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3D Cultures for Modelling the Microenvironment: Current Research Trends and Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 30914

Special Issue Editors


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Guest Editor
Department of Medical and Surgical Sciences and Biotechnology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 04100 Latina, Italy
Interests: cardiac microenvironment; cardiac repair mechanisms; 3D culture
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Guest Editor
Department of Molecular Medicine, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
Interests: biomaterials; stem cells; cardiac regeneration; cardiac tissue engineering; tissue modelling; diabetes; microenvironment

Special Issue Information

Dear Colleagues,

Methods and protocols for creating 3D cultures in vitro have been rapidly evolving in recent years, concerning both biomaterials and structure design. Creating a 3D microenvironment for cell cultures allows complex interactions and stimuli that are functional for efficient phenotypic control and for mimicking tissue homeostasis and pathology. These tools can be used to successfully generate artificial tissues or cellular organoids that could be used for modelling the microenvironment in a physiologically relevant way, drug screening, or exploiting tissue engineering strategies in the clinical translation of regenerative medicine approaches.

This Special Issue will gather scholars in the field of 3D cultures for the creation of in vitro microenvironments for the study of tissue homeostasis and pathology, particularly in the field of cardiovascular research. Potential topics include, but are not limited to the following: novel methods for creating 3D cultures and tissue patches; study of the microenvironment in 3D cultures; modelling human diseases or pathological conditions in vitro; tissue engineering for regenerative medicine purposes; stem cells differentiation in 3D cultures; bioprinting of artificial tissues; development of smart biomaterials; cell–extracellular matrix interaction in the context of 3D tissue development and function.

Dr. Isotta Chimenti
Dr. Roberto Gaetani
Guest Editors

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Keywords

  • 3D culture
  • Tissue engineering
  • Microenvironment
  • Disease modelling
  • Stem cells differentiation
  • Regenerative medicine
  • Biomaterials
  • Cell-extracellular matrix interaction.

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Published Papers (10 papers)

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Editorial

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4 pages, 201 KiB  
Editorial
3D Cultures for Modelling the Microenvironment: Current Research Trends and Applications
by Roberto Gaetani and Isotta Chimenti
Int. J. Mol. Sci. 2023, 24(13), 11109; https://doi.org/10.3390/ijms241311109 - 5 Jul 2023
Viewed by 865
Abstract
The importance of 3D culture systems for drug screening or physio-pathological models has exponentially increased in recent years [...] Full article

