Human Kidney Organoids and Tubuloids as Models of Complex Kidney Disease
2022; Elsevier BV; Volume: 192; Issue: 5 Linguagem: Inglês
10.1016/j.ajpath.2022.01.009
ISSN1525-2191
AutoresAna B. Nunez-Nescolarde, David J. Nikolic‐Paterson, Alexander N. Combes,
Tópico(s)Renal cell carcinoma treatment
ResumoKidney organoids derived from pluripotent stem cells and epithelial organoids derived from adult tissue (tubuloids) have been used to study various kidney disorders with a strong genetic component, such as polycystic kidney disease, Wilms tumor, and congenital nephrotic syndrome. However, complex disorders without clear genetic associations, such as acute kidney injury and many forms of chronic kidney disease, are only just beginning to be investigated using these in vitro approaches. Although organoids are a reductionist model, they contain clinically relevant cell populations that may help to elucidate human-specific pathogenic mechanisms. Thus, organoids may complement animal disease models to accelerate the translation of laboratory proof-of-concept research into clinical practice. This review discusses whether kidney organoids and tubuloids are suitable models for the study of complex human kidney disease and highlights their advantages and limitations compared with monolayer cell culture and animal models. Kidney organoids derived from pluripotent stem cells and epithelial organoids derived from adult tissue (tubuloids) have been used to study various kidney disorders with a strong genetic component, such as polycystic kidney disease, Wilms tumor, and congenital nephrotic syndrome. However, complex disorders without clear genetic associations, such as acute kidney injury and many forms of chronic kidney disease, are only just beginning to be investigated using these in vitro approaches. Although organoids are a reductionist model, they contain clinically relevant cell populations that may help to elucidate human-specific pathogenic mechanisms. Thus, organoids may complement animal disease models to accelerate the translation of laboratory proof-of-concept research into clinical practice. This review discusses whether kidney organoids and tubuloids are suitable models for the study of complex human kidney disease and highlights their advantages and limitations compared with monolayer cell culture and animal models. Chronic kidney disease (CKD) represents a major health problem, affecting approximately 13% of the global population and 37 million adult Americans.1Murray R. Zimmerman T. Agarwal A. Palevsky P.M. Quaggin S. Rosas S.E. Kramer H. Kidney-related research in the United States: a position statement from the National Kidney Foundation and the American Society of Nephrology.Am J Kidney Dis. 2021; 78: 161-167Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,2Lv J.C. Zhang L.X. Prevalence and disease burden of chronic kidney disease.Adv Exp Med Biol. 2019; 1165: 3-15Crossref PubMed Scopus (197) Google Scholar The most common causes for CKD and ultimately end-stage renal disease are diabetes and hypertension.3Webster A.C. Nagler E.V. Morton R.L. Masson P. Chronic kidney disease.Lancet. 2017; 389: 1238-1252Abstract Full Text Full Text PDF PubMed Scopus (1451) Google Scholar Therapeutic strategies, such as control of glucose levels and blood pressure, can slow some forms of CKD. However, patients remain at risk of cardiovascular complications and of progression to end-stage renal disease, where they will require life-long dialysis or a kidney transplant. As such, there is an urgent need to develop new human disease models to accelerate the discovery of novel treatments.Although nonhuman animal models have been widely used in nephrology to simulate the cellular and molecular mechanisms of human kidney diseases, differences between animal and human physiology are often cited as a reason why few preclinical studies lead to success in human clinical trials.4Polson A.G. Fuji R.N. The successes and limitations of preclinical studies in predicting the pharmacodynamics and safety of cell-surface-targeted biological agents in patients.Br J Pharmacol. 