scholarly journals iPSC technology-based regenerative medicine for kidney diseases

2021 ◽  
Author(s):  
Kenji Osafune
Keyword(s):  
Regenerative Medicine ◽  
Cell Therapy ◽  
Kidney Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Current Status ◽  
Renal Tubules ◽  
Discovery Research ◽  
Drug Discovery Research

AbstractWith few curative treatments for kidney diseases, increasing attention has been paid to regenerative medicine as a new therapeutic option. Recent progress in kidney regeneration using human-induced pluripotent stem cells (hiPSCs) is noteworthy. Based on the knowledge of kidney development, the directed differentiation of hiPSCs into two embryonic kidney progenitors, nephron progenitor cells (NPCs) and ureteric bud (UB), has been established, enabling the generation of nephron and collecting duct organoids. Furthermore, human kidney tissues can be generated from these hiPSC-derived progenitors, in which NPC-derived glomeruli and renal tubules and UB-derived collecting ducts are interconnected. The induced kidney tissues are further vascularized when transplanted into immunodeficient mice. In addition to the kidney reconstruction for use in transplantation, it has been demonstrated that cell therapy using hiPSC-derived NPCs ameliorates acute kidney injury (AKI) in mice. Disease modeling and drug discovery research using disease-specific hiPSCs has also been vigorously conducted for intractable kidney disorders, such as autosomal dominant polycystic kidney disease (ADPKD). In an attempt to address the complications associated with kidney diseases, hiPSC-derived erythropoietin (EPO)-producing cells were successfully generated to discover drugs and develop cell therapy for renal anemia. This review summarizes the current status and future perspectives of developmental biology of kidney and iPSC technology-based regenerative medicine for kidney diseases.

scholarly journals Kidney Organoids and Tubuloids

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1326 ◽  
Author(s):  
Fjodor A. Yousef Yengej ◽  
Jitske Jansen ◽  
Maarten B. Rookmaaker ◽  
Marianne C. Verhaar ◽  
Hans Clevers
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Kidney Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Metanephric Mesenchyme ◽  
Kidney Organoids

In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.

Abstract 061: Cell Fate Changes During Tubular Damage and Regeneration in the Mouse Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Vidya K Nagalakshmi ◽  
Minghong Li ◽  
R. A Gomez ◽  
Maria Luisa S Sequeira-Lopez
Keyword(s):  
Cell Fate ◽  
Ureteral Obstruction ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Lineage Tracing ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Atubular Glomeruli

Tubular degeneration, loss of renal tubules and interstitial fibrosis due to kidney injury lead to chronic renal disease and hypertension. Using a partial unilateral ureteral obstruction (pUUO) model in neonatal mice, we analyzed the fate cell changes that occur during obstruction and during recovery following the release of UUO. We traced the fate of cells derived from the renal stroma, cap mesenchyme and ureteric bud epithelium using Foxd1-Cre, Six2-Cre and HoxB7-Cre mice respectively, crossed with double fluorescent reporter (mT/mG) mice. pUUO was performed 24-36h after birth (n=84). In a group of pups (n=37), the obstruction was released after seven days. Sham operated animals (n=35) were used as controls. Lineage tracing revealed that Foxd1-derived interstitial pericytes acquired α-smooth muscle actin expression and underwent significant expansion due to pUUO (fibrotic area 91.06+/-6.77 %). Release of obstruction resulted in complete resolution of fibrotic areas (0.00%; p<0.005). Further, loss of Six2-derived cells at the glomerular-tubular junction in pUUO kidneys resulted in the formation of atubular glomeruli (39%). Atubular glomeruli were not observed after release. In addition, a significant loss of HoxB7-derived collecting duct tubules was observed during pUUO. Most collecting ducts recovered following release. Our study indicates that obstruction leads to significant tubular damage, expansion of interstitial pericytes, fibrosis, tubular loss and formation of atubular glomeruli. The striking recovery observed after release of ureteral obstruction suggests a reversal of cell fate changes and tubular regeneration. Elucidation of the cellular and molecular mechanisms mediating these events may be of use in the design of strategies for the prevention and/or treatment of kidney diseases and secondary hypertension.

scholarly journals Tubule-Specific Mst1/2 Deficiency Induces CKD via YAP and Non-YAP Mechanisms

2020 ◽  
Vol 31 (5) ◽  
pp. 946-961 ◽  
Author(s):  
Chunhua Xu ◽  
Li Wang ◽  
Yu Zhang ◽  
Wenling Li ◽  
Jinhong Li ◽  
...  
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Renal Tubules ◽  
Double Knockout ◽  
Core Components ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
The Hippo Pathway

BackgroundThe serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway’s main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied.MethodsWe used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency.ResultsMST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2.ConclusionsOur findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-α and YAP signaling activities.

scholarly journals Genome editing in large animals: current status and future prospects

2019 ◽  
Vol 6 (3) ◽  
pp. 402-420 ◽  
Author(s):  
Jianguo Zhao ◽  
Liangxue Lai ◽  
Weizhi Ji ◽  
Qi Zhou
Keyword(s):  
Regenerative Medicine ◽  
Genome Editing ◽  
Biomedical Research ◽  
Human Disease ◽  
Gene Editing ◽  
Disease Modeling ◽  
Current Status ◽  
Future Prospects ◽  
Recent Advances ◽  
Large Animals

