A driving force for change: interstitial flow as a morphoregulator

Rutkowski, Joseph M.; Swartz, Melody A.

doi:10.1016/j.tcb.2006.11.007

Cited by 265 publications

(224 citation statements)

References 60 publications

(54 reference statements)

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“…Although these experiments were conducted on a single cell type, we expect mechanotransduction of IF stresses to be a generally relevant mechanism that influences the morphology and function of cells expressing β1 integrins embedded within tissues experiencing IF (19), and we have found that flow induces polarization of vinculin for MCF10A breast epithelial cells and NIH 3T3 fibroblasts (SI Appendix, Fig. S5).…”

Section: Discussionmentioning

confidence: 99%

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Mechanotransduction of fluid stresses governs 3D cell migration

Polacheck

German

Mammoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

223

215

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Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 μm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK PY397 , F actin, and paxillindependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.mechanobiology | breast cancer | metastasis I ntegrins and associated focal adhesion (FA) proteins form a tension-sensitive mechanical link between the extracellular matrix (ECM) and the cytoskeleton, and serve as key components in the signaling cascade by which cells transduce mechanical signals into biological responses (mechanotransduction) (1, 2). Contractile stresses generated by the cell are balanced by tractions at cell-substrate adhesions, and the FA protein vinculin accumulates at regions of high substrate stress (3, 4). The FA protein paxillin colocalizes with vinculin (4) and mediates β1-integrin FA turnover through interaction with FA kinase (FAK) (5). The FAK-paxillin signaling axis recruits vinculin to β1 integrins at regions of high matrix adhesion tension (6), and paxillin-a key mechanosensor (7)-mediates protrusion formation at regions of high stress on 2D substrates (8), and FAK-paxillin-vinculin signaling is required for mechanosensing and durotaxis (9).The tumor microenvironment imparts mechanical and chemical signals on tumor and stromal cells (10), and advanced breast carcinomas are characterized by high interstitial fluid pressure (11), an indicator of poor prognosis (12). This elevated fluid pressure drives interstitial flow (IF) and alters chemical transport within the tumor (13), and IF influences tumor cell migration through the generation of autocrine chemokine gradients (14). Equally important, although not as well understood, is the physical drag imparted on the ECM and constitutive cells (15) by IF, which is analogous to the FA-activating shear stresses generated on endothelial cells by hemodynamic forces (16). With endothelial cells, shear stress can be the dominant mechanical stimulus that induces FAK activation and cytoskeletal remodeling; however, for cells embedded within a porous matrix scaffold, the ratio of the force due to the pressure drop across the cell to the total shear force is inversely proportional to hydrogel p...

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Section: Discussionmentioning

confidence: 99%

“…Importantly, silencing paxillin does not affect cell migration speed but does attenuate rheotaxis. IF is present in many tissues in vivo (19), and because FA polarization and rheotaxis result from a mechanical force balance, this 3D mechanotransduction mechanism may be fundamental to all cells embedded within porous ECM.…”

mentioning

confidence: 99%

Mechanotransduction of fluid stresses governs 3D cell migration

Polacheck

German

Mammoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

223

215

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“…According to the results, the described device generated shear stresses spanning over at least four orders of magnitude (0.007-15.4 dyne/cm 2 ). This range of shear stresses started from an extremely low level comparable to interstitial shear stress level (Park et al 2009;Chen et al 2012;Rutkowski and Swartz 2007) to a high level which was deemed to be injurious for chondrocytes (Lee et al 2003; Healy et al 2005;Zhu et al 2010b). It also had a broader scope than previous methods and had the advantage of controlling stimulus intensity in a particular range.…”

Section: Discussionmentioning

confidence: 99%

“…Chondrocyte metabolism and nutrient transport are regulated by the interstitial fluid through dynamic compression that drives flow through the matrix in vivo (Swartz and Fleury 2007). Because water makes up approximately 70-85 % of cartilage weight, accordingly interstitial flow always exists in cartilage tissues undergoing dynamic compression, imparting extremely low shear stress on the cell surface (Rutkowski and Swartz 2007). It has also been reported that the superficial and transitional zones of articular cartilage are remarkably exposed to fluid flow stimulus (Zhu et al 2010b).…”