2012; 166: 1600-1602Crossref PubMed Scopus (26) Google Scholar Therefore, the potential of replicating human physiology in vitro with human kidney tissues derived from induced pluripotent stem cells (iPSCs) and adult tissue has been met with great excitement. Directed differentiation of iPSCs generates miniature three-dimensional (3D) kidney tissues by mimicking the sequence of molecular signals involved in the formation of kidney progenitor cell types in the developing embryo. The first described iPSC-derived kidney organoids contained stroma, vasculature, and tubular epithelial structures that self-organize into nephrons containing proximal, medial, and distal segments (Figure 1).5Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (14654) Google Scholar, 6Schutgens F. Rookmaaker M.B. Margaritis T. Rios A. Ammerlaan C. Jansen J. Gijzen L. Vormann M. Vonk A. Viveen M. Yengej F.Y. Derakhshan S. de Winter-de Groot K.M. Artegiani B. van Boxtel R. Cuppen E. Hendrickx A.P.A. van den Heuvel-Eibrink M.M. Heitzer E. Lanz H. Beekman J. Murk J.-L. Masereeuw R. Holstege F. Drost J. Verhaar M.C. Clevers H. Tubuloids derived from human adult kidney and urine for personalized disease modeling.Nat Biotechnol. 2019; 37: 303-313Crossref PubMed Scopus (177) Google Scholar, 7Takasato M. Er P.X. Chiu H.S. Maier B. Baillie G.J. Ferguson C. Parton R.G. Wolvetang E.J. Roost M.S. Chuva de Sousa Lopes S.M. Little M.H. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568Crossref PubMed Scopus (838) Google Scholar, 8Freedman B.S. Brooks C.R. Lam A.Q. Fu H. Morizane R. Agrawal V. Saad A.F. Li M.K. Hughes M.R. Werff R.V. Peters D.T. Lu J. Baccei A. Siedlecki A.M. Valerius M.T. Musunuru K. McNagny K.M. Steinman T.I. Zhou J. Lerou P.H. Bonventre J.V. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.Nat Commun. 2015; 6: 8715Crossref PubMed Scopus (422) Google Scholar, 9Czerniecki S.M. Cruz N.M. Harder J.L. Menon R. Annis J. Otto E.A. Gulieva R.E. Islas L.V. Kim Y.K. Tran L.M. Martins T.J. Pippin J.W. Fu H. Kretzler M. Shankland S.J. Himmelfarb J. Moon R.T. Paragas N. Freedman B.S. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping.Cell Stem Cell. 2018; 22: 929-940.e4Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 10Morizane R. Lam A.Q. Freedman B.S. Kishi S. Valerius M.T. Bonventre J.V. Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (493) Google Scholar, 11Taguchi A. Kaku Y. Ohmori T. Sharmin S. Ogawa M. Sasaki H. Nishinakamura R. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells.Cell Stem Cell. 2014; 14: 53-67Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar Subsequent experimental protocols have enabled the production of ureteric epithelium or increased the production of specific cell types, such as vasculature or podocytes.12Low J.H. Li P. Chew E.G.Y. Zhou B. Suzuki K. Zhang T. Lian M.M. Liu M. Aizawa E. Rodriguez Esteban C. Yong K.S.M. Chen Q. Campistol J.M. Fang M. Khor C.C. Foo J.N. Izpisua Belmonte J.C. Xia Y. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network.Cell Stem Cell. 2019; 25: 373-387.e9Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 13Yoshimura Y. Taguchi A. Tanigawa S. Yatsuda J. Kamba T. Takahashi S. Kurihara H. Mukoyama M. Nishinakamura R. Manipulation of nephron-patterning signals enables selective induction of podocytes from human pluripotent stem cells.J Am Soc Nephrol. 2019; 30: 304-321Crossref PubMed Scopus (41) Google Scholar, 14Xia Y. Nivet E. Sancho-Martinez I. Gallegos T. Suzuki K. Okamura D. Wu M.-Z. Dubova I. Esteban C.R. Montserrat N. Campistol J.M. Belmonte J.C.I. Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells.Nat Cell Biol. 2013; 15: 1507-1515Crossref PubMed Scopus (248) Google Scholar, 15Howden S.E. Wilson S.B. Groenewegen E. Starks L. Forbes T.A. Tan K.S. Vanslambrouck J.M. Holloway E.M. Chen Y.H. Jain S. Spence J.R. Little M.H. Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk.Cell Stem Cell. 2021; 28: 671-684.e6Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 16Uchimura K. Wu H. Yoshimura Y. Humphreys B.D. Human pluripotent stem cell-derived kidney organoids with improved collecting duct maturation and injury modeling.Cell Rep. 2020; 33: 108514Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Kidney organoids have also been produced by directed differentiation from other types of pluripotent stem cells, such as embryonic stem cells. However, the capacity to generate iPSCs from any adult cell type circumvents ethical issues associated with human embryonic stem cells and enables generation of kidney tissue from patient-derived cells. The latter has been particularly powerful to study genetic variants of interest. It uses clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to generate gene-corrected control cell iPSC (isogenic) lines to investigate the cellular and molecular roles of a specific variant on an otherwise identical genetic background.8Freedman B.S. Brooks C.R. Lam A.Q. Fu H. Morizane R. Agrawal V. Saad A.F. Li M.K. Hughes M.R. Werff R.V. Peters D.T. Lu J. Baccei A. Siedlecki A.M. Valerius M.T. Musunuru K. McNagny K.M. Steinman T.I. Zhou J. Lerou P.H. Bonventre J.V. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.Nat Commun. 2015; 6: 8715Crossref PubMed Scopus (422) Google Scholar,12Low J.H. Li P. Chew E.G.Y. Zhou B. Suzuki K. Zhang T. Lian M.M. Liu M. Aizawa E. Rodriguez Esteban C. Yong K.S.M. Chen Q. Campistol J.M. Fang M. Khor C.C. Foo J.N. Izpisua Belmonte J.C. Xia Y. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network.Cell Stem Cell. 2019; 25: 373-387.e9Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar To date, iPSC-derived kidney organoids have been extensively used to study developmental processes, to model early-onset genetic diseases such as congenital nephrotic syndrome, and to screen for nephrotoxicity.8Freedman B.S. Brooks C.R. Lam A.Q. Fu H. Morizane R. Agrawal V. Saad A.F. Li M.K. Hughes M.R. Werff R.V. Peters D.T. Lu J. Baccei A. Siedlecki A.M. Valerius M.T. Musunuru K. McNagny K.M. Steinman T.I. Zhou J. Lerou P.H. Bonventre J.V. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.Nat Commun. 2015; 6: 8715Crossref PubMed Scopus (422) Google Scholar,10Morizane R. Lam A.Q. Freedman B.S. Kishi S. Valerius M.T. Bonventre J.V. Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (493) Google Scholar,17Ohmori T. De S. Tanigawa S. Miike K. Islam M. Soga M. Era T. Shiona S. Nakanishi K. Nakazato H. Nishinakamura R. Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells.Sci Rep. 2021; 11: 3982Crossref PubMed Scopus (8) Google ScholarA different strategy has been used to generate adult-derived epithelial organoids, or tubuloids, from human kidney biopsies and urine samples. Tubuloids express molecular markers characteristic of renal epithelial cell types and recapitulate some injury and repair mechanisms observed in the adult kidney (Figure 1).6Schutgens F. Rookmaaker M.B. Margaritis T. Rios A. Ammerlaan C. Jansen J. Gijzen L. Vormann M. Vonk A. Viveen M. Yengej F.Y. Derakhshan S. de Winter-de Groot K.M. Artegiani B. van Boxtel R. Cuppen E. Hendrickx A.P.A. van den Heuvel-Eibrink M.M. Heitzer E. Lanz H. Beekman J. Murk J.-L. Masereeuw R. Holstege F. Drost J. Verhaar M.C. Clevers H. Tubuloids derived from human adult kidney and urine for personalized disease modeling.Nat Biotechnol. 2019; 37: 303-313Crossref PubMed Scopus (177) Google Scholar,18Gijzen L. Yousef Yengej F.A. Schutgens F. Vormann M.K. Ammerlaan C.M.E. Nicolas A. Kurek D. Vulto P. Rookmaaker M.B. Lanz H.L. Verhaar M.C. Clevers H. Culture and analysis of kidney tubuloids and perfused tubuloid cells-on-a-chip.Nat Protoc. 2021; 16: 2023-2050Crossref PubMed Scopus (17) Google Scholar Tubuloids have been employed to model BK-virus infection, cystic fibrosis, and kidney tumors in a personalized manner.6Schutgens F. Rookmaaker M.B. Margaritis T. Rios A. Ammerlaan C. Jansen J. Gijzen L. Vormann M. Vonk A. Viveen M. Yengej F.Y. Derakhshan S. de Winter-de Groot K.M. Artegiani B. van Boxtel R. Cuppen E. Hendrickx A.P.A. van den Heuvel-Eibrink M.M. Heitzer E. Lanz H. Beekman J. Murk J.