2024
Tabibzadeh, Nahid; Morizane, Ryuji
Advancements in therapeutic development: kidney organoids and organs on a chip Journal Article
In: Kidney Int, vol. 105, no. 4, pp. 702–708, 2024, ISSN: 1523-1755.
@article{pmid38296026,
title = {Advancements in therapeutic development: kidney organoids and organs on a chip},
author = {Nahid Tabibzadeh and Ryuji Morizane},
doi = {10.1016/j.kint.2023.11.035},
issn = {1523-1755},
year = {2024},
date = {2024-04-01},
journal = {Kidney Int},
volume = {105},
number = {4},
pages = {702--708},
abstract = {The use of animal models in therapeutic development has long been the standard practice. However, ethical concerns and the inherent species differences have prompted a reevaluation of the experimental approach in human disease studies. The urgent need for alternative model systems that better mimic human pathophysiology has led to the emergence of organoids, innovative in vitro models, to simulate human organs in vitro. These organoids have gained widespread acceptance in disease models and drug development research. In this mini review, we explore the recent strides made in kidney organoid differentiation and highlight the synergistic potential of incorporating organ-on-chip systems. The emergent use of microfluidic devices reveals the importance of fluid flow in the maturation of kidney organoids and helps decipher pathomechanisms in kidney diseases. Recent research has uncovered their potential applications across a wide spectrum of kidney research areas, including hemodynamic forces at stake in kidney health and disease, immune cell infiltration, or drug delivery and toxicity. This convergence of cutting-edge technologies not only holds promise for expediting therapeutic development but also reflects an acknowledgment of the need to embrace innovative and more human-centric research models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The use of animal models in therapeutic development has long been the standard practice. However, ethical concerns and the inherent species differences have prompted a reevaluation of the experimental approach in human disease studies. The urgent need for alternative model systems that better mimic human pathophysiology has led to the emergence of organoids, innovative in vitro models, to simulate human organs in vitro. These organoids have gained widespread acceptance in disease models and drug development research. In this mini review, we explore the recent strides made in kidney organoid differentiation and highlight the synergistic potential of incorporating organ-on-chip systems. The emergent use of microfluidic devices reveals the importance of fluid flow in the maturation of kidney organoids and helps decipher pathomechanisms in kidney diseases. Recent research has uncovered their potential applications across a wide spectrum of kidney research areas, including hemodynamic forces at stake in kidney health and disease, immune cell infiltration, or drug delivery and toxicity. This convergence of cutting-edge technologies not only holds promise for expediting therapeutic development but also reflects an acknowledgment of the need to embrace innovative and more human-centric research models.
Oishi, Haruka; Tabibzadeh, Nahid; Morizane, Ryuji
Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids Journal Article
In: Biofabrication, 2024, ISSN: 1758-5090.
@article{pmid38547531,
title = {Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids},
author = {Haruka Oishi and Nahid Tabibzadeh and Ryuji Morizane},
doi = {10.1088/1758-5090/ad38df},
issn = {1758-5090},
year = {2024},
date = {2024-03-01},
journal = {Biofabrication},
abstract = {High-throughput drug screening is crucial for advancing healthcare through drug discovery. However, a significant limitation arises from available in vitro models using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in 3D tissues. Recent advancements in stem cell biology have facilitated the generation of organoids-3D tissue constructs that mimic human organs in vitro. Kidney organoids, derived from human pluripotent stem cells, represent a significant breakthrough in disease representation. They encompass major kidney cell types organized within distinct nephron segments, surrounded by stroma and endothelial cells. This tissue allows for the assessment of structural alterations such as nephron loss, a characteristic of chronic kidney disease. Despite these advantages, the complexity of 3D structures has hindered the use of organoids for large-scale drug screening, and the drug screening pipelines utilizing these complex in vitro models are yet to be established for high-throughput screening. In this study, we address the technical limitations of kidney organoids through fully automated 3D imaging, aided by a machine-learning approach for automatic profiling of nephron segment-specific epithelial morphometry. Kidney organoids were exposed to the nephrotoxic agent cisplatin to model severe acute kidney injury. An FDA-approved drug library was tested for therapeutic and nephrotoxicity screening. The fully automated pipeline of 3D image acquisition and analysis identified nephrotoxic or therapeutic drugs during cisplatin chemotherapy. The nephrotoxic potential of these drugs aligned with previous in vivo and human reports. Additionally, Imatinib, a tyrosine kinase inhibitor used in hematological malignancies, was identified as a potential preventive therapy for cisplatin-induced kidney injury. Our proof-of-concept report demonstrates that the automated screening process, using 3D morphometric assays with kidney organoids, enables high-throughput screening for nephrotoxicity and therapeutic assessment in 3D tissue constructs.
