The multifaceted role of aquaporins in physiological cell migration

Abstract

Cell migration is an essential process that underlies many physiological processes, including the immune response, organogenesis in the embryo, and angiogenesis, as well as pathological processes such as cancer metastasis. Cells have at their disposal a variety of migratory behaviors and mechanisms that seem to be specific to cell type and the microenvironment. Research over the past two decades has elucidated the water channel protein family of aquaporins (AQPs) as a regulator of many cell migration-related processes, from physical phenomena to biological signaling pathways. The roles that AQPs play in cell migration are both cell type- and isoform-specific; thus, a large swath of information has accumulated as researchers seek to identify the responses across these distinct variables. There does not seem to be a universal role that AQPs play in cell migration; the complex interplay between AQPs and cell volume management, signaling pathway activation, and in a few identified circumstances, gene expression regulation, has shown the intricate, and perhaps paradoxical, role of AQPs in cell migration. The objective of this review is to provide an organized and integrated collection of recent work that has elucidated the many mechanisms by which AQPs regulate cell migration.NEW & NOTEWORTHY Research has elucidated the water channel protein family of aquaporins (AQPs) as a regulator of many cell migration-related processes, from physical phenomena to biological signaling pathways. The roles that AQPs play in cell migration are both cell type- and isoform-specific; thus, a large swath of information has accumulated as researchers seek to identify the responses across these distinct variables. This review compiles insights into the recent findings linking AQPs to physiological cell migration.

Keywords: actin polymerization; aquaporins; cell adhesion; cell migration; ion channels.

Graphical abstract

Figure 1.

An overview of AQP isoforms found in various migratory cell types in healthy (A) and pathological contexts (B). AQP, aquaporin. Figure was created using BioRender.com.

Figure 2.

Timeline detailing important milestones discovered to enhance the field’s understanding regarding the roles AQPs play in cell migration. AQP, aquaporin. Figure was created using BioRender.com.

Figure 3.

AQP colocalization with migratory-related proteins and downstream signaling. Putative pathways are determined via direct localization or activation of proteins via AQPs or the signals they transport. The speculated downstream pathways have been altered by AQP inhibition or knockdown, yet the direct relationship is not yet defined. AQP, aquaporin. Figure was created using BioRender.com.

Figure 4.

A graphical representation of the osmotic engine model. A cell is migrating in a confining channel and uses fluxes (J) of ions and water at the front and back of the cell to propel itself forward. The proteins below the fluxes have been implicated in the movement of water or ions at the front or back of the confined cell. AQP, aquaporin. Figure was created using BioRender.com.

Figure 5.

AQPs and immune cell responses in contact hypersensitivity models. A: AQP9 regulates neutrophil function: AQP9 regulates numerous steps in the chemoattractant-based migration toward a site of tissue damage. Though not yet determined, we hypothesize that AQP9 can regulate neutrophil transendothelial migration, including the process of cell rolling and extravasation. B: AQP3 regulates CD4+ T-cell function: AQP3 induces activation, transendothelial migration, and chemokine-induced migration for CD4+ T-cells. C: AQP7 regulates dendritic cell function: AQP7 induces DC chemotactic migration specifically toward (CCL21 and CXCL12), antigen uptake, and accumulation in LNs following activation. Though it is not yet determined, we hypothesize that AQP7 may also play a role in DC activation, presentation of uptaken antigens, and migration from the site of inflammation into the lymphatic system. AQP, aquaporin. Figure was created using BioRender.com.

Figure 6.

AQPs as a regulators of macrophage activation and cell migration. A: following knock out of AQP1, there is an enhanced M0 to M2 transition, resulting in increased M2 migration. Macrophages are still capable of making the transition while expressing AQP1, yet there is a dramatic change in activation following knockout. The researchers originally believed this inhibitory effect was the cause of high M0 membrane tension closing AQP1s water permeability. This, however, was uninvestigated and does not provide relevant insight into the actual mechanism of inhibition. B: following macrophage M1 activation, AQP1 will regulate the transition to M2 state by activation of various signaling pathways, though the actual mechanisms by which AQP regulates these pathways and how they initiate the transition remain unknown. C: finally, in M1 stimulated macrophages, AQP1 plays a conventional role in cell migration: following its knockout, the cells move slower. Solid arrows represent a transition between activated states, dashed arrows represent cell migration. AQP, aquaporin; WT, wild type. Figure was created using BioRender.com.