-L. Masereeuw R. Holstege F. Drost J. Verhaar M.C. Clevers H. Tubuloids derived from human adult kidney and urine for personalized disease modeling.Nat Biotechnol. 2019; 37: 303-313Crossref PubMed Scopus (177) Google Scholar However, important aspects of kidney disease, such as the transition between acute kidney injury (AKI) and CKD, and kidney fibrosis, have not been comprehensively modeled in iPSC- or adult-derived kidney organoids. This review considers whether kidney organoids and tubuloids may be suitable to study complex kidney diseases and highlights their advantages and limitations compared with animal models and two-dimensional monolayer cell cultures.Kidney DiseaseKidney function can be impaired by a wide range of insults and diseases, including diabetes, high blood pressure, glomerular or interstitial nephritis, fibrosis, inherited conditions, injury, and infections. These can be viewed as either acute or chronic diseases. In acute conditions, such as AKI and rapidly progressive glomerulonephritis, kidney function is lost over the course of days to weeks. In chronic kidney diseases, kidney function is gradually lost over months to years in response to an ongoing insult.The extent to which organoids can mimic aspects of human diseases depends on their capacity to replicate the cellular and molecular response to disease stimuli mounted by the human kidney. For instance, episodes of AKI can be triggered by ischemia, sepsis, and nephrotoxic drugs, among other factors.19Leblanc M. Kellum J.A. Gibney R.T.N. Lieberthal W. Tumlin J. Mehta R. Risk factors for acute renal failure: inherent and modifiable risks.Curr Opin Crit Care. 2005; 11: 533-536Crossref PubMed Scopus (122) Google Scholar These insults can lead to injury and maladaptive repair in podocytes and tubules, including fibrotic changes. Although nephrons within human kidney organoids can be subjected to injuries that induce AKI, the lack of measurable kidney function and urine output is an impediment to the use of some standard assays used in clinical research. However, established cellular and molecular biomarkers of kidney injury and function are suitable for organoid assays.Diseases that develop over a long time are associated with aging, repeated injuries, and comorbidities that result in oxidative stress, inflammation, and maladaptive repair.2Lv J.C. Zhang L.X. Prevalence and disease burden of chronic kidney disease.Adv Exp Med Biol. 2019; 1165: 3-15Crossref PubMed Scopus (197) Google Scholar,3Webster A.C. Nagler E.V. Morton R.L. Masson P. Chronic kidney disease.Lancet. 2017; 389: 1238-1252Abstract Full Text Full Text PDF PubMed Scopus (1451) Google Scholar This is also true for many features of CKD, including fibrosis, ischemic injury, and inflammation associated with glomerular and interstitial nephritis. Sterile inflammation is triggered by damage-associated molecular patterns being released into the kidney parenchyma, which stimulates chemokine and cytokine production, complement activation, and the recruitment and activation of leukocytes that exacerbate kidney injury.20Kurts C. Panzer U. Anders H.-J. Rees A.J. The immune system and kidney disease: basic concepts and clinical implications.Nat Rev Immunol. 2013; 13: 738-753Crossref PubMed Scopus (420) Google Scholar Recurring or persistent insults to the kidney contribute to the pathologic dysregulation of the inflammatory response. For example, patients with type 2 diabetes exhibit increased numbers of proinflammatory type 17 and type 1 helper T cells and decreased numbers of regulatory T cells, which contributes to chronic inflammation.21Jagannathan-Bogdan M. McDonnell M.E. Shin H. Rehman Q. Hasturk H. Apovian C.M. Nikolajczyk B.S. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes.J Immunol. 