.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High-throughput drug screening is crucial for advancing healthcare through drug discovery. However, a significant limitation arises from available in vitro models using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in 3D tissues. Recent advancements in stem cell biology have facilitated the generation of organoids-3D tissue constructs that mimic human organs in vitro. Kidney organoids, derived from human pluripotent stem cells, represent a significant breakthrough in disease representation. They encompass major kidney cell types organized within distinct nephron segments, surrounded by stroma and endothelial cells. This tissue allows for the assessment of structural alterations such as nephron loss, a characteristic of chronic kidney disease. Despite these advantages, the complexity of 3D structures has hindered the use of organoids for large-scale drug screening, and the drug screening pipelines utilizing these complex in vitro models are yet to be established for high-throughput screening. In this study, we address the technical limitations of kidney organoids through fully automated 3D imaging, aided by a machine-learning approach for automatic profiling of nephron segment-specific epithelial morphometry. Kidney organoids were exposed to the nephrotoxic agent cisplatin to model severe acute kidney injury. An FDA-approved drug library was tested for therapeutic and nephrotoxicity screening. The fully automated pipeline of 3D image acquisition and analysis identified nephrotoxic or therapeutic drugs during cisplatin chemotherapy. The nephrotoxic potential of these drugs aligned with previous in vivo and human reports. Additionally, Imatinib, a tyrosine kinase inhibitor used in hematological malignancies, was identified as a potential preventive therapy for cisplatin-induced kidney injury. Our proof-of-concept report demonstrates that the automated screening process, using 3D morphometric assays with kidney organoids, enables high-throughput screening for nephrotoxicity and therapeutic assessment in 3D tissue constructs.
.
2023
Tabibzadeh, Nahid; Satlin, Lisa M; Jain, Sanjay; Morizane, Ryuji
Navigating the kidney organoid: insights into assessment and enhancement of nephron function Journal Article
In: Am J Physiol Renal Physiol, vol. 325, no. 6, pp. F695–F706, 2023, ISSN: 1522-1466.
@article{pmid37767571,
title = {Navigating the kidney organoid: insights into assessment and enhancement of nephron function},
author = {Nahid Tabibzadeh and Lisa M Satlin and Sanjay Jain and Ryuji Morizane},
doi = {10.1152/ajprenal.00166.2023},
issn = {1522-1466},
year = {2023},
date = {2023-12-01},
journal = {Am J Physiol Renal Physiol},
volume = {325},
number = {6},
pages = {F695--F706},
abstract = {Kidney organoids are three-dimensional structures generated from pluripotent stem cells (PSCs) that are capable of recapitulating the major structures of mammalian kidneys. As this technology is expected to be a promising tool for studying renal biology, drug discovery, and regenerative medicine, the functional capacity of kidney organoids has emerged as a critical question in the field. Kidney organoids produced using several protocols harbor key structures of native kidneys. Here, we review the current state, recent advances, and future challenges in the functional characterization of kidney organoids, strategies to accelerate and enhance kidney organoid functions, and access to PSC resources to advance organoid research. The strategies to construct physiologically relevant kidney organoids include the use of organ-on-a-chip technologies that integrate fluid circulation and improve organoid maturation. These approaches result in increased expression of the major tubular transporters and elements of mechanosensory signaling pathways suggestive of improved functionality. Nevertheless, continuous efforts remain crucial to create kidney tissue that more faithfully replicates physiological conditions for future applications in kidney regeneration medicine and their ethical use in patient care. Kidney organoids are three-dimensional structures derived from stem cells, mimicking the major components of mammalian kidneys. Although they show great promise, their functional capacity has become a critical question. This review explores the advancements and challenges in evaluating and enhancing kidney organoid function, including the use of organ-on-chip technologies, multiomics data, and in vivo transplantation. Integrating these approaches to further enhance their physiological relevance will continue to advance disease modeling and regenerative medicine applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kidney organoids are three-dimensional structures generated from pluripotent stem cells (PSCs) that are capable of recapitulating the major structures of mammalian kidneys. As this technology is expected to be a promising tool for studying renal biology, drug discovery, and regenerative medicine, the functional capacity of kidney organoids has emerged as a critical question in the field. Kidney organoids produced using several protocols harbor key structures of native kidneys. Here, we review the current state, recent advances, and future challenges in the functional characterization of kidney organoids, strategies to accelerate and enhance kidney organoid functions, and access to PSC resources to advance organoid research. The strategies to construct physiologically relevant kidney organoids include the use of organ-on-a-chip technologies that integrate fluid circulation and improve organoid maturation. These approaches result in increased expression of the major tubular transporters and elements of mechanosensory signaling pathways suggestive of improved functionality. Nevertheless, continuous efforts remain crucial to create kidney tissue that more faithfully replicates physiological conditions for future applications in kidney regeneration medicine and their ethical use in patient care. Kidney organoids are three-dimensional structures derived from stem cells, mimicking the major components of mammalian kidneys. Although they show great promise, their functional capacity has become a critical question. This review explores the advancements and challenges in evaluating and enhancing kidney organoid function, including the use of organ-on-chip technologies, multiomics data, and in vivo transplantation. Integrating these approaches to further enhance their physiological relevance will continue to advance disease modeling and regenerative medicine applications.
