Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney

With the prevalence of end-stage renal disease rising 8% per annum globally(1), there is an urgent need for renal regenerative strategies. The kidney is a mesodermal organ that differentiates from the intermediate mesoderm (IM) through the formation of a ureteric bud (UB) and the interaction between this bud and the adjacent IM-derived metanephric mesenchyme(2) (MM). The nephrons arise from a nephron progenitor population derived from the MM (ref. 3). The IM itself is derived from the posterior primitive streak(4). Although the developmental origin of the kidney is well understood(2), nephron formation in the human kidney is completed before birth(5). Hence, there is no postnatal stem cell able to replace lost nephrons. In this study, we have successfully directed the differentiation of human embryonic stem cells (hESCs) through posterior primitive streak and IM under fully chemically defined monolayer culture conditions using growth factors used during normal embryogenesis. This differentiation protocol results in the synchronous induction of UB and MM that forms a self-organizing structure, including nephron formation, in vitro. Such hESC-derived components show broad renal potential ex vivo, illustrating the potential for pluripotent-stem-cell-based renal regeneration.