2011; 186: 1162-1172Crossref PubMed Scopus (301) Google Scholar In addition, CKD involves loss of the glomerular microvasculature and peritubular capillary rarefaction, that, together with renal anemia due to the lack of sufficient erythropoietin production, contribute to hypoxia, oxidative stress, and mitochondrial dysfunction.20Kurts C. Panzer U. Anders H.-J. Rees A.J. The immune system and kidney disease: basic concepts and clinical implications.Nat Rev Immunol. 2013; 13: 738-753Crossref PubMed Scopus (420) Google Scholar,22Zuk A. Bonventre J.V. Acute kidney injury.Annu Rev Med. 2016; 67: 293-307Crossref PubMed Scopus (405) Google Scholar Sustained kidney injury can also involve chronic metabolic dysregulation, including hyperglycemia and hyperlipidemia. Proximal tubular cells have a high metabolic demand, and their large number of mitochondria utilize fatty acid β-oxidation, rather than the less efficient glycolysis, for production of ATP. However, kidney damage may dysregulate fatty acid β-oxidation, causing intracellular lipid accumulation and increased glycolysis, which further promotes mitochondrial dysfunction, inflammation, and fibrosis.23Kang H.M. Ahn S.H. Choi P. Ko Y.A. Han S.H. Chinga F. Park A.S. Tao J. Sharma K. Pullman J. Bottinger E.P. Goldberg I.J. Susztak K. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.Nat Med. 2015; 21: 37-46Crossref PubMed Scopus (666) Google Scholar,24Jang H.S. Noh M.R. Kim J. Padanilam B.J. Defective mitochondrial fatty acid oxidation and lipotoxicity in kidney diseases.Front Med (Lausanne). 2020; 7: 65Crossref PubMed Scopus (43) Google Scholar All these long-term changes may not be fully reproduced in iPSC-derived kidney organoids, which are produced in single batches with nephrons suitable for disease modeling for approximately 7 to 10 days.7Takasato M. Er P.X. Chiu H.S. Maier B. Baillie G.J. Ferguson C. Parton R.G. Wolvetang E.J. Roost M.S. Chuva de Sousa Lopes S.M. Little M.H. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568Crossref PubMed Scopus (838) Google Scholar,10Morizane R. Lam A.Q. Freedman B.S. Kishi S. Valerius M.T. Bonventre J.V. Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (493) Google Scholar,12Low J.H. Li P. Chew E.G.Y. Zhou B. Suzuki K. Zhang T. Lian M.M. Liu M. Aizawa E. Rodriguez Esteban C. Yong K.S.M. Chen Q. Campistol J.M. Fang M. Khor C.C. Foo J.N. Izpisua Belmonte J.C. Xia Y. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network.Cell Stem Cell. 2019; 25: 373-387.e9Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar,25Przepiorski A. Sander V. Tran T. Hollywood J.A. Sorrenson B. Shih J.H. Wolvetang E.J. McMahon A.P. Holm T.M. Davidson A.J. A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells.Stem Cell Rep. 2018; 11: 470-484Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Similarly, tubuloids also have a defined experimental window; however, they offer an advantage of being used across multiple passages (>15 passages) (Figure 1).6Schutgens F. Rookmaaker M.B. Margaritis T. Rios A. Ammerlaan C. Jansen J. Gijzen L. Vormann M. Vonk A. Viveen M. Yengej F.Y. Derakhshan S. de Winter-de Groot K.M. Artegiani B. van Boxtel R. Cuppen E. Hendrickx A.P.A. van den Heuvel-Eibrink M.M. Heitzer E. Lanz H. Beekman J. Murk J.-L. Masereeuw R. Holstege F. Drost J. Verhaar M.C. Clevers H. Tubuloids derived from human adult kidney and urine for personalized disease modeling.Nat Biotechnol. 2019; 37: 303-313Crossref PubMed Scopus (177) Google Scholar,18Gijzen L. Yousef Yengej F.A. Schutgens F. Vormann M.K. Ammerlaan C.M.E. Nicolas A. Kurek D. Vulto P. Rookmaaker M.B. Lanz H.L. Verhaar M.C. Clevers H. Culture and analysis of kidney tubuloids and perfused tubuloid cells-on-a-chip.Nat Protoc. 