Research

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12 pages, 3272 KiB  
Article
Integrating Oxygen and 3D Cell Culture System: A Simple Tool to Elucidate the Cell Fate Decision of hiPSCs
by Rubina Rahaman Khadim, Raja Kumar Vadivelu, Tia Utami, Fuad Gandhi Torizal, Masaki Nishikawa and Yasuyuki Sakai
Int. J. Mol. Sci. 2022, 23(13), 7272; https://doi.org/10.3390/ijms23137272 - 30 Jun 2022
Cited by 1 | Viewed by 1685
Abstract
Oxygen, as an external environmental factor, plays a role in the early differentiation of human stem cells, such as induced pluripotent stem cells (hiPSCs). However, the effect of oxygen concentration on the early-stage differentiation of hiPSC is not fully understood, especially in 3D [...] Read more.
Oxygen, as an external environmental factor, plays a role in the early differentiation of human stem cells, such as induced pluripotent stem cells (hiPSCs). However, the effect of oxygen concentration on the early-stage differentiation of hiPSC is not fully understood, especially in 3D aggregate cultures. In this study, we cultivated the 3D aggregation of hiPSCs on oxygen-permeable microwells under different oxygen concentrations ranging from 2.5 to 20% and found that the aggregates became larger, corresponding to the increase in oxygen level. In a low oxygen environment, the glycolytic pathway was more profound, and the differentiation markers of the three germ layers were upregulated, suggesting that the oxygen concentration can function as a regulator of differentiation during the early stage of development. In conclusion, culturing stem cells on oxygen-permeable microwells may serve as a platform to investigate the effect of oxygen concentration on diverse cell fate decisions during development. Full article
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13 pages, 2628 KiB  
Article
Spheroid Culture Differentially Affects Cancer Cell Sensitivity to Drugs in Melanoma and RCC Models
by Aleksandra Filipiak-Duliban, Klaudia Brodaczewska, Arkadiusz Kajdasz and Claudine Kieda
Int. J. Mol. Sci. 2022, 23(3), 1166; https://doi.org/10.3390/ijms23031166 - 21 Jan 2022
Cited by 18 | Viewed by 3794
Abstract
2D culture as a model for drug testing often turns to be clinically futile. Therefore, 3D cultures (3Ds) show potential to better model responses to drugs observed in vivo. In preliminary studies, using melanoma (B16F10) and renal (RenCa) cancer, we confirmed that 3Ds [...] Read more.
2D culture as a model for drug testing often turns to be clinically futile. Therefore, 3D cultures (3Ds) show potential to better model responses to drugs observed in vivo. In preliminary studies, using melanoma (B16F10) and renal (RenCa) cancer, we confirmed that 3Ds better mimics the tumor microenvironment. Here, we evaluated how the proposed 3D mode of culture affects tumor cell susceptibility to anti-cancer drugs, which have distinct mechanisms of action (everolimus, doxorubicin, cisplatin). Melanoma spheroids showed higher resistance to all used drugs, as compared to 2D. In an RCC model, such modulation was only observed for doxorubicin treatment. As drug distribution was not affected by the 3D shape, we assessed the expression of MDR1 and mTor. Upregulation of MDR1 in RCC spheroids was observed, in contrast to melanoma. In both models, mTor expression was not affected by the 3D cultures. By NGS, 10 genes related with metabolism of xenobiotics by cytochrome p450 were deregulated in renal cancer spheroids; 9 of them were later confirmed in the melanoma model. The differences between 3D models and classical 2D cultures point to the potential to uncover new non-canonical mechanisms to explain drug resistance set by the tumor in its microenvironment. Full article
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14 pages, 1212 KiB  
Article
An Innovative In Vitro Open-Angle Glaucoma Model (IVOM) Shows Changes Induced by Increased Ocular Pressure and Oxidative Stress
by Stefania Vernazza, Sara Tirendi, Mario Passalacqua, Francesco Piacente, Sonia Scarfì, Francesco Oddone and Anna Maria Bassi
Int. J. Mol. Sci. 2021, 22(22), 12129; https://doi.org/10.3390/ijms222212129 - 9 Nov 2021
Cited by 4 | Viewed by 1875
Abstract
Primary Open-Angle Glaucoma (POAG) is a neurodegenerative disease, and its clinical outcomes lead to visual field constriction and blindness. POAG’s etiology is very complex and its pathogenesis is mainly explained through both mechanical and vascular theories. The trabecular meshwork (TM), the most sensitive [...] Read more.