Ruiz-Babot, Gerard; Eceiza, Ariane; Abollo-Jiménez, Fernando; Malyukov, Maria; Carlone, Diana L; Borges, Kleiton; Costa, Alexandra Rodrigues Da; Qarin, Shamma; Matsumoto, Takuya; Morizane, Ryuji; Skarnes, William C; Ludwig, Barbara; Chapple, Paul J; Guasti, Leonardo; Storr, Helen L; Bornstein, Stefan R; Breault, David T
Generation of glucocorticoid-producing cells derived from human pluripotent stem cells Journal Article
In: Cell Rep Methods, vol. 3, no. 11, pp. 100627, 2023, ISSN: 2667-2375.
@article{pmid37924815,
title = {Generation of glucocorticoid-producing cells derived from human pluripotent stem cells},
author = {Gerard Ruiz-Babot and Ariane Eceiza and Fernando Abollo-Jiménez and Maria Malyukov and Diana L Carlone and Kleiton Borges and Alexandra Rodrigues Da Costa and Shamma Qarin and Takuya Matsumoto and Ryuji Morizane and William C Skarnes and Barbara Ludwig and Paul J Chapple and Leonardo Guasti and Helen L Storr and Stefan R Bornstein and David T Breault},
doi = {10.1016/j.crmeth.2023.100627},
issn = {2667-2375},
year = {2023},
date = {2023-11-01},
journal = {Cell Rep Methods},
volume = {3},
number = {11},
pages = {100627},
abstract = {Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency.
Kroll, Katharina T; Mata, Mariana M; Homan, Kimberly A; Micallef, Virginie; Carpy, Alejandro; Hiratsuka, Ken; Morizane, Ryuji; Moisan, Annie; Gubler, Marcel; Walz, Antje-Christine; Marrer-Berger, Estelle; Lewis, Jennifer A
Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies Journal Article
In: Proc Natl Acad Sci U S A, vol. 120, no. 35, pp. e2305322120, 2023, ISSN: 1091-6490.
@article{pmid37603766,
title = {Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies},
author = {Katharina T Kroll and Mariana M Mata and Kimberly A Homan and Virginie Micallef and Alejandro Carpy and Ken Hiratsuka and Ryuji Morizane and Annie Moisan and Marcel Gubler and Antje-Christine Walz and Estelle Marrer-Berger and Jennifer A Lewis},
doi = {10.1073/pnas.2305322120},
issn = {1091-6490},
year = {2023},
date = {2023-08-01},
journal = {Proc Natl Acad Sci U S A},
volume = {120},
number = {35},
pages = {e2305322120},
abstract = {T cell bispecific antibodies (TCBs) are the focus of intense development for cancer immunotherapy. Recently, peptide-MHC (major histocompatibility complex)-targeted TCBs have emerged as a new class of biotherapeutics with improved specificity. These TCBs simultaneously bind to target peptides presented by the polymorphic, species-specific MHC encoded by the human leukocyte antigen (HLA) allele present on target cells and to the CD3 coreceptor expressed by human T lymphocytes. Unfortunately, traditional models for assessing their effects on human tissues often lack predictive capability, particularly for "on-target, off-tumor" interactions. Here, we report an immune-infiltrated, kidney organoid-on-chip model in which peripheral blood mononuclear cells (PBMCs) along with nontargeting (control) or targeting TCB-based tool compounds are circulated under flow. The target consists of the RMF peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) presented on HLA-A2 via a bivalent T cell receptor-like binding domain. Using our model, we measured TCB-mediated CD8 T cell activation and killing of RMF-HLA-A2-presenting cells in the presence of PBMCs and multiple tool compounds. DP47, a non-pMHC-targeting TCB that only binds to CD3 (negative control), does not promote T cell activation and killing. Conversely, the nonspecific ESK1-like TCB (positive control) promotes CD8 T cell expansion accompanied by dose-dependent T cell-mediated killing of multiple cell types, while WT1-TCB* recognizing the RMF-HLA-A2 complex with high specificity, leads solely to selective killing of WT1-expressing cells within kidney organoids under flow. Our 3D kidney organoid model offers a platform for preclinical testing of cancer immunotherapies and investigating tissue-immune system interactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
