RGDS-Modified Superporous Poly(2-Hydroxyethyl Methacrylate)-Based Scaffolds as 3D In Vitro Leukemia Model

Svozilová, Hana; Plichta, Zdeněk; Proks, Vladimír; Studená, Radana; Baloun, Jiří; Doubek, Michael; Pospı́šilová, Šárka

doi:10.3390/ijms22052376

Cited by 10 publications

(6 citation statements)

References 50 publications

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“…37 For example, Svozilová et al optimized a BM niche model of leukemia, recapitulating the trabecular bone structure using a hydrogel scaffold, using needle-shaped ammonium oxalate as a porogen. 43 Apoorva et al designed biomaterials-based hydrogels with tunable mechanical stiffness for B lymphoma growth, demonstrating that a lymphoid-like stiffness influences BCR expression levels in malignant cells, with consequences for proliferation and drug resistance. 44 Along with the possibility of tuning physical properties, matrices can also be functionalized with a wide variety of compounds to make them biologically active.…”

Section: Scaffold-based Modelsmentioning

confidence: 99%

Emerging Strategies in 3D Culture Models for Hematological Cancers

Barozzi

Scielzo

2023

HemaSphere

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In vitro cell cultures are fundamental and necessary tools in cancer research and personalized drug discovery. Currently, most cells are cultured using two-dimensional (2D) methods, and drug testing is mainly performed in animal models. However, new and improved methods that implement three-dimensional (3D) cell-culturing techniques provide compelling evidence that more advanced experiments can be performed, yielding valuable new insights. In 3D cell-culture experiments, the cell environment can be manipulated to mimic the complexity and dynamicity of the human tissue microenvironment, possibly leading to more accurate representations of cell-to-cell interactions, tumor biology, and predictions of drug response. The 3D cell cultures can also potentially provide alternative ways to study hematological cancers and are expected to eventually bridge the gap between 2D cell culture and animal models. The present review provides an overview of the complexity of the lymphoid microenvironment and a summary of the currently used 3D models that aim at recreating it for hematological cancer research. We here dissect the differences and challenges between, and potential advantages of, different culture methods and present our vision of the most promising future strategies in the hematological field.

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Section: Scaffold-based Modelsmentioning

confidence: 99%

Emerging Strategies in 3D Culture Models for Hematological Cancers

Barozzi

Scielzo

2023

HemaSphere

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“…Recently, primary CLL cells were cultured in 3D-printed, commercially available CELLINK Bioink, which maintained 40% CLL-cell viability after one month [120]. It is tempting to speculate that adding CD40L and/or interleukins could improve these 3D models and also induce significant proliferation [121]. It has been shown that T-cell signals can be introduced to scaffolds via injection, the covalent linking of recombinant factors [122], or seeding with supportive cells producing the desired factors.…”

Section: In Vitro: Cll Co-cultures In 3dmentioning

confidence: 99%

In Vitro and In Vivo Models of CLL–T Cell Interactions: Implications for Drug Testing

Hoferkova

Kadakova

Mráz

2022

Cancers

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T cells are key components in environments that support chronic lymphocytic leukemia (CLL), activating CLL-cell proliferation and survival. Here, we review in vitro and in vivo model systems that mimic CLL–T-cell interactions, since these are critical for CLL-cell division and resistance to some types of therapy (such as DNA-damaging drugs or BH3-mimetic venetoclax). We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INFγ) and additional B-cell receptor (BCR) activation with anti-IgM antibody. We also summarize strategies for CLL co-transplantation with autologous T cells into immunodeficient mice (NOD/SCID, NSG, NOG) to generate patient-derived xenografts (PDX) and the role of T cells in transgenic CLL mouse models based on TCL1 overexpression (Eµ-TCL1). We further discuss how these in vitro and in vivo models could be used to test drugs to uncover the effects of targeted therapies (such as inhibitors of BTK, PI3K, SYK, AKT, MEK, CDKs, BCL2, and proteasome) or chemotherapy (fludarabine and bendamustine) on CLL–T-cell interactions and CLL proliferation.

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“…4 Development of three-dimensional (3D) models that are able to accurately mimic the CLL microenvironment may help to bridge the gap between current in vitro systems and the physiologic CLL microenvironment in vivo, overcoming some of the current limitations of in vitro CLL studies. Recent efforts have been made toward the development of bone marrow-specific CLL models, 5,6 yet it is currently accepted that the LN is the critical site of CLL proliferation. 2 We attempted to establish a model that incorporates key aspects of CLL LN biology, taking into account physiological relevance.…”

Section: Introductionmentioning

confidence: 99%

In Vitro 3D Spheroid Culture System Displays Sustained T Cell-dependent CLL Proliferation and Survival

Haselager,

van Driel,

Perelaer

et al. 2023

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Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironmental cells and signals. The lymph node (LN) is the critical site of in vivo CLL proliferation and development of resistance to both chemotherapy and targeted agents. We present a new model that incorporates key aspects of the CLL LN, which enables investigation of CLL cells in the context of a protective niche. We describe a three-dimensional (3D) in vitro culture system using ultra-low attachment plates to create spheroids of CLL cells derived from peripheral blood. Starting from CLL:T cell ratios as observed in LN samples, CLL activation was induced by either direct stimulation and/or indirectly via T cells. Compared with two-dimensional cultures, 3D cultures promoted CLL proliferation in a T cell-dependent manner, and enabled expansion for up to 7 weeks, including the formation of follicle-like structures after several weeks of culture. This model enables high-throughput drug screening, of which we describe response to Btk inhibition, venetoclax resistance, and T cell-mediated cytotoxicity as examples. In summary, we present the first LN-mimicking in vitro 3D culture for primary CLL, which enables readouts such as real-time drug screens, kinetic growth assays, and spatial localization. This is the first in vitro CLL system that allows testing of response and resistance to venetoclax and Bruton's tyrosine kinase inhibitors in the context of the tumor microenvironment, thereby opening up new possibilities for clinically useful applications.

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RGDS-Modified Superporous Poly(2-Hydroxyethyl Methacrylate)-Based Scaffolds as 3D In Vitro Leukemia Model

Cited by 10 publications

References 50 publications

Emerging Strategies in 3D Culture Models for Hematological Cancers

Emerging Strategies in 3D Culture Models for Hematological Cancers

In Vitro and In Vivo Models of CLL–T Cell Interactions: Implications for Drug Testing

In Vitro 3D Spheroid Culture System Displays Sustained T Cell-dependent CLL Proliferation and Survival

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