AbstractLarge animals (non-human primates, livestock and dogs) are playing important roles in biomedical research, and large livestock animals serve as important sources of meat and milk. The recently developed programmable DNA nucleases have revolutionized the generation of gene-modified large animals that are used for biological and biomedical research. In this review, we briefly introduce the recent advances in nuclease-meditated gene editing tools, and we outline these editing tools’ applications in human disease modeling, regenerative medicine and agriculture. Additionally, we provide perspectives regarding the challenges and prospects of the new genome editing technology.

cAMP-dependent chloride secretion mediates tubule enlargement and cyst formation by cultured mammalian collecting duct cells

2009 ◽  
Vol 296 (2) ◽  
pp. F446-F457 ◽  
Author(s):  
Roberto Montesano ◽  
Hafida Ghzili ◽  
Fabio Carrozzino ◽  
Bernard C. Rossier ◽  
Eric Féraille
Keyword(s):  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Fluid Secretion ◽  
Cyst Formation ◽  
Chloride Secretion ◽  
Cystic Kidney ◽  
Pcr Analysis ◽  
Renal Tubules

Polycystic kidney diseases result from disruption of the genetically defined program that controls the size and geometry of renal tubules. Cysts which frequently arise from the collecting duct (CD) result from cell proliferation and fluid secretion. From mCCDcl1 cells, a differentiated mouse CD cell line, we isolated a clonal subpopulation (mCCD-N21) that retains morphogenetic capacity. When grown in three-dimensional gels, mCCD-N21 cells formed highly organized tubular structures consisting of a palisade of polarized epithelial cells surrounding a cylindrical lumen. Subsequent addition of cAMP-elevating agents (forskolin or cholera toxin) or of membrane-permeable cAMP analogs (CPT-cAMP) resulted in rapid and progressive dilatation of existing tubules, leading to the formation of cystlike structures. When grown on filters, mCCD-N21 cells exhibited a high transepithelial resistance as well as aldosterone- and/or vasopressin-induced amiloride-sensitive and -insensitive current. The latter was in part inhibited by Na+-K+-2Cl− cotransporter (bumetanide) and chloride channel (NPPB) inhibitors. Real-time PCR analysis confirmed the expression of NKCC1, the ubiquitous Na+-K+-2Cl− cotransporter and cystic fibrosis transmembrane regulator (CFTR) in mCCD-N21 cells. Tubule enlargement and cyst formation were prevented by inhibitors of Na+-K+-2Cl− cotransporters (bumetanide or ethacrynic acid) or CFTR (NPPB or CFTR inhibitor-172). These results further support the notion that cAMP signaling plays a key role in renal cyst formation, at least in part by promoting chloride-driven fluid secretion. This new in vitro model of tubule-to-cyst conversion affords a unique opportunity for investigating the molecular mechanisms that govern the architecture of epithelial tubes, as well as for dissecting the pathophysiological processes underlying cystic kidney diseases.

scholarly journals Current Status and Future Prospects of Perinatal Stem Cells

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 6
Author(s):  
Paz de la Torre ◽  
Ana I. Flores
Keyword(s):  
Stem Cells ◽  
Regenerative Medicine ◽  
Cell Therapy ◽  
Cord Blood ◽  
New Technologies ◽  
Primary Source ◽  
Cell Types ◽  
Current Status ◽  
Clinical Settings ◽  
Hematopoietic Stem

The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.

scholarly journals Pax-2 controls multiple steps of urogenital development

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4057-4065 ◽  
Author(s):  
M. Torres ◽  
E. Gomez-Pardo ◽  
G.R. Dressler ◽  
P. Gruss
Keyword(s):  
Kidney Development ◽  
Kidney Diseases ◽  
System Development ◽  
Collecting Duct ◽  
Early Embryo ◽  
Urogenital System ◽  
Newborn Mice ◽  
Intermediate Mesoderm ◽  
Mouse Mutants ◽  
Urogenital Development

Urogenital system development in mammals requires the coordinated differentiation of two distinct tissues, the ductal epithelium and the nephrogenic mesenchyme, both derived from the intermediate mesoderm of the early embryo. The former give rise to the genital tracts, ureters and kidney collecting duct system, whereas mesenchymal components undergo epithelial transformation to form nephrons in both the mesonephric (embryonic) and metanephric (definitive) kidney. Pax-2 is a transcriptional regulator of the paired-box family and is widely expressed during the development of both ductal and mesenchymal components of the urogenital system. We report here that Pax-2 homozygous mutant newborn mice lack kidneys, ureters and genital tracts. We attribute these defects to dysgenesis of both ductal and mesenchymal components of the developing urogenital system. The Wolffian and Mullerian ducts, precursors of male and female genital tracts, respectively, develop only partially and degenerate during embryogenesis. The ureters, inducers of the metanephros are absent and therefore kidney development does not take place. Mesenchyme of the nephrogenic cord fails to undergo epithelial transformation and is not able to form tubules in the mesonephros. In addition, we show that the expression of specific markers for each of these components is de-regulated in Pax-2 mutants. These data show that Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases.

Sign in / Sign up

Export Citation Format

Share Document