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The structural-functional hallmark of the liver sinusoidal endothelium is the presence of fenestrae grouped in sieve plates. Fenestrae are open membrane bound pores supported by a (sub)membranous cytoskeletal lattice. Changes in number and diameter of fenestrae alter bidirectional transport between the sinusoidal blood and the hepatocytes. Their physiological relevance has been shown in different liver disease models. Although the structural organization of fenestrae has been well documented using different electron microscopy approaches, the dynamic nature of those pores remained an enigma until the recent developments in the research field of four dimensional (4-D) AFM. In this contribution we highlight how AFM as a biophysical nanocharacterization tool enhanced our understanding in the dynamic behaviour of liver sinusoidal endothelial fenestrae. Different AFM probing approaches, including spectroscopy, enabled mapping of topography and nanomechanical properties at unprecedented resolution under live cell imaging conditions. This dynamic biophysical characterization approach provided us with novel information on the ‘short’ life-span, formation, disappearance and closure of hepatic fenestrae. These observations are briefly reviewed against the existing literature. Electronic supplementary material The online version of this article (10.1007/s12551-020-00699-0) contains supplementary material, which is available to authorized users.

With the arrival of atomic force microscopy (AFM) about thirty years ago, this new imaging tool opened up a new area for the exploration of biological samples, ranging from the tissue and cellular level down to the supramolecular scale. Commercial instruments of this new imaging technique began to appear in the five years following its discovery in 1986 by Binnig, Quate & Gerber. From that point onwards the AFM has attracted many liver biologists, and the number of publications describing structure-function relationships on the diverse set of liver cells has grown steadily ever since. It is therefore timely to reflect on the achievements of AFM in disclosing the cellular architecture of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, stellate cells and liver-associated natural killer cells. In this thematic paper, we present new data and provide an in-depth overview of the current AFM literature on liver cell biology. We furthermore include a future outlook on how this scanning probe imaging tool and its latest developments can contribute to clarify various structural and functional aspects of cells in liver health and disease. (c) 2017 Elsevier Ltd. All rights reserved.

With the arrival of atomic force microscopy (AFM) about thirty years ago, this new imaging tool opened up a new area for the exploration of biological samples, ranging from the tissue and cellular level down to the supramolecular scale. Commercial instruments of this new imaging technique began to appear in the five years following its discovery in 1986 by Binnig, Quate & Gerber. From that point onwards the AFM has attracted many liver biologists, and the number of publications describing structure-function relationships on the diverse set of liver cells has grown steadily ever since. It is therefore timely to reflect on the achievements of AFM in disclosing the cellular architecture of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, stellate cells and liver-associated natural killer cells. In this thematic paper, we present new data and provide an in-depth overview of the current AFM literature on liver cell biology. We furthermore include a future outlook on how this scanning probe imaging tool and its latest developments can contribute to clarify various structural and functional aspects of cells in liver health and disease. (c) 2017 Elsevier Ltd. All rights reserved.