Biophysics and biofluid dynamics of primary cilia: evidence for and against the flow-sensing function

Primary cilia have been called “the forgotten organelle” for over 20 yr. As cilia now have their own journal and several books devoted to their study, perhaps it is time to reconsider the moniker “forgotten organelle.” In fact, during the drafting of this review, 12 relevant publications have been issued; we therefore apologize in advance for any relevant work we inadvertently omitted. What purpose is yet another ciliary review? The primary goal of this review is to specifically examine the evidence for and against the hypothesized flow-sensing function of primary cilia expressed by differentiated epithelia within a kidney tubule, bringing together differing disciplines and their respective conceptual and experimental approaches. We will show that understanding the biophysics/biomechanics of primary cilia provides essential information for understanding any potential role of ciliary function in disease. We will summarize experimental and mathematical models used to characterize renal fluid flow and incident force on primary cilia and to characterize the mechanical response of cilia to an externally applied force and discuss possible ciliary-mediated cell signaling pathways triggered by flow. Throughout, we stress the importance of separating the effects of fluid shear and stretch from the action of hydrodynamic drag.

In Vivo Hemodynamic Performance of Wild-Type vs. Mutant Zebrafish Embryos Using High-Speed Confocal Micro-PIV

In developing cardiovascular systems, definite performance comparison between disease and healthy hemodynamics requires quantitative tools to support advanced microscopy. Mutations in the activin receptor-like kinase 1 (ALK1) gene are responsible for the autosomal dominant vascular disease, hereditary hemorrhagic telangiectasia type 2 (HHT2), characterized by high flow arteriovenous malformations (AVMs) [1]. Recent studies show that the zebrafish mutant violet beauregrade (vbg), which harbors a mutation in alk1, develops an abnormal circulation with dilated cranial vessels and AVMs [2]. Quantitative understanding of mechanical influences on the alk1 mutant phenotype will aid treatment of HHT2 patients. Inspired by earlier studies that demonstrate the capability of using confocal micro-PIV technique to quantify biofluid dynamics in vivo [3], primarily in major vessels (dorsal aorta, vitelline veins), the present study focused on secondary branching great vessels of zebrafish embryos where microcirculation flow regimes are different. Furthermore, confocal microscopy, essentially being an imaging modality, requires rigorous validation efforts with respect to the gold standard measurement protocols (such as PIV) and synthetic scan data. Another objective of this work was to document the intra-species differences of wall shear stress (WSS) and flow physics during embryonic development in aortic arch systems of zebrafish [4].