2021; 16: 2023-2050Crossref PubMed Scopus (17) Google Scholar As is discussed later, the organoid model is endowed with several advantages and can greatly improve the understanding of human biology and disease.The Organoid ModelDevelopment of the Human KidneyThe adult kidney plays a vital role in removing metabolic waste products from the bloodstream, regulating blood pressure and volume, maintaining fluid homeostasis, and producing erythropoietin and active vitamin D. The metanephric kidneys arise from progenitor cell types specified in the intermediate mesoderm of the early embryo, which in the mouse occurs between embryonic days 7.5 and 8.5. These progenitor populations form vestigial pronephric and mesonephric kidneys before formation of the metanephric kidney, which persists into adulthood. At embryonic day 10.5 in mouse, or 5 weeks in humans, interactions between the metanephric mesenchyme and ureteric bud progenitor populations initiate formation of the metanephric kidney.26Lindström N.O. McMahon J.A. Guo J. Tran T. Guo Q. Rutledge E. Parvez R.K. Saribekyan G. Schuler R.E. Liao C. Kim A.D. Abdelhalim A. Ruffins S.W. Thornton M.E. Basking L. Grubbs B. Kesselman C. McMahon A.P. Conserved and divergent features of human and mouse kidney organogenesis.J Am Soc Nephrol. 2018; 29: 785Crossref PubMed Scopus (115) Google Scholar,27Costantini F. Kopan R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development.Dev Cell. 2010; 18: 698-712Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar The metanephric mesenchyme contains nephron, stromal, and vascular progenitors, and produces inductive signals that trigger outgrowth of the nephric duct, forming a single ureteric bud on each side of the embryo. Once the ureteric bud enters the mesenchyme, it is surrounded by SIX2-expressing nephron progenitor cells and undergoes repetitive branching to establish the ureteric epithelium (UE) or collecting duct network that drains renal filtrate to the bladder. WNT9B, expressed by the nephric duct and UE, triggers nephron progenitor cells to undergo a mesenchymal-to-epithelial transition to form early committing nephrons. The structure of the kidney is progressively built during development by interactive branching and nephron induction events at the tips of the ureteric tree, while existing nephron, ureteric epithelium, vascular, and stromal populations progressively expand and mature. Between weeks 14 to 22 of human embryonic development, ureteric bud branching stops, but nephrons continue to form, and connect to other nephrons instead of the ureteric tip in a process called arcading.27Costantini F. Kopan R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development.Dev Cell. 2010; 18: 698-712Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar,28Carroll T.J. Park J.S. Hayashi S. Majumdar A. McMahon A.P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system.Dev Cell. 2005; 9: 283-292Abstract Full Text Full Text PDF PubMed Scopus (651) Google ScholarEarly committing nephrons transition through anatomically distinct structures starting with pretubular aggregates, followed by cyst-like epithelial renal vesicles and tubular comma- and S-shaped body nephrons. Each stage of early nephron formation is marked by distinct gene expression signatures with precursors of distal, medial, proximal, and glomerular nephron segments foreshadowed in the renal vesicle and evident in the S-shaped body.27Costantini F. Kopan R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development.Dev Cell. 2010; 18: 698-712Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar,28Carroll T.J. Park J.S. Hayashi S. Majumdar A. McMahon A.P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system.Dev Cell. 2005; 9: 283-292Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar The S-shaped body progresses to a capillary loop nephron, where a distinct glomerulus is evident and contains endothelial capillaries. At this stage, the glomerulus is connected to the UE via short proximal, medial, and distal nephron segments. Despite these segmental identities being established early on, single-cell RNA-sequencing studies of the developing kidney suggest further maturation of individual nephron segments occurs over time as the nephrons continue to grow and begin to produce urine.29Naganuma H. Miike