T cell bispecific antibodies (TCBs) are the focus of intense development for cancer immunotherapy. Recently, peptide-MHC (major histocompatibility complex)-targeted TCBs have emerged as a new class of biotherapeutics with improved specificity. These TCBs simultaneously bind to target peptides presented by the polymorphic, species-specific MHC encoded by the human leukocyte antigen (HLA) allele present on target cells and to the CD3 coreceptor expressed by human T lymphocytes. Unfortunately, traditional models for assessing their effects on human tissues often lack predictive capability, particularly for "on-target, off-tumor" interactions. Here, we report an immune-infiltrated, kidney organoid-on-chip model in which peripheral blood mononuclear cells (PBMCs) along with nontargeting (control) or targeting TCB-based tool compounds are circulated under flow. The target consists of the RMF peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) presented on HLA-A2 via a bivalent T cell receptor-like binding domain. Using our model, we measured TCB-mediated CD8 T cell activation and killing of RMF-HLA-A2-presenting cells in the presence of PBMCs and multiple tool compounds. DP47, a non-pMHC-targeting TCB that only binds to CD3 (negative control), does not promote T cell activation and killing. Conversely, the nonspecific ESK1-like TCB (positive control) promotes CD8 T cell expansion accompanied by dose-dependent T cell-mediated killing of multiple cell types, while WT1-TCB* recognizing the RMF-HLA-A2 complex with high specificity, leads solely to selective killing of WT1-expressing cells within kidney organoids under flow. Our 3D kidney organoid model offers a platform for preclinical testing of cancer immunotherapies and investigating tissue-immune system interactions.
Yoon, Sung-Hee; Meyer, Mark B; Arevalo, Carlos; Tekguc, Murat; Zhang, Chengcheng; Wang, Jialiang S; Andrade, Christian D Castro; Strauss, Katelyn; Sato, Tadatoshi; Benkusky, Nancy A; Lee, Seong Min; Berdeaux, Rebecca; Foretz, Marc; Sundberg, Thomas B; Xavier, Ramnik J; Adelmann, Charles H; Brooks, Daniel J; Anselmo, Anthony; Sadreyev, Ruslan I; Rosales, Ivy A; Fisher, David E; Gupta, Navin; Morizane, Ryuji; Greka, Anna; Pike, J Wesley; Mannstadt, Michael; Wein, Marc N
A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis Journal Article
In: J Clin Invest, vol. 133, no. 9, 2023, ISSN: 1558-8238.
@article{pmid36862513,
title = {A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis},
author = {Sung-Hee Yoon and Mark B Meyer and Carlos Arevalo and Murat Tekguc and Chengcheng Zhang and Jialiang S Wang and Christian D Castro Andrade and Katelyn Strauss and Tadatoshi Sato and Nancy A Benkusky and Seong Min Lee and Rebecca Berdeaux and Marc Foretz and Thomas B Sundberg and Ramnik J Xavier and Charles H Adelmann and Daniel J Brooks and Anthony Anselmo and Ruslan I Sadreyev and Ivy A Rosales and David E Fisher and Navin Gupta and Ryuji Morizane and Anna Greka and J Wesley Pike and Michael Mannstadt and Marc N Wein},
doi = {10.1172/JCI163627},
issn = {1558-8238},
year = {2023},
date = {2023-05-01},
journal = {J Clin Invest},
volume = {133},
number = {9},
abstract = {The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.