Section: Introductionmentioning

confidence: 99%

An integrated microfluidic device for characterizing chondrocyte metabolism in response to distinct levels of fluid flow stimulus

Zhong

Wang

et al. 2013

Microfluid Nanofluid

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In this work, we presented a novel integrated microfluidic perfusion system to generate multiple parameter fluid flow-induced shear stresses simultaneously and investigated the effects of distinct levels of fluid flow stimulus on the responses of chondrocytes, including the changes of morphology and metabolism. Based on the electric circuit analogy, two devices were fabricated, each with four chambers to enable eight different shear stresses spanning over four orders of magnitude from 0.007 to 15.4 dyne/cm 2 with computational fluid dynamics analysis. Chondrocytes subjected to shear stresses (7.5 and 15.4 dyne/cm 2 ) for 24 h reoriented their cytoskeleton to align with the direction of flow. Meanwhile, the collagen I, collagen II and aggrecan expression of chondrocytes increased in different ranges, respectively. Furthermore, interleukin-6 as a proinflammatory cytokine can be detected at shear stress of 7.5 and 15.4 dyne/cm 2 in mRNA level. These results indicated that fluid flow was beneficial for chondrocyte metabolism at interstitial levels (0.007 and 0.046 dyne/cm 2 ), but induced an increase in fibrocartilage phenotype with increasing magnitude of stimulation. Moreover, a moderate level of flow stimulus (7.5 dyne/ cm 2 ) could also result in detrimental cytokine release. This work described a simple and versatile way to rapidly screen cell responses to fluid flow stimulus from interstitial shear stress level to pathological level, providing multi-condition fluid flow-induced microenvironment in vitro for understanding deeply chondrocyte metabolism, cartilage reconstruction and osteoarthritis etiology.

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“…The interstitial fluid flow associated with edema, even though it can be extremely slow, can have important effects on tissue morphogenesis and function, cell migration and differentiation and matrix remodeling, among other processes [108]. Abnormally increased interstitial flow rates can occur during low-grade inflammation and can also trigger fibroblasts to differentiate or remodel the extracellular matrix, contributing thus to the development of tissue fibrosis [107,[109][110][111][112].…”

Section: Splanchnic Interstitium Mesenteric Lymphatics and Peritoneamentioning

confidence: 99%

Portal hypertension-related inflammatory phenotypes: From a vitelline and amniotic point of view

Aller¹,

Arias²,

Prieto³

et al. 2012

ABB

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Prehepatic portal hypertension induces a splanchnic low-grade inflammatory response that could switch to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease. The extraembryonic origin of the portal system maybe determines the regression to an extraembryonic phenotype, i.e., vitellogenic and amniotic, during the evolution of both types of portal hypertension. Thus, prehepatic portal hypertension, or compensated hypertension by portal vein ligation in the rat, is associated with molecular mechanisms related to vitellogenesis, where hepatic steatosis and splanchnic angiogenesis stand out. In turn, extrahepatic cholestasis in the rat induces intrahepatic portal hypertension, or decompensated hypertension, with ascites and hepatorenal syndrome. The splanchnic interstitium, the mesenteric lymphatic system, and the peritoneal mesothelium seem to create an inflammatory pathway that could have a key pathophysiological relevance in the production of ascites. The hypothetical comparison between the ascitic and the amniotic fluid also allows for translational investtigation. The induced regression of the splanchnic system to extraembryonic functions by portal hypertension highlights the great relevance of the extraembryonic structures even during post-natal life.

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A driving force for change: interstitial flow as a morphoregulator

Cited by 265 publications

References 60 publications

Mechanotransduction of fluid stresses governs 3D cell migration

Mechanotransduction of fluid stresses governs 3D cell migration

An integrated microfluidic device for characterizing chondrocyte metabolism in response to distinct levels of fluid flow stimulus

Portal hypertension-related inflammatory phenotypes: From a vitelline and amniotic point of view

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