Responses of endothelial cells to extremely slow flows

Park, Joong Yull; White, Joshua B.; Walker, Neff; Kuo, Cheng Ling; Cha, Wol-Suk; Meyerhoff, Mark E.; Takayama, Shuichi

doi:10.1063/1.3576932

Cited by 42 publications

(44 citation statements)

References 33 publications

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“…Once astrocytes were infused and grown to confluence on 3D ECM gels, endothelial cells were introduced and allowed to attach to the astrocytes forming a continuous cell layer on the ECM with direct cell-cell contact. The co-cultured cells were exposed to a controlled low flow through the vascular channel (0.1 dyne/cm 2 )31, mimicking the capillary flow in the brain. Under this condition, the BMECs were grown to form intact barrier in the dynamic co-culture with astrocytes on the surface of 3D ECM after 48 h. These cells remained viable for one week after flow was introduced into the vascular microchannels.…”

Section: Resultsmentioning

confidence: 99%

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A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

et al. 2016

Sci Rep

168

157

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The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes–permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

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Section: Resultsmentioning

confidence: 99%

“…Extremely low fluidic flow was applied to the medium channels to mimic the blood flow in the microvessels as described previously3146. The microdevice was perfused at a flow velocity at about 20 μL/min following cell seeding, and then the flow velocity in the medium channel was decreased to ~1 μL/min due to the split flow of the chip.…”

Section: Methodsmentioning

confidence: 99%

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

et al. 2016

Sci Rep

168

157

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“…Such extremely low shear stress (<0.1 dyne/cm 2 ) can not only provide physiological microenvironment but also correlate with tissue morphogenesis and pathogenesis. 15,16 Although interstitial flow in bone has been reported elsewhere; 17 however, the mechano-responsive behaviors of MSCs in response to extremely low interstitial level of fluidic flow and the mechanism behind these phenomena are still elusive.…”

Section: Regulation Of Cell Migration and Osteogenic Differentiationmentioning

confidence: 98%

Regulation of cell migration and osteogenic differentiation in mesenchymal stem cells under extremely low fluidic shear stress

Gao

Zhang

et al. 2014

Biomicrofluidics

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Mesenchymal stem cells (MSCs) are multipotent stem cells predominantly obtained from bone marrow, which are sensitive to mechanical loadings in physiological microenvironment. However, how the MSCs sense and respond to extremely low fluidic shear stress analogous to interstitial flow in vivo is poorly understood. In this work, we present a functional microfluidic device to examine the migration and differentiation behaviors of MSCs in response to multiple orders of physiologically relevant interstitial flow levels. The different magnitudes of fluid flow-induced shear stress were produced by a hydraulic resistance-based microfluidic perfusion system consisting of a microchannel network and a parallel of uniform cell culture chambers. By changing the length and width of the flow-in channels, the multiple magnitudes of low shear stresses could be generated ranging from ∼10−5 to ∼10−2 dyne/cm2. We demonstrated enhanced significant F-actin expression and cell migration in MSCs under applied fluidic shear stress at ∼10−2 dyne/cm2. We also demonstrated a significant osteogenic differentiation under this interstitial level of slow flows from ∼10−2 to ∼10−4 dyne/cm2 in MSCs by analyzing alkaline phosphatase activity and osteopontin staining. Moreover, cytochalasin D and Rho-inhibitor Y-27632 significantly reduced the cytoskeleton F-actin expression and osteogenic differentiation in MSCs, indicating the mediated mechanical responses of MSCs under extremely low fluidic shear stress, possibly as a consequence of Rho-associated kinase pathway. The established microfluidic perfusion system with multiple shear-flow capabilities is simple and easy to operate, providing a flexible platform for studying the responses of diverse types of cells to the multiple interstitial flow levels in a single assay.

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“…Past studies with flow have indicated that endothelial cells gradually orient and elongate along the direction of fluid flow under uniform shear stress, as evidenced by rapid inclination of cell junctions along the flow, and gradual reorganization of the cytoskeleton, especially with peripheral actin stress fiber formation [25-28]. Such reorientation may benefit the cells by altering the stress profile over the cell surface, by enhancing communication pathways for the conveyance of shearing-induced intracellular molecules, or potentially by improving cell-cell connections and flexibility in the context of a vascular monolayer [20,24,28-32].…”

Section: Introductionmentioning

confidence: 99%

Shear- vs. nanotopography-guided control of growth of endothelial cells on RGD-nanoparticle-nanowell arrays

et al. 2013

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Endothelialization of therapeutic cardiovascular implants is essential for their intravascular hemocompatibility. We previously described a novel nanowell-RGD-nanoparticle ensemble, which when applied to surfaces led to enhanced endothelialization and retention under static conditions and low flow rates. In the present study we extend our work to determine the interrelated effects of flow rate and the orientation of ensemble-decorated surface arrays on the growth, adhesion and morphology of endothelial cells. Human umbilical vascular endothelial cells (HUVECs) were grown on array surfaces with either 1 μm × 5 μm spacing (“parallel to flow”) and 5 μm × 1 μm spacing (“perpendicular to flow”) and were exposed to a range of shear stress of (0 to 4.7 ± 0.2 dyn·cm-2 ), utilizing a pulsatile flow chamber. Under physiological flow (4.7 ± 0.2 dyn·cm-2), RGD-nanoparticle-nanowell array patterning significantly enhanced cell adhesion and spreading compared with control surfaces and with static conditions. Furthermore, improved adhesion coincided with higher alignment to surface patterning, intimating the importance of interaction and response to the array surface as a means of resisting flow detachment. Under sub-physiological condition (1.7 ± 0.3 dyn·cm-2; corresponding to early angiogenesis), nanowell-nanoparticle patterning did not provide enhanced cell growth and adhesion compared with control surfaces. However, it revealed increased alignment along the direction of flow, rather than the direction of the pattern, thus potentially indicating a threshold for cell guidance and related retention. These results could provide a cue for controlling cell growth and alignment under varying physiological conditions.

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Responses of endothelial cells to extremely slow flows

Cited by 42 publications

References 33 publications

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

Regulation of cell migration and osteogenic differentiation in mesenchymal stem cells under extremely low fluidic shear stress

Shear- vs. nanotopography-guided control of growth of endothelial cells on RGD-nanoparticle-nanowell arrays

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