Primary Open-Angle Glaucoma (POAG) is a neurodegenerative disease, and its clinical outcomes lead to visual field constriction and blindness. POAG’s etiology is very complex and its pathogenesis is mainly explained through both mechanical and vascular theories. The trabecular meshwork (TM), the most sensitive tissue of the eye anterior segment to oxidative stress (OS), is the main tissue involved in early-stage POAG, characterized by an increase in pressure. Preclinical assessments of neuroprotective drugs on animal models have not always shown correspondence with human clinical studies. In addition, intra-ocular pressure management after a glaucoma diagnosis does not always prevent blindness. Recently, we have been developing an innovative in vitro 3Dadvanced human trabecular cell model on a millifluidicplatform as a tool to improve glaucoma studies. Herein, we analyze the effects of prolonged increased pressure alone and, in association with OS, on such in vitro platform. Moreover, we verify whethersuch damaged TM triggers apoptosis on neuron-like cells. The preliminary results show that TM cells are less sensitive to pressure elevation than OS, and OS-damaging effects were worsened by the pressure increase. The stressed TM releases harmful signals, which increase apoptosis stimuli on neuron-like cells, suggesting its pivotal role in the glaucoma cascade. Full article
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15 pages, 6552 KiB  
Article
Perfusable System Using Porous Collagen Gel Scaffold Actively Provides Fresh Culture Media to a Cultured 3D Tissue
by Chikahiro Imashiro, Kai Yamasaki, Ryu-ichiro Tanaka, Yusuke Tobe, Katsuhisa Sakaguchi and Tatsuya Shimizu
Int. J. Mol. Sci. 2021, 22(13), 6780; https://doi.org/10.3390/ijms22136780 - 24 Jun 2021
Cited by 8 | Viewed by 2619
Abstract
Culturing three-dimensional (3D) tissues with an appropriate microenvironment is a critical and fundamental technology in broad areas of cutting-edge bioengineering research. In addition, many technologies have engineered tissue functions. However, an effective system for transporting nutrients, waste, or oxygen to affect the functions [...] Read more.
Culturing three-dimensional (3D) tissues with an appropriate microenvironment is a critical and fundamental technology in broad areas of cutting-edge bioengineering research. In addition, many technologies have engineered tissue functions. However, an effective system for transporting nutrients, waste, or oxygen to affect the functions of cell tissues has not been reported. In this study, we introduce a novel system that employs diffusion and convection to enhance transportation. To demonstrate the concept of the proposed system, three layers of normal human dermal fibroblast cell sheets are used as a model tissue, which is cultured on a general dish or porous collagen scaffold with perfusable channels for three days with and without the perfusion of culture media in the scaffold. The results show that the viability of the cell tissue was improved by the developed system. Furthermore, glucose consumption, lactate production, and oxygen transport to the tissues were increased, which might improve the viability of tissues. However, mechanical stress in the proposed system did not cause damage or unintentional functional changes in the cultured tissue. We believe that the introduced culturing system potentially suggests a novel standard for 3D cell cultures. Full article
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19 pages, 4768 KiB  
Article
Tumor Extracellular Matrix Stiffness Promptly Modulates the Phenotype and Gene Expression of Infiltrating T Lymphocytes
by Maila Chirivì, Fabio Maiullari, Marika Milan, Dario Presutti, Chiara Cordiglieri, Mariacristina Crosti, Maria Lucia Sarnicola, Andrea Soluri, Marina Volpi, Wojciech Święszkowski, Daniele Prati, Marta Rizzi, Marco Costantini, Dror Seliktar, Chiara Parisi, Claudia Bearzi and Roberto Rizzi
Int. J. Mol. Sci. 2021, 22(11), 5862; https://doi.org/10.3390/ijms22115862 - 30 May 2021
Cited by 28 | Viewed by 3971
Abstract
The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of [...] Read more.
The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host’s immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM. Full article
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25 pages, 6607 KiB  
Article
A Human Osteochondral Tissue Model Mimicking Cytokine-Induced Key Features of Arthritis In Vitro
by Alexandra Damerau, Moritz Pfeiffenberger, Marie-Christin Weber, Gerd-Rüdiger Burmester, Frank Buttgereit, Timo Gaber and Annemarie Lang
Int. J. Mol. Sci. 2021, 22(1), 128; https://doi.org/10.3390/ijms22010128 - 24 Dec 2020
Cited by 6 | Viewed by 2587
Abstract
Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related [...] Read more.
Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes—key features of RA—and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup. Full article
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Review

