Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

Mauretti, A Arianna; Rossi, Fabrizio; Bax, Noortje Noortje; Miano, Carmen; Miraldi, Fabio; Goumans, Marie–José; Messina, Elisa; Giacomello, Alessandro; Bouten, Cvc Carlijn; Sahlgren, Cecilia

doi:10.1557/mrc.2017.82

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…For instance, FAK-associated pathways, typically initiated from cellular interactions with neural ECM molecules such as laminin, play an essential role in the neurogenesis of stem cells. However, such beneficial FAK pathways are often suppressed due to the dominating cell-cell interactions in neurospheres, resulting in less controlled differentiation of stem cells (51)(52)(53)(54)(55)(56)(57). In this regard, we verified that SMART neurospheres, incorporating 3D cell-matrix interactions, induced significantly higher expression of FAK compared to control spheroids (Fig.…”

Section: Smart Neurospheres Generated By Controlled 3d Smart Assemblysupporting

confidence: 55%

Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

et al. 2021

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Although stem cell therapy holds enormous potential for treating debilitating injuries and diseases in the central nervous system, low survival and inefficient differentiation have restricted its clinical applications. Recently, 3D cell culture methods, such as stem cell-based spheroids and organoids, have demonstrated advantages by incorporating tissue-mimetic 3D cell-cell interactions. However, a lack of drug and nutrient diffusion, insufficient cell-matrix interactions, and tedious fabrication procedures have compromised their therapeutic effects in vivo. To address these issues, we developed a biodegradable nanomaterial-templated 3D cell assembly method that enables the formation of hybrid stem cell spheroids with deep drug delivery capabilities and homogeneous incorporation of 3D cell-matrix interactions. Hence, high survival rates, controlled differentiation, and functional recovery were demonstrated in a spinal cord injury animal model. Overall, our hybrid stem cell spheroids represent a substantial development of material-facilitated 3D cell culture systems and can pave the way for stem cell-based treatment of CNS injuries.

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Section: Smart Neurospheres Generated By Controlled 3d Smart Assemblysupporting

confidence: 55%

Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

et al. 2021

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“…It is reported that cardiac cells grown in 3D spheroids have increased NOTCH signaling. 51 Marconi et al also highlight the role of NOTCH signaling on cellular behavior and inter-cellular communication within organoids. 52 Hence, down-regulated NOTCH signaling possibly leads to the limited growth ability of WU-225 in 3D culture.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Larsson,

Bhatia,

Calizo

et al. 2023

Neuro-Oncology

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Background Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Methods Genomic analysis was performed on all PDX-tumor pairs. Select PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. Results We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%) and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. Conclusions These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.

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“…The findings indicate an increase in Notch signaling activation in the 3D spheroid culture due to the in vivo-like microenvironment (Figure 2g). Under hypoxia conditions, fetal CPCs spheroids showed an increased expression in all Notch components and Hey1 (Figure 2h), whereas adult CPCs spheroids displayed upregulation in Notch1, Notch3, and Hey 1 when compared to the respective monolayer culture [84]. Enhancement of Notch signaling is achieved under hypoxia conditions due to the 3D environment and cell-ECM interactions.…”

Section: Spheroidsmentioning

confidence: 95%

“…Spheroids are another 3D cell culture technique of creating an in vivo-like microenvironment by providing multicellular cell-cell and cell-ECM interactions [18]. The Notch signaling pathways of Notch1, Notch2, Notch3, Jag1, and Hey1 were studied in the spheroid culture of human CPCs, which include both adult and fetal human CPCs from adult and fetal human hearts, respectively, under normoxia and hypoxia conditions [84]. Under normoxia, the fetal CPCs spheroids showed upregulation of Notch2, Notch3, Jag1, and Hey 1 compared with a 2D monolayer culture, whereas adult CPCs spheroids displayed upregulation of Notch1, Notch3, and Hey 1.…”

Section: Spheroidsmentioning

confidence: 99%

“…Enhancement of Notch signaling is achieved under hypoxia conditions due to the 3D environment and cell-ECM interactions. The cells in spheroids are tightly compact and allow for the secretion of ECM proteins that can influence cell behavior in the microenvironment [84,85]. Moreover, the CPC spheroids were transplanted to recapture Notch1-Jag1 signaling or repair right ventricular heart failure in an athymic rat model.…”

Section: Spheroidsmentioning

confidence: 99%

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Bioengineering Systems for Modulating Notch Signaling in Cardiovascular Development, Disease, and Regeneration

Gomez

Joshi

Yang

et al. 2021

JCDD

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The Notch intercellular signaling pathways play significant roles in cardiovascular development, disease, and regeneration through modulating cardiovascular cell specification, proliferation, differentiation, and morphogenesis. The dysregulation of Notch signaling leads to malfunction and maldevelopment of the cardiovascular system. Currently, most findings on Notch signaling rely on animal models and a few clinical studies, which significantly bottleneck the understanding of Notch signaling-associated human cardiovascular development and disease. Recent advances in the bioengineering systems and human pluripotent stem cell-derived cardiovascular cells pave the way to decipher the role of Notch signaling in cardiovascular-related cells (endothelial cells, cardiomyocytes, smooth muscle cells, fibroblasts, and immune cells), and intercellular crosstalk in the physiological, pathological, and regenerative context of the complex human cardiovascular system. In this review, we first summarize the significant roles of Notch signaling in individual cardiac cell types. We then cover the bioengineering systems of microfluidics, hydrogel, spheroid, and 3D bioprinting, which are currently being used for modeling and studying Notch signaling in the cardiovascular system. At last, we provide insights into ancillary supports of bioengineering systems, varied types of cardiovascular cells, and advanced characterization approaches in further refining Notch signaling in cardiovascular development, disease, and regeneration.

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Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

Cited by 7 publications

References 28 publications

Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

Hybrid SMART spheroids to enhance stem cell therapy for CNS injuries

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Bioengineering Systems for Modulating Notch Signaling in Cardiovascular Development, Disease, and Regeneration

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