Carrisoza-Gaytan, Rolando; Kroll, Katharina T; Hiratsuka, Ken; Gupta, Navin R; Morizane, Ryuji; Lewis, Jennifer A; Satlin, Lisa M
Functional maturation of kidney organoid tubules: PIEZO1-mediated Ca signaling Journal Article
In: Am J Physiol Cell Physiol, vol. 324, no. 3, pp. C757–C768, 2023, ISSN: 1522-1563.
@article{pmid36745528,
title = {Functional maturation of kidney organoid tubules: PIEZO1-mediated Ca signaling},
author = {Rolando Carrisoza-Gaytan and Katharina T Kroll and Ken Hiratsuka and Navin R Gupta and Ryuji Morizane and Jennifer A Lewis and Lisa M Satlin},
doi = {10.1152/ajpcell.00288.2022},
issn = {1522-1563},
year = {2023},
date = {2023-03-01},
journal = {Am J Physiol Cell Physiol},
volume = {324},
number = {3},
pages = {C757--C768},
abstract = {Kidney organoids cultured on adherent matrices in the presence of superfusate flow generate vascular networks and exhibit more mature podocyte and tubular compartments compared with static controls (Homan KA, Gupta N, Kroll KT, Kolesky DB, Skylar-Scott M, Miyoshi T, Mau D, Valerius MT, Ferrante T, Bonventre JV, Lewis JA, Morizane R. 16: 255-262, 2019; Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH. 526: 564-568, 2015.). However, their physiological function has yet to be systematically investigated. Here, we measured mechano-induced changes in intracellular Ca concentration ([Ca]) in tubules isolated from organoids cultured for 21-64 days, microperfused in vitro or affixed to the base of a specimen chamber, and loaded with fura-2 to measure [Ca]. A rapid >2.5-fold increase in [Ca] from a baseline of 195.0 ± 22.1 nM ( = 9; ≤ 0.001) was observed when microperfused tubules from organoids >40 days in culture were subjected to luminal flow. In contrast, no response was detected in tubules isolated from organoids <30 days in culture. Nonperfused tubules (41 days) subjected to a 10-fold increase in bath flow rate also exhibited a threefold increase in [Ca] from baseline ( < 0.001). Mechanosensitive PIEZO1 channels contribute to the flow-induced [Ca] response in mouse distal tubule (Carrisoza-Gaytan R, Dalghi MG, Apodaca GL, Kleyman TR, Satlin LM. 33: 824.25, 2019.). Immunodetectable apical and basolateral PIEZO1 was identified in tubular structures by 21 days in culture. Basolateral PIEZO1 appeared to be functional as basolateral exposure of nonperfused tubules to the PIEZO1 activator Yoda 1 increased [Ca] ( ≤ 0.001) in segments from organoids cultured for >30 days, with peak [Ca] increasing with advancing days in culture. These results are consistent with a maturational increase in number and/or activity of flow/stretch-sensitive Ca channels, including PIEZO1, in tubules of static organoids in culture.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kidney organoids cultured on adherent matrices in the presence of superfusate flow generate vascular networks and exhibit more mature podocyte and tubular compartments compared with static controls (Homan KA, Gupta N, Kroll KT, Kolesky DB, Skylar-Scott M, Miyoshi T, Mau D, Valerius MT, Ferrante T, Bonventre JV, Lewis JA, Morizane R. 16: 255-262, 2019; Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH. 526: 564-568, 2015.). However, their physiological function has yet to be systematically investigated. Here, we measured mechano-induced changes in intracellular Ca concentration ([Ca]) in tubules isolated from organoids cultured for 21-64 days, microperfused in vitro or affixed to the base of a specimen chamber, and loaded with fura-2 to measure [Ca]. A rapid >2.5-fold increase in [Ca] from a baseline of 195.0 ± 22.1 nM ( = 9; ≤ 0.001) was observed when microperfused tubules from organoids >40 days in culture were subjected to luminal flow. In contrast, no response was detected in tubules isolated from organoids <30 days in culture. Nonperfused tubules (41 days) subjected to a 10-fold increase in bath flow rate also exhibited a threefold increase in [Ca] from baseline ( < 0.001). Mechanosensitive PIEZO1 channels contribute to the flow-induced [Ca] response in mouse distal tubule (Carrisoza-Gaytan R, Dalghi MG, Apodaca GL, Kleyman TR, Satlin LM. 33: 824.25, 2019.). Immunodetectable apical and basolateral PIEZO1 was identified in tubular structures by 21 days in culture. Basolateral PIEZO1 appeared to be functional as basolateral exposure of nonperfused tubules to the PIEZO1 activator Yoda 1 increased [Ca] ( ≤ 0.001) in segments from organoids cultured for >30 days, with peak [Ca] increasing with advancing days in culture. These results are consistent with a maturational increase in number and/or activity of flow/stretch-sensitive Ca channels, including PIEZO1, in tubules of static organoids in culture.
