Towards Modelling Genetic Kidney Diseases with Human Pluripotent Stem Cells

Abstract

<b><i>Background:</i></b> Kidney disease causes major suffering and premature mortality worldwide. With no cure for kidney failure currently available, and with limited options for treatment, there is an urgent need to develop effective pharmaceutical interventions to slow or prevent kidney disease progression. <b><i>Summary:</i></b> In this review, we consider the feasibility of using human pluripotent stem cell-derived kidney tissues, or organoids, to model genetic kidney disease. Notable successes have been made in modelling genetic tubular diseases (e.g., cystinosis), polycystic kidney disease, and medullary cystic kidney disease. Organoid models have also been used to test novel therapies that ameliorate aberrant cell biology. Some progress has been made in modelling congenital glomerular disease, even though glomeruli within organoids are developmentally immature. Less progress has been made in modelling structural kidney malformations, perhaps because sufficiently mature metanephric mesenchyme-derived nephrons, ureteric bud-derived branching collecting ducts, and a prominent stromal cell population are not generated together within a single protocol. <b><i>Key Messages:</i></b> We predict that the field will advance significantly if organoids can be generated with a full complement of cell lineages and with kidney components displaying key physiological functions, such as glomerular filtration. The future economic upscaling of reproducible organoid generation will facilitate more widespread research applications, including the potential therapeutic application of these stem cell-based technologies.

Kidney organoids recapitulate human basement membrane assembly in health and disease

“…A key finding from this study is that organoids form BMs early during differentiation, and more importantly, recapitulate a sequence of assembly events with initial deposition of laminin followed by incorporation of collagen IV, nidogen and perlecan (Brown et al, 2017;Sasaki et al, 2004). Kidney organoids have also provided new insights into disease processes (Rooney et al, 2021;Tanigawa et al, 2018;Tian and Lennon, 2019). We found that organoids with a pathological missense variant in COL4A5 differentiated and deposited core BM proteins, including a collagen IV 345 network, which is described in missense variants.…”

Kidney organoids: A system to study human basement membrane assembly in health and disease

“…We discovered that organoids form BMs early during differentiation, and more importantly, recapitulate a sequence of assembly events with initial deposition of laminin followed by incorporation of type IV collagen, nidogen and perlecan (Brown et al, 2017;Sasaki et al, 2004). Kidney organoids have also provided new insights into developmental programmes and disease processes (Rooney et al, 2021;Tanigawa et al, 2018;Tian and Lennon, 2019). We found that organoids with a pathological missense variant in COL4A5 differentiated and deposited core BM proteins, including a collagen 345 network, which is described in missense variants.…”

Building human renal tracts

“…In addition, they have the potential to differentiate into the three germ layers (mesoderm, endoderm and ectoderm) of the early embryo and thus form all organs. As recently reviewed [ 6 , 7 ] and depicted in Fig. 1 , there are two sources of PSCs for research studies.…”

“…Moreover, other types of molecule, especially transcription factors and extracellular matrix proteins, were found to be expressed by the developing kidney and were essential for its normal development [13] . Of note, the genes encoding several of these molecules have been found to be mutated in individuals with congenital kidney disease [7] . The UB and MM themselves each originate from separate compartments within the intermediate mesoderm [14] , that itself has formed during gastulation, the name of the event when the three germ layers form early on in embryogenesis.…”

“…In the last decade, as reviewed [ 6 , 7 ], several laboratories around the world have published protocols in which human PSC can be driven by sequential addition of specific growth factors and other chemicals to form kidney like tissues in 2D and in 3D, or organoid, culture ( Fig. 1 ).…”