Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model

Kim, Sudong; Chung, Minhwa; Ahn, Jung Yong; Lee, Somin; Jeon, Noo Li

doi:10.1039/c6lc00910g

Cited by 187 publications

(191 citation statements)

References 49 publications

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“…It is noteworthy that we observed endothelial sprouting with the direction of TVF and interstitial flow. Numerous studies using other microfluidic models have reported that angiogenic sprouts preferentially form against the direction of interstitial flow (Song and Munn, 2011;Song et al, 2012;Vickerman and Kamm, 2012;Kim et al, 2016). However, these previous studies were done with HUVECs, which are venous microvascular ECs, in contrast to our study using MAECs, an arterial endothelial cell type.…”

Section: Discussionmentioning

confidence: 62%

Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

Akbari

Spychalski

Rangharajan

et al. 2019

Preprint

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Sprouting angiogenesis, the infiltration and extension of endothelial cells from pre-existing blood vessels, helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, regulation of angiogenesis by the different flow dynamics that arise due to vessel branching, such as impinging flow stagnation at the base of a bifurcating 2-vessel, are not well understood. Here we used a recently developed 3-D microfluidic model to investigate the role of the flow conditions that occur due to vessel bifurcations on endothelial sprouting. We observed that bifurcating fluid flow located at the vessel bifurcation point suppresses the formation of angiogenic sprouts. Similarly, laminar shear stress at a magnitude of ~3 dyn/cm 2 applied in the branched vessels downstream of the bifurcation point, inhibited the formation of angiogenic sprouts. In contrast, co-application of ~1 µm/s average transvascular flow across the endothelial monolayer with bifurcating fluid flow and laminar shear stress induced the formation of angiogenic sprouts. These results suggest that transvascular flow imparts a competing effect against bifurcating fluid flow and laminar shear stress in regulating endothelial sprouting. To our knowledge, these findings are the first report on the stabilizing role of bifurcating fluid flow on endothelial sprouting. These results also demonstrate the importance of local flow dynamics due to branched vessel geometry in determining the location of sprouting angiogenesis. -3-

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Section: Discussionmentioning

confidence: 62%

Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

Akbari

Spychalski

Rangharajan

et al. 2019

Preprint

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“…Besides the basic components required, the type of method or device used can have a large impact on the outcome of experiments. For instance, not having control over the interstitial flow can already result in different sprouting behaviour [21] or in false gradients [71]. Choosing a suitable system depends on the process and effect that is targeted in the research; a practical approach is to first generate an understanding of the in vivo process and deduct what the main factors are, as has been outlined in this review.…”

Section: Discussionmentioning

confidence: 99%

“…This also applies to branching as additional tip cells can emerge from an existing sprout [20]. The sprouts follow gradients of chemotactic factors like VEGF, Semaphorins, and Ephrins as well as physical forces from interstitial flow, strain, and matrix stiffness ( Figure 2B3) [9,11,16,18,[21][22][23][24]. During sprout formation, the inside of these sprouts open up, forming a lumen that can be perfused from the original vessel.…”

Section: Angiogenesismentioning

confidence: 99%

“…By loading the central gel chamber with endothelial cells, different gradients can be created either by adding growth factors to the medium channels or adding fibroblasts or other cell types in the side gel chambers. A similar chip design was used for investigating the effects of physical cues on sprouting; in this case, interstitial flow was generated that promoted sprouting against the direction of the flow [21]. These type of systems have also been used in the research on tumour vasculature and the effect of different drugs on the vasculature and tumour progression [75][76][77][78][79].…”

Section: Angiogenesis-based Platformsmentioning

confidence: 99%

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Recapitulating the Vasculature Using Organ-On-Chip Technology

Pollet

Toonder

2020

Bioengineering

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The development of Vasculature-on-Chip has progressed rapidly over the last decade and recently, a wealth of fabrication possibilities has emerged that can be used for engineering vessels on a chip. All these fabrication methods have their own advantages and disadvantages but, more importantly, the capability of recapitulating the in vivo vasculature differs greatly between them. The first part of this review discusses the biological background of the in vivo vasculature and all the associated processes. We then evaluate the biological relevance of different fabrication methods proposed for Vasculature-on-Chip, we indicate their possibilities and limitations, and we assess which fabrication methods are capable of recapitulating the intrinsic complexity of the vasculature. This review illustrates the complexity involved in developing in vitro vasculature and provides an overview of fabrication methods for Vasculature-on-Chip in relation to the biological relevance of such methods.

