Key Points
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Directing the differentiation of stem cells to kidney tissues requires an understanding of kidney morphogenesis
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The kidney is a mesodermal organ and hence is derived from the primitive streak
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The primitive streak-derived intermediate mesoderm gives rise to both the ureteric bud and the metanephric mesenchyme
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The anterior intermediate mesoderm forms the mesonephric duct, which gives rise to the ureteric bud whereas the posterior intermediate mesoderm gives rise to the metanephric mesenchyme; both regions are required to recreate the entire kidney
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Using their understanding of kidney development, a number of groups have developed approaches to generate nephrons or whole kidney organoids from human pluripotent stem cells
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Kidney tissues generated in vitro are now being investigated as tools for disease modelling, drug screening, cell therapy and bioengineering of replacement renal tissue
Abstract
The treatment of renal failure has seen little change in the past 70 years. Patients with end-stage renal disease (ESRD) are treated with renal replacement therapy, including dialysis or organ transplantation. The growing imbalance between the availability of donor organs and prevalence of ESRD is pushing an increasing number of patients to undergo dialysis. Although the prospect of new treatment options for patients through regenerative medicine has long been suggested, advances in the generation of human kidney cell types through the directed differentiation of human pluripotent stem cells over the past 2 years have brought this prospect closer to delivery. These advances are the result of careful research into mammalian embryogenesis. By understanding the decision points made within the embryo to pattern the kidney, it is now possible to recreate self-organizing kidney tissues in vitro. In this Review, we describe the key decision points in kidney development and how these decisions have been mimicked experimentally. Recreation of human nephrons from human pluripotent stem cells opens the door to patient-derived disease models and personalized drug and toxicity screening. In the long term, we hope that these efforts will also result in the generation of bioengineered organs for the treatment of kidney disease.
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Acknowledgements
M.H.L. is a Senior Principal Research Fellow of the National Health and Medical Research Council (ID1042093). A.N.C. is an Australian Research Council (ARC) DECRA Postdoctoral Fellow (DE150100652). The laboratory is supported by funding from the NHMRC (ID1041277), NIH (DK107344-01) and the ARC (DP130102939).
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Glossary
- Human embryonic stem cells
-
Pluripotent stem cells derived from the early preimplantation embryo; they are thought to arise from the epiblast.
- Induced pluripotent stem cell
-
Pluripotent stem cell generated from a somatic cell via transcriptional reprogramming. The approach was pioneered in mice in 2006 and can also be performed in human somatic cells.
- Pluripotent stem cells
-
Cells that have the potential to differentiate into any cell type of the body.
- Epiblast
-
One of two distinct layers of the inner cell mass of the preimplantation embryo. The epiblast can give rise to all three germ layers: ectoderm, mesoderm and endoderm; the kidneys are derived from the mesoderm.
- Primitive streak
-
Elongated region of cells along the axis of the embryo that represents the site of gastrulation. It arises via the movement of lateral cells toward the medial axis and gives rise to the endoderm and mesoderm of the embryo with the rostro-caudal and medial-lateral axes of the embryo defined by its position.
- Visceral endoderm
-
Extra-embryonic tissue that surrounds the epiblast before gastrulation.
- Node
-
Site where gastrulation occurs in the developing embryo.
- Paraxial mesoderm
-
Region of the trunk mesoderm that lies along the spinal cord and gives rise to bone, cartilage, skeletal muscle and dermis via somitogenesis. It is characterized by the expression of Tcf15, Tbx6 and Pax3.
- Lateral plate mesoderm
-
Region of the trunk mesoderm that is located most distally from the spinal cord and gives rise to the heart, smooth muscles, blood cells, endothelium, the spleen and limbs. It is characterized by the expression of Osr1, Foxf1 and Nkx2-5.
- Intermediate mesoderm
-
Region of the trunk mesoderm that develops between the paraxial mesoderm and the lateral plate mesoderm. It differentiates into the nephric duct and the nephrogenic mesenchyme, which give rise to the urogenital system including the kidney, the gonads, and the adrenal cortex. It is marked by the expression of Pax2, Lhx1 (anterior) and Hoxd11, Eya1 (posterior).