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14 pages, 1349 KiB  
Review
Multicellular 3D Models for the Study of Cardiac Fibrosis
by Vittorio Picchio, Erica Floris, Yuriy Derevyanchuk, Claudia Cozzolino, Elisa Messina, Francesca Pagano, Isotta Chimenti and Roberto Gaetani
Int. J. Mol. Sci. 2022, 23(19), 11642; https://doi.org/10.3390/ijms231911642 - 1 Oct 2022
Cited by 9 | Viewed by 3405
Abstract
Ex vivo modelling systems for cardiovascular research are becoming increasingly important in reducing lab animal use and boosting personalized medicine approaches. Integrating multiple cell types in complex setups adds a higher level of significance to the models, simulating the intricate intercellular communication of [...] Read more.
Ex vivo modelling systems for cardiovascular research are becoming increasingly important in reducing lab animal use and boosting personalized medicine approaches. Integrating multiple cell types in complex setups adds a higher level of significance to the models, simulating the intricate intercellular communication of the microenvironment in vivo. Cardiac fibrosis represents a key pathogenetic step in multiple cardiovascular diseases, such as ischemic and diabetic cardiomyopathies. Indeed, allowing inter-cellular interactions between cardiac stromal cells, endothelial cells, cardiomyocytes, and/or immune cells in dedicated systems could make ex vivo models of cardiac fibrosis even more relevant. Moreover, culture systems with 3D architectures further enrich the physiological significance of such in vitro models. In this review, we provide a summary of the multicellular 3D models for the study of cardiac fibrosis described in the literature, such as spontaneous microtissues, bioprinted constructs, engineered tissues, and organs-on-chip, discussing their advantages and limitations. Important discoveries on the physiopathology of cardiac fibrosis, as well as the screening of novel potential therapeutic molecules, have been reported thanks to these systems. Future developments will certainly increase their translational impact for understanding and modulating mechanisms of cardiac fibrosis even further. Full article
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24 pages, 1732 KiB  
Review
Clinical Application Perspectives of Lung Cancers 3D Tumor Microenvironment Models for In Vitro Cultures
by Irena Wieleba, Kamila Wojas-Krawczyk, Paweł Krawczyk and Janusz Milanowski
Int. J. Mol. Sci. 2022, 23(4), 2261; https://doi.org/10.3390/ijms23042261 - 18 Feb 2022
Cited by 6 | Viewed by 3218
Abstract
Despite the enormous progress and development of modern therapies, lung cancer remains one of the most common causes of death among men and women. The key element in the development of new anti-cancer drugs is proper planning of the preclinical research phase. The [...] Read more.
Despite the enormous progress and development of modern therapies, lung cancer remains one of the most common causes of death among men and women. The key element in the development of new anti-cancer drugs is proper planning of the preclinical research phase. The most adequate basic research exemplary for cancer study are 3D tumor microenvironment in vitro models, which allow us to avoid the use of animal models and ensure replicable culture condition. However, the question tormenting the scientist is how to choose the best tool for tumor microenvironment research, especially for extremely heterogenous lung cancer cases. In the presented review we are focused to explain the key factors of lung cancer biology, its microenvironment, and clinical gaps related to different therapies. The review summarized the most important strategies for in vitro culture models mimicking the tumor–tumor microenvironmental interaction, as well as all advantages and disadvantages were depicted. This knowledge could facilitate the right decision to designate proper pre-clinical in vitro study, based on available analytical tools and technical capabilities, to obtain more reliable and personalized results for faster introduction them into the future clinical trials. Full article
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27 pages, 2393 KiB  
Review
3D Modeling of Epithelial Tumors—The Synergy between Materials Engineering, 3D Bioprinting, High-Content Imaging, and Nanotechnology
by Poonam Trivedi, Rui Liu, Hongjie Bi, Chunlin Xu, Jessica M. Rosenholm and Malin Åkerfelt
Int. J. Mol. Sci. 2021, 22(12), 6225; https://doi.org/10.3390/ijms22126225 - 9 Jun 2021
Cited by 12 | Viewed by 4865
Abstract
The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail [...] Read more.
The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail in clinical trials, partially due to the use of too simplified in vitro models and a lack of mimicking the tumor microenvironment in drug efficacy testing. This review focuses on the origin and mechanism of epithelial cancers, followed by experimental models designed to recapitulate the epithelial cancer structure and microenvironment, such as 2D and 3D cell culture models and animal models. A specific focus is put on novel technologies for cell culture of spheroids, organoids, and 3D-printed tissue-like models utilizing biomaterials of natural or synthetic origins. Further emphasis is laid on high-content imaging technologies that are used in the field to visualize in vitro models and their morphology. The associated technological advancements and challenges are also discussed. Finally, the review gives an insight into the potential of exploiting nanotechnological approaches in epithelial cancer research both as tools in tumor modeling and how they can be utilized for the development of nanotherapeutics. Full article
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