Konoe, Ran; Morizane, Ryuji
Strategies for Improving Vascularization in Kidney Organoids: A Review of Current Trends Journal Article
In: Biology (Basel), vol. 12, no. 4, 2023, ISSN: 2079-7737.
@article{pmid37106704,
title = {Strategies for Improving Vascularization in Kidney Organoids: A Review of Current Trends},
author = {Ran Konoe and Ryuji Morizane},
doi = {10.3390/biology12040503},
issn = {2079-7737},
year = {2023},
date = {2023-03-01},
journal = {Biology (Basel)},
volume = {12},
number = {4},
abstract = {Kidney organoids possess the potential to revolutionize the treatment of renal diseases. However, their growth and maturation are impeded by insufficient growth of blood vessels. Through a PubMed search, we have identified 34 studies that attempted to address this challenge. Researchers are exploring various approaches including animal transplantation, organ-on-chips, and extracellular matrices (ECMs). The most prevalent method to promote the maturation and vascularization of organoids involves transplanting them into animals for in vivo culture, creating an optimal environment for organoid growth and the development of a chimeric vessel network between the host and organoids. Organ-on-chip technology permits the in vitro culture of organoids, enabling researchers to manipulate the microenvironment and investigate the key factors that influence organoid development. Lastly, ECMs have been discovered to aid the formation of blood vessels during organoid differentiation. ECMs from animal tissue have been particularly successful, although the underlying mechanisms require further research. Future research building upon these recent studies may enable the generation of functional kidney tissues for replacement therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kidney organoids possess the potential to revolutionize the treatment of renal diseases. However, their growth and maturation are impeded by insufficient growth of blood vessels. Through a PubMed search, we have identified 34 studies that attempted to address this challenge. Researchers are exploring various approaches including animal transplantation, organ-on-chips, and extracellular matrices (ECMs). The most prevalent method to promote the maturation and vascularization of organoids involves transplanting them into animals for in vivo culture, creating an optimal environment for organoid growth and the development of a chimeric vessel network between the host and organoids. Organ-on-chip technology permits the in vitro culture of organoids, enabling researchers to manipulate the microenvironment and investigate the key factors that influence organoid development. Lastly, ECMs have been discovered to aid the formation of blood vessels during organoid differentiation. ECMs from animal tissue have been particularly successful, although the underlying mechanisms require further research. Future research building upon these recent studies may enable the generation of functional kidney tissues for replacement therapies.
2022
Aceves, Jeffrey O.; Heja, Szilvia; Kobayashi, Kenichi; Robinson, Sanlin S.; Miyoshi, Tomoya; Matsumoto, Takuya; Schäffers, Olivier J. M.; Morizane, Ryuji; Lewis, Jennifer A.
3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake Journal Article
In: Sci Rep, vol. 12, no. 1, 2022, ISSN: 2045-2322.
@article{Aceves2022,
title = {3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake},
author = {Jeffrey O. Aceves and Szilvia Heja and Kenichi Kobayashi and Sanlin S. Robinson and Tomoya Miyoshi and Takuya Matsumoto and Olivier J. M. Schäffers and Ryuji Morizane and Jennifer A. Lewis},
doi = {10.1038/s41598-022-19293-3},
issn = {2045-2322},
year = {2022},
date = {2022-12-00},
journal = {Sci Rep},
volume = {12},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {Abstract Three-dimensional, organ-on-chip models that recapitulate kidney tissue are needed for drug screening and disease modeling. Here, we report a method for creating a perfusable 3D proximal tubule model composed of epithelial cells isolated from kidney organoids matured under static conditions. These organoid-derived proximal tubule epithelial cells (OPTECs) are seeded in cylindrical channels fully embedded within an extracellular matrix, where they form a confluent monolayer. A second perfusable channel is placed adjacent to each proximal tubule within these reusable multiplexed chips to mimic basolateral drug transport and uptake. Our 3D OPTEC-on-chip model exhibits significant upregulation of organic cation (OCT2) and organic anion (OAT1/3) transporters, which leads to improved drug uptake, compared to control chips based on immortalized proximal tubule epithelial cells. Hence, OPTEC tubules exhibit a higher normalized lactate dehydrogenase (LDH) release, when exposed to known nephrotoxins, cisplatin and aristolochic acid, which are diminished upon adding OCT2 and OAT1/3 transport inhibitors. Our integrated multifluidic platform paves the way for personalized kidney-on-chip models for drug screening and disease modeling. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tekguc, MURAT; GAAL, RONALD C. VAN; UZEL, SEBASTIEN G. M.; GUPTA, NAVIN; RIELLA, LEONARDO V.; LEWIS, JENNIFER A.; MORIZANE, RYUJI
Kidney organoids: a pioneering model for kidney diseases Journal Article
In: Translational Research, vol. 250, pp. 1–17, 2022, ISSN: 1931-5244.
