Differentiation of a Contractile, Ureter-Like Tissue, from Embryonic Stem Cell–Derived Ureteric Bud and Ex Fetu Mesenchyme

May Sallam; Anwar A. Palakkan; Christopher G. Mills; Julia Tarnick; Mona Elhendawi; Lorna Marson; Jamie A. Davies

doi:10.1681/ASN.2019101075

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Visual Abstract

Significance Statement

There is intense interest in engineering new kidneys from embryonic stem cells and induced pluripotent stem cells as research models, and perhaps eventually for clinical transplant. Although protocols exist for producing renal organoids from stem cells, these organoids lack an essential component, the ureter. The authors describe the production of ureter-like tissue consisting of embryonic stem cell–derived ureteric buds that organize ex fetu mesenchyme around it to form smooth muscle layers. These muscles spontaneously contract with a periodicity that is a little slower than that of peristalsis in natural ureters. This work represents a step toward developing organoids with a ureter, although inducing the tissue to elongate into a tube and connect it to the kidney is a remaining challenge.

Abstract

Background There is intense interest in replacing kidneys from stem cells. It is now possible to produce, from embryonic or induced pluripotent stem cells, kidney organoids that represent immature kidneys and display some physiologic functions. However, current techniques have not yet resulted in renal tissue with a ureter, which would be needed for engineered kidneys to be clinically useful.

Methods We used a published sequence of growth factors and drugs to induce mouse embryonic stem cells to differentiate into ureteric bud tissue. We characterized isolated engineered ureteric buds differentiated from embryonic stem cells in three-dimensional culture and grafted them into ex fetu mouse kidney rudiments.

Results Engineered ureteric buds branched in three-dimensional culture and expressed Hoxb7, a transcription factor that is part of a developmental regulatory system and a ureteric bud marker. When grafted into the cortex of ex fetu kidney rudiments, engineered ureteric buds branched and induced nephron formation; when grafted into peri-Wolffian mesenchyme, still attached to a kidney rudiment or in isolation, they did not branch but instead differentiated into multilayer ureter-like epithelia displaying robust expression of the urothelial marker uroplakin. This engineered ureteric bud tissue also organized the mesenchyme into smooth muscle that spontaneously contracted, with a period a little slower than that of natural ureteric peristalsis.

Conclusions Mouse embryonic stem cells can be differentiated into ureteric bud cells. Grafting those UB-like structures into peri-Wolffian mesenchyme of cultured kidney rudiments can induce production of urothelium and organize the mesenchyme to produce rhythmically contracting smooth muscle layers. This development may represent a significant step toward the goal of renal regeneration.

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