AUTHOR=El-Achkar Tarek M. , Winfree Seth , Talukder Niloy , Barwinska Daria , Ferkowicz Michael J. , Al Hasan Mohammad TITLE=Tissue Cytometry With Machine Learning in Kidney: From Small Specimens to Big Data JOURNAL=Frontiers in Physiology VOLUME=Volume 13 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.832457 DOI=10.3389/fphys.2022.832457 ISSN=1664-042X ABSTRACT=Advances in cellular and molecular interrogation of kidney tissue have ushered a new era of understanding the pathogenesis of kidney disease and potentially identifying molecular targets for therapeutic intervention. Classifying cells in situ and identifying subtypes and states induced by injury is a foundational task in this context. High resolution Imaging-based approaches such as large-scale fluorescence 3D imaging offer significant advantages because they allow preservation of tissue architecture and provide a definition of the spatial context of each cell. We recently described the Volumetric Tissue Exploration and Analysis cytometry tool which enables an interactive analysis, quantitation and semi-automated classification of labeled cells in 3D image volumes. We also established and demonstrated an imaging-based classification using deep learning of cells in intact tissue using 3D nuclear staining with 4′,6-diamidino-2-phenylindole (DAPI). In this mini-review, we will discuss recent advancements in analyzing 3D imaging of kidney tissue, and how combining machine learning with cytometry is a powerful approach to leverage the depth of content provided by high resolution imaging into a highly informative analytical output. Therefore, imaging a small tissue specimen will yield big scale data that will enable cell classification in a spatial context and provide novel insights on pathological changes induced by kidney disease.