Co-induction of stromal and epithelial progenitors for renal regeneration

Public summary

* Four days of differentiation generates an induced metanephric mesenchyme (iMM).

* iMM contains both nephron progenitor cells and renal stromal progenitor cells.

* iMM gives rise to sophisticated, vascularized nephron-like structures beneath the kidney capsule.

* In contrast to iMM, mature organoids rapidly lose differentiated features and fail to productively engraft.

* iMM grafts contain mesangial cells in addition to mature tubules.

Abstract

Multiple pools of developmental progenitors are needed for kidney regeneration, but directing differentiation of each of these independently is rate limiting and disruptive to the process. We demonstrate that a mere 4 days of differentiation generates an induced metanephric mesenchyme (iMM) containing both nephron progenitor cells and renal stromal progenitor cells. When implanted beneath the kidney capsule of immunodeficient mice, iMM differentiates into podocytes, mesangial cells, and tubules that recruit host blood vessels to form glomeruli and peritubular capillaries. In contrast, mature organoids rapidly lose differentiated features after implantation and fail to become productively vascularized by the host. By examining morphological changes and gene expression patterns, we demarcate a window of opportunity for successful implantation during which iMM exists in vitro. Young organoid cultures containing epithelial and stromal progenitor cells thus provide a rapid, one-pot starting material for nephron regeneration, a concept that may be broadly applicable to many organ systems.