@article{Tekguc2022,
title = {Kidney organoids: a pioneering model for kidney diseases},
author = {MURAT Tekguc and RONALD C. VAN GAAL and SEBASTIEN G.M. UZEL and NAVIN GUPTA and LEONARDO V. RIELLA and JENNIFER A. LEWIS and RYUJI MORIZANE},
doi = {10.1016/j.trsl.2022.06.012},
issn = {1931-5244},
year = {2022},
date = {2022-12-00},
journal = {Translational Research},
volume = {250},
pages = {1--17},
publisher = {Elsevier BV},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hiratsuka, Ken; Miyoshi, Tomoya; Kroll, Katharina T.; Gupta, Navin R.; Valerius, M. Todd; Ferrante, Thomas; Yamashita, Michifumi; Lewis, Jennifer A.; Morizane, Ryuji
Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery Journal Article
In: Sci. Adv., vol. 8, no. 38, 2022, ISSN: 2375-2548.
@article{Hiratsuka2022,
title = {Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery},
author = {Ken Hiratsuka and Tomoya Miyoshi and Katharina T. Kroll and Navin R. Gupta and M. Todd Valerius and Thomas Ferrante and Michifumi Yamashita and Jennifer A. Lewis and Ryuji Morizane},
doi = {10.1126/sciadv.abq0866},
issn = {2375-2548},
year = {2022},
date = {2022-09-23},
journal = {Sci. Adv.},
volume = {8},
number = {38},
publisher = {American Association for the Advancement of Science (AAAS)},
abstract = {
Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease.
PKHD1
-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease.
-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.
Rizki-Safitri, Astia; Gupta, Navin; Hiratsuka, Ken; Kobayashi, Kenichi; Zhang, Chengcheng; Ida, Kazumi; Satlin, Lisa M.; Morizane, Ryuji
Live functional assays reveal longitudinal maturation of transepithelial transport in kidney organoids Journal Article
In: Front. Cell Dev. Biol., vol. 10, 2022, ISSN: 2296-634X.
@article{Rizki-Safitri2022,
title = {Live functional assays reveal longitudinal maturation of transepithelial transport in kidney organoids},
author = {Astia Rizki-Safitri and Navin Gupta and Ken Hiratsuka and Kenichi Kobayashi and Chengcheng Zhang and Kazumi Ida and Lisa M. Satlin and Ryuji Morizane},
doi = {10.3389/fcell.2022.978888},
issn = {2296-634X},
year = {2022},
date = {2022-08-15},
journal = {Front. Cell Dev. Biol.},
volume = {10},
publisher = {Frontiers Media SA},
abstract = {Kidney organoids derived from hPSCs have opened new opportunities to develop kidney models for preclinical studies and immunocompatible kidney tissues for regeneration. Organoids resemble native nephrons that consist of filtration units and tubules, yet little is known about the functional capacity of these organoid structures. Transcriptomic analyses provide insight into maturation and transporter activities that represent kidney functions. However, functional assays in organoids are necessary to demonstrate the activity of these transport proteins in live tissues. The three-dimensional (3D) architecture adds complexity to real-time assays in kidney organoids. Here, we develop a functional assay using live imaging to assess transepithelial transport of rhodamine 123 (Rh123), a fluorescent substrate of P-glycoprotein (P-gp), in organoids affixed to coverslip culture plates for accurate real-time observation. The identity of organoid structures was probed using Lotus Tetragonolobus Lectin (LTL), which binds to glycoproteins present on the surface of proximal tubules. Within 20 min of the addition of Rh123 to culture media, Rh123 accumulated in the tubular lumen of organoids. Basolateral-to-apical accumulation of the dye/marker was reduced by pharmacologic inhibition of MDR1 or OCT2, and OCT2 inhibition reduced the Rh123 uptake. The magnitude of Rh123 transport was maturation-dependent, consistent with MDR1 expression levels assessed by RNA-seq and immunohistochemistry. Specifically, organoids on day 21 exhibit less accumulation of Rh123 in the lumen unlike later-stage organoids from day 30 of differentiation. Our work establishes a live functional assessment in 3D kidney organoids, enabling the functional phenotyping of organoids in health and disease. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gupta, Navin; Morizane, Ryuji
Kidney development to kidney organoids and back again Journal Article
In: Semin Cell Dev Biol, vol. 127, pp. 68–76, 2022, ISSN: 1096-3634.