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“…Recently, several studies using microfluidic platform have been reported that recreate the 3D context of each aspect of the TME and metastasis in vitro. [10][11][12][13] However, to our knowledge, no versatile in vitro experimental model that reconstitutes direct interplay between constituents of the TME during tumorigenesis has yet been reported. Here we describe a biomimetic TME model to mimic the complex inter actions of the tumor, stromal, and endothe lial cells, all of which are essential components of the TME that hinder the effective treatment of cancers.…”

mentioning

confidence: 99%

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

Chung

Ahn

Son

et al. 2017

Adv Healthcare Materials

Self Cite

109

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COMMUNICATION (1 of 7)© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Biomimetic Model of Tumor Microenvironment on Microfluidic PlatformMinhwan Chung, Jungho Ahn, Kyungmin Son, Sudong Kim, and Noo Li Jeon* DOI: 10.1002/adhm.201700196 "cure." [4,5] The TME is a complex, inter acting system including the tumor itself, other noncancerous cell types such as immune, stromal and endothelial cells, and the extracellular matrix surrounding these cells. [6,7] This complexity has largely prevented a comprehensive understanding of TME in conventional in vitro models, which have been too simple to recapitulate the intricate interactions ( Figure 1A). [8,9] During recent decades, microfabrication technologies have been shown to be valu able tools in the exploration of tumor pro gression. Recently, several studies using microfluidic platform have been reported that recreate the 3D context of each aspect of the TME and metastasis in vitro. [10][11][12][13] However, to our knowledge, no versatile in vitro experimental model that reconstitutes direct interplay between constituents of the TME during tumorigenesis has yet been reported. Here we describe a biomimetic TME model to mimic the complex inter actions of the tumor, stromal, and endothe lial cells, all of which are essential components of the TME that hinder the effective treatment of cancers. [14][15][16] We used a micro fluidic platform from our previous studies. [17,18] Various effects of extracellular matrix (ECM) and the stroma on the physiology of tumor cells and angiogenesis were tested. Finally, we could mimic simultaneous angiogenesis and lymphangiogenesis in the TME with interactions between the tumor cells.Although the cancer stroma is well known for its many roles in multiple cancer stages, direct interactions between cancer and stromal cells have remained largely unknown. [19] Addition ally, cancer cell interaction with the ECM is another TME factor that regulates the behavior of the cancer cells and their resist ance to drugs. [20] Recently, in vitro activation of tumor stoma and corresponding ECM remodeling have been reported using a microfluidic platform. [21] However, single cell responses of the cancer cells in response to the stroma coculture and ECM composition has not yet been described. To examine cancer stromal cell interaction with a 3D ECM, we used a micro fluidic 3D cell culture platform previously reported from our group. [17,18] The array of microposts in the platform enabled straightforward micropatterning of the hydrogel which allowed flexible experimental configurations. We first cocultured cancer and stromal cells within fibrin gel in different microchannels, which still allowed the cells to interact with each other in a par acrine manner ( Figure 1B). Twice as many fibroblasts as cancer cells were patterned to exclude an autocrine or indirect effectThe "Tumor microenvironment" (TME) is a complex, interacting system of the tumor and its surrounding environment. The TME has drawn more attention recently in attempts to overcome current drug...

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Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model

Cited by 187 publications

References 49 publications

Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

Recapitulating the Vasculature Using Organ-On-Chip Technology

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

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