Kidney development to kidney organoids and back again

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Abstract

Kidney organoid technology has led to a renaissance in kidney developmental biology. The complex underpinnings of mammalian kidney development have provided a framework for the generation of kidney cells and tissues from human pluripotent stem cells. Termed kidney organoids, these 3-dimensional structures contain kidney-specific cell types distributed similarly to in vivo architecture. The adult human kidney forms from the reciprocal induction of two disparate tissues, the metanephric mesenchyme (MM) and ureteric bud (UB), to form nephrons and collecting ducts, respectively. Although nephrons and collecting ducts are derived from the intermediate mesoderm (IM), their development deviates in time and space to impart distinctive inductive signaling for which separate differentiation protocols are required. Here we summarize the directed differentiation protocols which generate nephron kidney organoids and collecting duct kidney organoids, making note of similarities as much as differences. We discuss limitations of these present approaches and discuss future directions to improve kidney organoid technology, including a greater understanding of anterior IM and its derivatives to enable an improved differentiation protocol to collecting duct organoids for which historic and future developmental biology studies will be instrumental.

Introduction

Developmental biology has informed the derivation of human stem cell-derived cells and tissues. Directed differentiation protocols, involving the sequential application of small molecules and growth factors to mimic signals governing organogenesis, have been deciphered to generate the major organs of the human body, including the kidney [1]. The adult kidney develops from the reciprocal induction of the MM and UB. Derived from the posterior intermediate mesoderm (pIM), the MM is a heterogenous populations of nephron progenitor cells (NPCs), stromal progenitor cells (SPCs), and endothelial progenitor cells (EPCs), which give rise to nephron structures and their surrounding interstitium. Derived from the anterior intermediate mesoderm (aIM), UB progenitor cells differentiate into the branched collecting duct network that drains individual nephrons to the bladder via a solitary ureter. Importantly, the formation of nephron structures is predicated upon inductive signals from developing collecting duct, and vice versa, in a process termed reciprocal induction. Given their disparate origins, separate directed differentiation protocols have been required to generate nephron kidney organoids and collecting duct kidney organoids.

Historically, studies in kidney developmental biology have been enriched by knowledge of congenital anomalies of the kidney and urinary tract (CAKUT), a group of quite common genetic disorders often stemming from the malunion of the MM and UB. Mutations involving growth factors and their receptors responsible for CAKUT has shed light on the signaling pathways involved in the separate formation of the MM and UB, as well as their reciprocal induction. Drawing from these studies, kidney organoids have been generated from modulated Wnt, FGF, TGF-β/BMP, and RA signaling, as discussed in detail below. Due to the cessation of nephrogenesis by birth in humans [2], kidney development has historically been of little clinical importance, in terms of mitigatable disease. However, the advent of kidney organoids has re-invigorated kidney developmental biology, which should be instrumental in improving organoid technology towards revolutionizing the fields of drug development and regenerative medicine.

Section snippets

Three germ layer and primitive streak

Mammalian development begins with the union of male and female haploid gametes, forming a single diploid pluripotent stem cell which undergoes iterative proliferation and differentiation. After approximately 7 cell doublings, a blastula consists of a hollow spheroid of ~128 (2^7) undifferentiated cells. The primitive streak forms in the caudal and mid-line aspect of the blastula to determine the site of gastrulation, initiate germ layer formation, and establish bilateral symmetry via

In vitro differentiation of stem cells

Drawing from our knowledge of mammalian kidney development, multiple reproducible methods have been deciphered which turn human pluripotent stem cells (hPSCs) into kidney cells and tissues, termed kidney organoids [56]. While there is some debate to its definition, we accept Hans Clevers’ definition of an organoid as a 3-dimensional structure grown from stem cells and consisting of organ-specific cell types that self-organizes through spatially restricted lineage commitment [57]. Such organoids

Differentiation towards collecting duct kidney organoids

While 2015 was an influential year for the development of nephron kidney organoids, the time since has seen a dramatic degree of publications towards hPSC-derived collecting duct kidney organoids. Yet one of the first demonstrations of directed differentiation to kidney tissue of any sort was published in 2013, prior to the demonstration that MM originates from the pIM and UB from the aIM. Xia et al. published a two-step protocol over the course of 4 days to generate hPSCs capable of

Conclusion

Kidney developmental studies have enabled the generation of hPSC-derived human kidney ex vivo. Significant strides have been made to first develop, and further modify, protocols to generate kidney organoids bearing nephron or collecting duct structures. Numerous groups have published independent directed differentiation protocols to kidney which collectively share similar sequential signaling pathway activation through intermediate cells bearing characteristic markers. The utility of one

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors thank the support from the following grants: National Institutes of Health (NIH) T32 fellowship training grant (DK007527, to N.G.), Harvard Stem Cell Institute interdisciplinary grant (to N.G.), Brigham and Women’s Hospital Research Excellence Award (to N.G. and R.M.), Brigham and Women’s Hospital Faculty Career Development Award (R.M.), Harvard Stem Cell Institute Seed Grant (R.M.), DiaComp Pilot & Feasibility Program (R.M.), NIH DP2EB029388 award (R.M.), NIH U01EB028899 grant

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