Redefining the In Vivo Origin of Metanephric Nephron Progenitors Enables Generation of Complex Kidney Structures from Pluripotent Stem Cells

• Published in: Cell stem cell 2014-01, Vol.14 (1), p.53-67
• Main Authors: Taguchi, Atsuhiro, Kaku, Yusuke, Ohmori, Tomoko, Sharmin, Sazia, Ogawa, Minetaro, Sasaki, Hiroshi, Nishinakamura, Ryuichi
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Cell Differentiation; Cells, Cultured; Colony-Forming Units Assay; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Humans; Immunoblotting; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Kidney - chemistry; Kidney - cytology; Kidney - metabolism; Mesoderm - cytology; Mesoderm - metabolism; Nephrons - cytology; Nephrons - metabolism; Organ Culture Techniques; Organogenesis - physiology; Signal Transduction
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2013.11.010

Recapitulating three-dimensional (3D) structures of complex organs, such as the kidney, from pluripotent stem cells (PSCs) is a major challenge. Here, we define the developmental origins of the metanephric mesenchyme (MM), which generates most kidney components. Unexpectedly, we find that posteriorly located T+ MM precursors are developmentally distinct from Osr1+ ureteric bud progenitors during the postgastrulation stage, and we identify phasic Wnt stimulation and stage-specific growth factor addition as molecular cues that promote their development into the MM. We then use this information to derive MM from PSCs. These progenitors reconstitute the 3D structures of the kidney in vitro, including glomeruli with podocytes and renal tubules with proximal and distal regions and clear lumina. Furthermore, the glomeruli are efficiently vascularized upon transplantation. Thus, by reevaluating the developmental origins of metanephric progenitors, we have provided key insights into kidney specification in vivo and taken important steps toward kidney organogenesis in vitro. [Display omitted] •Metanephric mesenchyme (MM) is derived from posterior intermediate mesoderm•MM and ureteric bud progenitors are not derived from a common Osr1+ progenitor•Mouse and human PSCs generate metanephric nephron progenitors in vitro•Induced nephron progenitors generate complex 3D kidney structures in vitro Nishinakamura et al. show that reevaluation of the developmental origin of kidney nephron progenitors allows for efficient derivation of 3D kidney structures from mouse and human pluripotent stem cells.