic strain on cells within a 3D environment. To this end, this work explored the effect of gradual increase in stimulation frequency on the response of human umbilical artery smooth muscle cells (HUASMCs) embedded in a 3D collagen matrix. The results demonstrate that, with an applied strain of 5%, the gradual increase of frequency from 0.1 to 1 Hz improved collagen remodeling by HUASMCs compared to samples constantly stimulated at 1 Hz. The expression of collagen, elastin and matrix metalloproteinase-2 (MMP-2) genes was similar at 7 days for gradual and 1 Hz samples which showed lower amounts than static counterparts. Interestingly the mechanical properties of the constructs, specifically the amplitude of the time constants and the elastic equilibrium modulus, were enhanced by gradual increase of frequency. Taken together, these results show an increase in collagen remodeling by the HUASMCs overtime under incremental cyclic mechanical strain. This work suggests that only the in-depth investigation of the effects of stimulation parameters on the behavior of vSMC under cyclic strain in a 3D environment could lead to the design of optimized control strategies for enhanced vascular tissue generation and maturation in bioreactors.
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Affiliation(s)
- L Lévesque
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
| | - C Loy
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
| | - A Lainé
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
| | - B Drouin
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
| | - P Chevallier
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
| | - D Mantovani
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met- Materials Engineering, Research Center of CHU de Quebec, Division of Regenerative Medicine, Université Laval, Quebec, Quebec, Canada G1V 0A6
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Saw SN, Tay JJH, Poh YW, Yang L, Tan WC, Tan LK, Clark A, Biswas A, Mattar CNZ, Yap CH. Altered Placental Chorionic Arterial Biomechanical Properties During Intrauterine Growth Restriction. Sci Rep 2018; 8:16526. [PMID: 30409992 PMCID: PMC6224524 DOI: 10.1038/s41598-018-34834-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 10/24/2018] [Indexed: 12/16/2022] Open
Abstract
Intrauterine growth restriction (IUGR) is a pregnancy complication due to placental dysfunction that prevents the fetus from obtaining enough oxygen and nutrients, leading to serious mortality and morbidity risks. There is no treatment for IUGR despite having a prevalence of 3% in developed countries, giving rise to an urgency to improve our understanding of the disease. Applying biomechanics investigation on IUGR placental tissues can give important new insights. We performed pressure-diameter mechanical testing of placental chorionic arteries and found that in severe IUGR cases (RI > 90th centile) but not in IUGR cases (RI < 90th centile), vascular distensibility was significantly increased from normal. Constitutive modeling demonstrated that a simplified Fung-type hyperelastic model was able to describe the mechanical properties well, and histology showed that severe IUGR had the lowest collagen to elastin ratio. To demonstrate that the increased distensibility in the severe IUGR group was related to their elevated umbilical resistance and pulsatility indices, we modelled the placental circulation using a Windkessel model, and demonstrated that vascular compliance (and not just vascular resistance) directly affected blood flow pulsatility, suggesting that it is an important parameter for the disease. Our study showed that biomechanics study on placenta could extend our understanding on placenta physiology.
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Affiliation(s)
- Shier Nee Saw
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Jess Jia Hwee Tay
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Yu Wei Poh
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
| | - Liying Yang
- Department of Obstetrics & Gynecology, Singapore General Hospital, Singapore, Singapore
| | - Wei Ching Tan
- Department of Obstetrics & Gynecology, Singapore General Hospital, Singapore, Singapore
| | - Lay Kok Tan
- Department of Obstetrics & Gynecology, Singapore General Hospital, Singapore, Singapore
| | - Alys Clark
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Arijit Biswas
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Singapore, Singapore
| | - Citra Nurfarah Zaini Mattar
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Singapore, Singapore
| | - Choon Hwai Yap
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.
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50
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Castle PE, Scheven UM, Crouch AC, Cao AA, Goergen CJ, Greve JM. Anatomical location, sex, and age influence murine arterial circumferential cyclic strain before and during dobutamine infusion. J Magn Reson Imaging 2018; 49:69-80. [PMID: 30291650 PMCID: PMC6519256 DOI: 10.1002/jmri.26232] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/04/2018] [Indexed: 02/06/2023] Open
Abstract
Background One of the primary biomechanical factors influencing arterial health is their deformation across the cardiac cycle, or cyclic strain, which is often associated with arterial stiffness. Deleterious changes in the cardiovascular system, e.g., increased arterial stiffness, can remain undetected until the system is challenged, such as under a cardiac stressor like dobutamine. Purpose To quantify cyclic strain in mice at different locations along the arterial tree prior to and during dobutamine infusion, while evaluating the effects of sex and age. Study Type Control/cohort study. Animal Model Twenty C57BL/6 mice; male, female; ∼12 and 24 weeks of age; n = 5 per group. Field Strength/Sequence 7T; CINE MRI with 12 frames, velocity compensation, and prospective cardiac gating. Assessment Prior to and during the infusion of dobutamine, Green–Lagrange circumferential cyclic strain was calculated from perimeter measurements derived from CINE data acquired at the carotid artery, suprarenal and infrarenal abdominal aorta, and iliac artery. Statistical Tests Analysis of variance (ANOVA) followed by post‐hoc tests was used to evaluate the influence of dobutamine, anatomical location, sex, and age. Results Heart rates did not differ between groups prior to or during dobutamine infusion (P = 0.87 and P = 0.08, respectively). Dobutamine increased cyclic strain in each group. Within a group, increases in strain were similar across arteries. At the suprarenal aorta, strain was reduced in older mice at baseline (young 27.6 > mature 19.3%, P = 0.01) and during dobutamine infusion (young 53.0 > mature 36.2%, P = 0.005). In the infrarenal aorta, the response (dobutamine – baseline) was reduced in older mice (young 21.9 > mature 13.5%, P = 0.04). Data Conclusion Dobutamine infusion increases circumferential cyclic strain throughout the arterial tree of mice. This effect is quantifiable using CINE MRI. The results demonstrate that strain prior to and during dobutamine is influenced by anatomical location, sex, and age. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:69–80.
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Affiliation(s)
- Paige E Castle
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Ulrich M Scheven
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - A Colleen Crouch
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Amos A Cao
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Craig J Goergen
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| | - Joan M Greve
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
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