- Notochord
-
Midline structure along the axis of the embryo located ventrally to the neural tube that has a critical role in patterning during development.
- Nephrogenic cord
-
Non-epithelial mesodermal mass alongside the nephric duct that originates from the intermediary mesoderm and is marked by Osr1 and Wt1 expression. It gives rise to the mesonephric and metanephric mesenchyme that form the mesonephric tubules of the mesonephros and the nephrons of the kidney.
- Nephric duct
-
Epithelial tube structure derived from the intermediary mesoderm in both the pronephros and mesonephros that gives rise to the ureteric bud, which forms the collecting ducts and the ureter of the metanephros. It also contributes to the male reproductive tract but regresses in the female. Marked by Gata3, Lhx1, Pax2 and Ecad expression.
- Pronephros
-
First and most rostral excretory organ to form along the mammalian embryo axis. The pronephros degenerates as the mesonephros is formed.
- Mesonephros
-
Second excretory organ to form along the mammalian embryo axis. It is composed of mesonephric tubules and degenerates during fetal development with sexually dimorphic regression (some tubules are retained in males to form the rete testis).
- Metanephros
-
Final and permanent excretory organ to form in mammals. It arises as an interaction between the ureteric bud and the metanephric mesenchyme and its excretory function commences before birth.
- Anterior intermediate mesoderm
-
The most rostral portion of the forming intermediate mesoderm from which the nephric duct and the pronephric tubules arise. It is formed by the first cells to migrate from the primitive streak.
- Ureteric epithelium
-
Tissue derived from the ureteric bud that invades the metanephric mesenchyme and then branches dichotomously to form the ureteric tree.
- Posterior intermediate mesoderm
-
Most caudal portion of the forming intermediary mesoderm from which the nephrogenic mesenchyme arises. It is formed by cells that migrate out of the primitive streak at a later time point than cells that give rise to the anterior intermediate mesoderm.
- Metanephric mesenchyme
-
Caudal part of the nephrogenic mesenchyme that gives rise to the nephrons, the stromal interstitium and some vascular elements within the final metanephric kidney. Marked by the expression of Osr1, Six1, Six2, Eya1, Wt1 and Gdnf.
- Tailbud
-
This proliferating mass of cells at the caudal end of the embryo, sometimes referred to as the caudal cell mass or caudal eminence, is the source of cells that contribute to the elongating body axis.
- Ureteric bud
-
Epithelial bud that arises from the caudal nephric duct adjacent to the metanephric mesenchyme in response to GDNF, a chemoattractant secreted by the metanephric mesenchyme.
- Ureteric tree
-
Tree-like structure derived from the dichotomous branching of the ureteric epithelium that gives rise to the collecting ducts in the metanephros. The ends of each branch are called 'ureteric tips' and express Ret, Gfra1 and Wnt11.
- Cap mesenchyme
-
Derivative of the metanephric mesenchyme adjacent to the tips of the branching ureteric bud that gives rise to all of the cell types of the nephron via mesenchymal-to-epithelial transition; it is hence also referred to as the nephrogenic mesenchyme. It is marked by the expression of Osr1, Six2, Cited1, Eya1, Wt1, Pax2 and Gdnf.
- Organ-on-a-chip
-
Microfluidic cell culture chip that houses various cell types to mimic the 3D physiology (multicellular architecture, tissue-tissue interfaces, physicochemical and mechanical environment) of an organ.
- Artificial scaffolds
-
Structural element or framework used to hold cells or tissues together.
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Little, M., Combes, A. & Takasato, M. Understanding kidney morphogenesis to guide renal tissue regeneration. Nat Rev Nephrol 12, 624–635 (2016). https://doi.org/10.1038/nrneph.2016.126
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DOI: https://doi.org/10.1038/nrneph.2016.126
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