K. Ohmori T. Tanigawa S. Ichikawa T. Yamane M. Eto M. Niwa H. Kobayashi A. Nishinakamura R. Molecular detection of maturation stages in the developing kidney.Dev Biol. 2021; 470: 62-73Crossref PubMed Scopus (5) Google Scholar The adult kidney contains around 25 distinct cell types and an average of 1 million nephrons.26Lindström N.O. McMahon J.A. Guo J. Tran T. Guo Q. Rutledge E. Parvez R.K. Saribekyan G. Schuler R.E. Liao C. Kim A.D. Abdelhalim A. Ruffins S.W. Thornton M.E. Basking L. Grubbs B. Kesselman C. McMahon A.P. Conserved and divergent features of human and mouse kidney organogenesis.J Am Soc Nephrol. 2018; 29: 785Crossref PubMed Scopus (115) Google Scholar,30Little M.H. Returning to kidney development to deliver synthetic kidneys.Dev Biol. 2021; 474: 22-36Crossref PubMed Scopus (3) Google Scholar Nephrons filter the blood in the glomerulus, a specialized filtration unit that selectively removes fluids and molecules <70 kDa, including electrically charged solutes and ions. The first and mid segment of the proximal convoluted tubule, distal convoluted tubule, and connecting segment are embedded within the outer cortex of the kidney, whereas the last segment of the proximal convoluted tubule and loop of Henle are positioned within the medullary interstitium.31Jacobson H.R. Functional segmentation of the mammalian nephron.Am J Physiol. 1981; 241: F203-F218PubMed Google Scholar Nephrons form repetitively throughout development until around 38 weeks of gestation.32Ryan D. Sutherland M.R. Flores T.J. Kent A.L. Dahlstrom J.E. Puelles V.G. Bertram J.F. McMahon A.P. Little M.H. Moore L. Black M.J. Development of the human fetal kidney from mid to late gestation in male and female infants.EBioMedicine. 2018; 27: 275-283Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar No new nephrons form after this point, although existing nephrons have some capacity to repair in response to injury.iPSC-Derived Kidney OrganoidsUnder specific culture conditions, iPSC-derived kidney organoids have been shown to self-organize into tubular epithelial structures that resemble capillary loop-stage nephrons containing glomeruli and proximal, medial, and distal segments. These organoid nephrons are surrounded by endothelial cells and stromal cell types (Figure 1). iPSC-derived organoids are produced by replicating developmental programs and cues that drive kidney development in vivo. Specifically, signaling pathways, including Wnt, bone morphogenetic proteins, and fibroblast growth factor families, have been used to promote development of kidney progenitor populations from iPSCs, which self-organize into mini-kidneys that resemble aspects of the first and second trimester of human fetal kidney.7Takasato M. Er P.X. Chiu H.S. Maier B. Baillie G.J. Ferguson C. Parton R.G. Wolvetang E.J. Roost M.S. Chuva de Sousa Lopes S.M. Little M.H. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568Crossref PubMed Scopus (838) Google Scholar,8Freedman B.S. Brooks C.R. Lam A.Q. Fu H. Morizane R. Agrawal V. Saad A.F. Li M.K. Hughes M.R. Werff R.V. Peters D.T. Lu J. Baccei A. Siedlecki A.M. Valerius M.T. Musunuru K. McNagny K.M. Steinman T.I. Zhou J. Lerou P.H. Bonventre J.V. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.Nat Commun. 2015; 6: 8715Crossref PubMed Scopus (422) Google Scholar,10Morizane R. Lam A.Q. Freedman B.S. Kishi S. Valerius M.T. Bonventre J.V. Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200Crossref PubMed Scopus (493) Google Scholar,11Taguchi A. Kaku Y. Ohmori T. Sharmin S. Ogawa M. Sasaki H. Nishinakamura R. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells.Cell Stem Cell. 2014; 14: 53-67Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar Single-cell RNA-sequencing approaches revealed strong congruence between vascular, interstitial, and nephron cell types in human fetal kidney and iPSC-derived kidney organoids.33Wu H. Uchimura K. Donnelly E.L. Kirita Y. Morris S.A. Humphreys B.D. Com
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