Recapitulating kidney development: Progress and challenges

Abstract

Decades of research into the molecular and cellular regulation of kidney morphogenesis in rodent models, particularly the mouse, has provided both an atlas of the mammalian kidney and a roadmap for recreating kidney cell types with potential applications for the treatment of kidney disease. With advances in both our capacity to maintain nephron progenitors in culture, reprogram to kidney cell types and direct the differentiation of human pluripotent stem cells to kidney endpoints, renal regeneration via cellular therapy or tissue engineering may be possible. Human kidney models also have potential for disease modelling and drug screening. Such applications will rely upon the accuracy of the model at the cellular level and the capacity for stem-cell derived kidney tissue to recapitulate both normal and diseased kidney tissue. In this review, we will discuss the available cell sources, how well they model the human kidney and how far we are from application either as models or for tissue engineering.

Introduction

Chronic kidneydisease (CKD) describes the progressive deterioration of kidney function due to a variety of primary and secondary kidney diseases. The prevalence of CKD is rising worldwide and represents a significant burden of morbidity, mortality and healthcare expenditure [[1], [2], [3]]. In 2015, the total Medicare expenditure for all CKD and end-stage kidney disease (ESKD; requiring dialysis or transplantation) in the United States alone exceeded US$98 billion [1]. For many patients CKD progresses to ESKD over years or decades, providing ample opportunity for potential therapeutic intervention. Unfortunately there exists a paucity of disease modifying treatments due to a limited understanding of disease pathobiology for most causes of CKD.

Over the last two decades there has been an interest in augmenting existing treatments for ESKD with novel regenerative medicine approaches. Indeed, a number of approaches have been proposed as options for renal replacement, including adult porcine or embryonic kidney xenotransplantation [4,5]. Additional approaches envisaged have included bioprinting [6], renal assist devices in which primary cells were seeded on hollow fibre [7,8], recellularization of decellularized scaffolds [9] and direct cellular therapy, including the use of mesenchymal or bone marrow derived cell types [10]. With the isolation of human embryonic stem cells in 1998 [11] came the prospect of recreating human kidney tissue from this human pluripotent stem cell type. Significant advances in cellular reprogramming, including the capacity to generate induced pluripotent stem cells (iPSC) from any adult somatic cell type [12,13] and the capacity to enforce cellular transdifferentiation via the overexpression of key pioneer transcription factors [[14], [15], [16]] is beginning to provide additional approaches for the generation of cells for use in renal regeneration. In addition, continuous improvements in our understanding of kidney morphogenesis, and particularly the lineage relationships of the cells within the developing kidney, are also providing approaches for the isolation, maintenance and differentiation of progenitor cell types.

In this article, we will review the current situation with respect to potential cellular sources for renal regeneration, focussing most particularly on the directed differentiation of human pluripotent stem cells (hPSC) to kidney cell types. We will address the key questions of how accurately these recapitulate the human kidney and what challenges remain to using such cell types for disease modelling and regenerative medicine.