The nephron is the functional unit of the kidney, but the mechanism of nephron formation during human development is unclear. We conducted a detailed analysis of nephron development in humans and mice by immunolabeling, and we compared human and mouse nephron patterning to describe conserved and divergent features. We created protein localization maps that highlight the emerging patterns along the proximal–distal axis of the developing nephron and benchmark expectations for localization of functionally important transcription factors, which revealed unanticipated cellular diversity. Moreover, we identified a novel nephron subdomain marked by Wnt4 expression that we fate-mapped to the proximal mature nephron. Significant conservation was observed between human and mouse patterning. We also determined the time at which markers for mature nephron cell types first emerge—critical data for the renal organoid field. These findings have conceptual implications for the evolutionary processes driving the diversity of mammalian organ systems. Furthermore, these findings provide practical insights beyond those gained with mouse and rat models that will guide in vitro efforts to harness the developmental programs necessary to build human kidney structures.

Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney’s collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.

Significance: Retinoblastoma is a childhood tumor that forms in response to mutations in the RB1 gene and loss of functional RB protein. Prior studies suggested that retinoblastomas arise from cone photoreceptor precursors, whereas mouse models yield tumors deriving from other retinal cell types and lacking human retinoblastoma features. We show that in cultured human retinae, retinoblastomas initiate from RB-depleted cone precursors that are in a specific maturation state and form premalignant retinomas prior to retinoblastoma lesions, as is believed to occur in retinoblastoma patients. In contrast, Rb-deficient mouse cone precursors of similar maturation state and supplemented with human cone precursor-specific oncoproteins fail to proliferate. Thus, human species-specific developmental features underlie retinoblastoma genesis and may challenge the production of accurate retinoblastoma models.

Matsuo K, et al. J Gynecol Oncol. 2017 Sep;29(1):e15. https://doi.org/10.3802/jgo.2018.29.e15

Matsuo K, et al. J Gynecol Oncol. 2017 Dec;29:e91. https://doi.org/10.3802/jgo.2018.29.e91