A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells

Abstract

Recent studies using human pluripotent stem cells (hPSCs) have developed protocols to induce kidney-lineage cells and reconstruct kidney organoids. However, the separate generation of metanephric nephron progenitors (NPs), mesonephric NPs, and ureteric bud (UB) cells, which constitute embryonic kidneys, in in vitro differentiation culture systems has not been fully investigated. Here, we create a culture system in which these mesoderm-like cell types and paraxial and lateral plate mesoderm-like cells are separately generated from hPSCs. We recapitulate nephrogenic niches from separately induced metanephric NP-like and UB-like cells, which are subsequently differentiated into glomeruli, renal tubules, and collecting ducts in vitro and further vascularized in vivo. Our selective differentiation protocols should contribute to understanding the mechanisms underlying human kidney development and disease and also supply cell sources for regenerative therapies.

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

“…Human PSCs can be differentiated into ureteric epithelium or metanephric and mesonephric mesenchyme in vitro that recapitulates embryonic kidney ( Taguchi and Nishinakamura, 2017 ; Taguchi et al., 2014 ; Takasato et al., 2014 , 2015 ), or even generate kidney organoids from epiblast spheroids ( Freedman et al., 2015 ; Morizane et al., 2015 ). One of the major feats of kidney-like organoids from PSCs is its incredible ability to vascularize into glomerulus-like structures with interconnecting renal tubules and collecting ducts ( Bantounas et al., 2018 ; van den Berg et al., 2018 ; Sharmin et al., 2016 ; Tsujimoto et al., 2020 ). A reproducible and a scalable 3D organoid culture strategy is developed that supports vascularization in an animal model and therefore brings great promise to regenerative medicine ( Koike et al., 2019 ; Takebe et al., 2015 ).…”

Xeno‐regenerative medicine: A novel concept for donor kidney fabrication

“…4 Recently, researchers reported the development of ureteric bud, a tree-like structure of nephron, from iPS cells by culturing them with NPCs. 5,6 The resulting organoid established from iPS cells may produce urine as it has been shown to filter host blood following transplantation. 6 However, at present, organoids can only grow up to 1-2 mm, and hence, further studies are required before their clinical use in humans.…”

“…Morizane et al reported that they have successfully developed functional iPS cell–derived nephrons, which responded to the markers of tubular damage that were secreted upon administration of cisplatin 4 . Recently, researchers reported the development of ureteric bud, a tree‐like structure of nephron, from iPS cells by culturing them with NPCs 5,6 . The resulting organoid established from iPS cells may produce urine as it has been shown to filter host blood following transplantation 6 .…”

Development of pluripotent stem cell‐based human tenocytes

“…(2016) have demonstrated that Wnt‐ON/Bmp‐OFF induces the differentiation of primitive streak cells into TBX6 + paraxial mesoderm, whereas Wnt‐OFF/Bmp‐ON guides them to ISL1 + lateral plate mesoderm Tsujimoto et al. (2020) reported that Wnt‐ON/Bmp‐ON contributes to OSR1 + intermediate mesoderm differentiation from CDX1 + epiblast cells. These findings indicate that the lineage choices of PSCs during early mesoderm development in vitro, such as paraxial mesoderm versus lateral plate mesoderm and paraxial mesoderm versus intermediate mesoderm, is determined by the balance of Wnt and Bmp signals (Figure 2).…”