Chapter 24 - Reconstitution of the kidney glomerular capillary wall

Abstract

Podocytes play an important role in maintaining the function of the glomerulus, and their loss or dysfunction contribute to the initiation and progression of kidney disease. The tissue interface consisting of podocytes and fenestrated endothelial cells constitute the kidney’s glomerular capillary wall, which is the primary site for blood filtration. The development of in vitro models that can closely recapitulate the structure and function of the glomerulus can help advance current understanding of the mechanisms of organ development and disease progression and facilitate therapeutic development. Induced pluripotent stem (iPS) cells are an attractive source of specialized cells for the development of patient-specific in vitro models owing to their remarkable ability to self-renew indefinitely and differentiate into almost any cell type when provided appropriate cues. Additionally, microfluidic devices provide a dynamic tissue culture environment for reconstituting glomerular tissue-tissue interface. In this chapter, we first provide an overview of some of the essential features that an engineered microphysiological system must possess in order to accurately model the glomerular capillary wall in vitro. We also present some of the challenges that must be addressed when integrating stem cell biology with microengineered systems including organ-on-a-chip devices. We then present our method for directing the differentiation of human iPS cells into functional podocytes with characteristics associated with the mature phenotype. Furthermore, we describe integration of the stem cell-derived podocytes into endothelium-lined microfluidic organ-on-a-chip device to reconstitute the structure and function of the kidney glomerulus. We highlight application of this organ engineering strategy to study the roles of mechanical forces and the role of podocyte-endothelium interface in tissue development and function, as well as modeling of disease phenotypes. Finally, we highlight some engineering approaches that could help progress toward regenerative medicine, disease modeling, toxicity testing, and drug discovery using organ-on-a-chip microphysiological systems.