Fluid flow-induced shear stress controls the metabolism of proximal tubule kidney epithelial cells through primary cilium-dependent lipophagy and mitochondria biogenesis.

Miceli, Caterina; Roccio, Federica; Penalva-Mousset, Lucille; Morel, Étienne; Codogno, Patrice; Dupont, Nicolas

doi:10.1080/15548627.2020.1823125

Cited by 7 publications

(5 citation statements)

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“…This observation agrees with several studies reporting increased mitochondrial biogenesis in vivo in response to fluid shear stress. [ 64 ] Mitochondrial function is a very important aspect of intestinal cell differentiation and function as well as intestinal homeostasis. [ 65 ] The increased transcytotic potential of cells cultured in the IOC might be linked to this increased mitochondrial activity and this question warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Capturing and Quantifying Particle Transcytosis with Microphysiological Intestine‐on‐Chip Models

et al. 2022

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gens, and exclusion of microbiota and exogenous hazards including bacteria. The ability of intestinal epithelial cells to actively transcytose nano-and micronsized particles has long been established, but the mechanisms and extent to which this process occurs in healthy intestinal tissues have been the object of significant discussion. [1] Specialized epithelial Microfold (M) cells located in the gut associated lymphoid tissue (GALT) have high particle transcytotic capabilities. [2] In addition to their role in shaping intestinal immune homeostasis, M cells have been postulated to play a key role in particle transport. However, they represent <1% of the cellular population in the human small intestine and while M cells may contribute to particle transport across the intestinal epithelium, several studies have shown that they are not essential to particle transport. [3][4][5] Conversely, there is strong evidence that nano-and micro-particles are efficiently transported across enterocytes in villi within the small intestine. [1,[6][7][8] For example, Reineke et al. conclusively demonstrated in a rat model that nonphagocytic processes are key to the absorption of nano-and even micro-particles in the small intestine and, consequently, to their systemic bioavailability. [1] These studies refute the view that enterocyte transcytosis is a neglectable process in the small Understanding the intestinal transport of particles is critical in several fields ranging from optimizing drug delivery systems to capturing health risks from the increased presence of nano-and micro-sized particles in human environment. While Caco-2 cell monolayers grown on permeable supports are the traditional in vitro model used to probe intestinal absorption of dissolved molecules, they fail to recapitulate the transcytotic activity of polarized enterocytes. Here, an intestine-on-chip model is combined with in silico modeling to demonstrate that the rate of particle transcytosis is ≈350× higher across Caco-2 cell monolayers exposed to fluid shear stress compared to Caco-2 cells in standard "static" configuration. This relates to profound phenotypical alterations and highly polarized state of cells grown under mechanical stimulation and it is shown that transcytosis in the microphysiological model is energy-dependent and involves both clathrin and macropinocytosis mediated endocytic pathways. Finally, it is demonstrated that the increased rate of transcytosis through cells exposed to flow is explained by a higher rate of internal particle transport (i.e., vesicular cellular trafficking and basolateral exocytosis), rather than a change in apical uptake (i.e., binding and endocytosis). Taken together, the findings have important implications for addressing research questions concerning intestinal transport of engineered and environmental particles.

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Section: Discussionmentioning

confidence: 99%

Capturing and Quantifying Particle Transcytosis with Microphysiological Intestine‐on‐Chip Models

et al. 2022

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“…23 Under shear flow, the induced signaling cascades implicated in anti-oxidation, mitochondrial biogenesis, mitophagy, and metabolic homeostasis were widely discussed. 24,25 Currently, the effect of shear flow on the mitochondrial function of cancer cells was only reported for breast cancer by Park et al 12 How shear flow affects the mitochondrial function and leads to the altered characteristics in CRC cells was proposed herein.…”

Section: Introductionmentioning

confidence: 93%

Mechanical shear flow regulates the malignancy of colorectal cancer cells

Tseng,

Tsai,

Chen

et al. 2024

The Kaohsiung J of Med Scie

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Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm2 for 1 and 2 h separately. Resulting elevated caspase‐9 and ‐3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G1 phase. An elevated phosphor‐eNOSS1177 increased the production of nitric oxide and led to reactive oxygen species‐mediated oxidative stress. Shear flow also regulated epithelial–mesenchymal transition (EMT) by increasing E‐cadherin and ZO‐1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm2, the expressions of EMT were compared at lower (6.25 dynes/cm2) and at higher (25 dynes/cm2) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.

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“…Moreover, in KECs fluid flow stimulates AMPK-mediated mitochondrial biogenesis as assessed by the increased levels of mitochondrial proteins and DNA, and these flow-induced processes are dependent on primary cilia ( Figure 4B ). Finally, the concomitant cilia-dependent lipophagy and mitochondrial biogenesis contribute to ATP production, which is required to support energy-consuming cellular processes such as glucose reabsorption, gluconeogenesis and cytoskeletal remodeling in renal epithelial cells, demonstrating that the primary cilium, autophagy and mitochondrial metabolism are strictly interconnected ( Figure 4B ) [ 69 , 70 ].…”

Section: Novel Players In the Cilia-autophagy Game: Lysosomes And Mit...mentioning

confidence: 99%

Crosstalk between cilia and autophagy: implication for human diseases

et al. 2022

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Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders.

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Fluid flow-induced shear stress controls the metabolism of proximal tubule kidney epithelial cells through primary cilium-dependent lipophagy and mitochondria biogenesis.

Cited by 7 publications

References 1 publication

Capturing and Quantifying Particle Transcytosis with Microphysiological Intestine‐on‐Chip Models

Capturing and Quantifying Particle Transcytosis with Microphysiological Intestine‐on‐Chip Models

Mechanical shear flow regulates the malignancy of colorectal cancer cells

Crosstalk between cilia and autophagy: implication for human diseases

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