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      Differentiating Induced Pluripotent Stem Cells into Renal Cells: A New Approach to Treat Kidney Diseases

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          Abstract

          Renal disease is a major issue for global public health. Despite some progress in supportive care, the mortality rates among patients with this condition remain alarmingly high. Studies in pursuit of innovative strategies to treat renal diseases, especially stimulating kidney regeneration, have been developed. In this field, stem cell-based therapy has been a promising area. Induced pluripotent stem cell-derived renal cells (iPSC-RCs) represent an interesting source of cells for treating kidney diseases. Advances in regenerative medicine using iPSC-RCs and their application to the kidney are discussed in this review. Furthermore, the way differentiation protocols of induced pluripotent stem cells into renal cells may also be applied for the generation of kidney organoids is also described, contributing to studies in renal development, kidney diseases, and drug toxicity tests. The translation of the differentiation methodologies into animal model studies and the safety and feasibility of renal differentiated cells as a treatment for kidney injury are also highlighted. Although only few studies were published in this field, the results seem promising and support the use of iPSC-RCs as a potential therapy in the future.

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          Most cited references76

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          KDIGO Clinical Practice Guidelines for Acute Kidney Injury

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            Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

            The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.
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              Nephron organoids derived from human pluripotent stem cells model kidney development and injury

              Kidney cells and tissues derived from human pluripotent stem cells (hPSCs) would enable organ regeneration, disease modeling, and drug screening in vitro. We established an efficient, chemically defined protocol for differentiating hPSCs into multipotent nephron progenitor cells (NPCs) that can form nephron-like structures. By recapitulating metanephric kidney development in vitro, we generate SIX2+SALL1+WT1+PAX2+ NPCs with 90% efficiency within 9 days of differentiation. The NPCs possess the developmental potential of their in vivo counterparts and form PAX8+LHX1+ renal vesicles that self-pattern into nephron structures. In both 2D and 3D culture, NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle, and distal tubules in an organized, continuous arrangement that resembles the nephron in vivo. We also show that this organoid culture system can be used to study mechanisms of human kidney development and toxicity.
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                Author and article information

                Contributors
                Journal
                Stem Cells Int
                Stem Cells Int
                SCI
                Stem Cells International
                Hindawi
                1687-966X
                1687-9678
                2020
                7 August 2020
                : 2020
                : 8894590
                Affiliations
                1Laboratory of Immunology and Experimental Transplantation-LITEX, Medical School of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Sao Paulo, Brazil
                2Physiology Division, Natural and Biological Sciences Institute, Triangulo Mineiro Federal University, Uberaba, Minas Gerais, Brazil
                3National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
                4Kidney Transplant Unit, Hospital de Base, FAMERP/FUNFARME, Sao Jose do Rio Preto, Sao Paulo, Brazil
                5Urology and Nephrology Institute, Sao Jose Rio Preto, Sao Paulo, Brazil
                Author notes

                Academic Editor: Nádia K. Gumarães-Souza

                Author information
                https://orcid.org/0000-0003-2101-4551
                Article
                10.1155/2020/8894590
                7428838
                32831854
                c9881fd7-c047-4922-a6fb-fe31a7ff3ef0
                Copyright © 2020 Patrícia de Carvalho Ribeiro et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 May 2020
                : 21 July 2020
                : 28 July 2020
                Funding
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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