@article{pmid34627669,
title = {Kidney development to kidney organoids and back again},
author = {Navin Gupta and Ryuji Morizane},
doi = {10.1016/j.semcdb.2021.09.017},
issn = {1096-3634},
year = {2022},
date = {2022-07-01},
journal = {Semin Cell Dev Biol},
volume = {127},
pages = {68--76},
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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
Gupta, Navin; Matsumoto, Takuya; Hiratsuka, Ken; Saiz, Edgar Garcia; Galichon, Pierre; Miyoshi, Tomoya; Susa, Koichiro; Tatsumoto, Narihito; Yamashita, Michifumi; Morizane, Ryuji
Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair Journal Article
In: Sci Transl Med, vol. 14, no. 634, pp. eabj4772, 2022, ISSN: 1946-6242.
@article{pmid35235339,
title = {Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair},
author = {Navin Gupta and Takuya Matsumoto and Ken Hiratsuka and Edgar Garcia Saiz and Pierre Galichon and Tomoya Miyoshi and Koichiro Susa and Narihito Tatsumoto and Michifumi Yamashita and Ryuji Morizane},
doi = {10.1126/scitranslmed.abj4772},
issn = {1946-6242},
year = {2022},
date = {2022-03-01},
journal = {Sci Transl Med},
volume = {14},
number = {634},
pages = {eabj4772},
abstract = {Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 () and RAD51 recombinase () were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 () and RAD51 recombinase () were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.
2021
Rizki-Safitri, Astia; Traitteur, Tamara; Morizane, Ryuji
Bioengineered Kidney Models: Methods and Functional Assessments Journal Article
In: vol. 2, no. 4, 2021, ISSN: 2633-8823.
@article{Rizki-Safitri2021,
title = {Bioengineered Kidney Models: Methods and Functional Assessments},
author = {Astia Rizki-Safitri and Tamara Traitteur and Ryuji Morizane},
doi = {10.1093/function/zqab026},
issn = {2633-8823},
year = {2021},
date = {2021-06-08},
volume = {2},
number = {4},
publisher = {Oxford University Press (OUP)},
abstract = {Abstract
Investigations into bioengineering kidneys have been extensively conducted owing to their potential for preclinical assays and regenerative medicine. Various approaches and methods have been developed to improve the structure and function of bioengineered kidneys. Assessments of functional properties confirm the adequacy of bioengineered kidneys for multipurpose translational applications. This review is to summarize the studies performed in kidney bioengineering in the past decade. We identified 84 original articles from PubMed and Mendeley with keywords of kidney organoid or kidney tissue engineering. Those were categorized into 5 groups based on their approach: de-/recellularization of kidney, reaggregation of kidney cells, kidney organoids, kidney in scaffolds, and kidney-on-a-chip. These models were physiologically assessed by filtration, tubular reabsorption/secretion, hormone production, and nephrotoxicity. We found that bioengineered kidney models have been developed from simple cell cultures to multicellular systems to recapitulate kidney function and diseases. Meanwhile, only about 50% of these studies conducted functional assessments on their kidney models. Factors including cell composition and organization are likely to alter the applicability of physiological assessments in bioengineered kidneys. Combined with recent technologies, physiological assessments importantly contribute to the improvement of the bioengineered kidney model toward repairing and refunctioning the damaged kidney. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Saha, Krishanu; Sontheimer, Erik J; Brooks, P J; Dwinell, Melinda R; Gersbach, Charles A; Liu, David R; Murray, Stephen A; Tsai, Shengdar Q; Wilson, Ross C; Anderson, Daniel G; Asokan, Aravind; Banfield, Jillian F; Bankiewicz, Krystof S; Bao, Gang; Bulte, Jeff W M; Bursac, Nenad; Campbell, Jarryd M; Carlson, Daniel F; Chaikof, Elliot L; Chen, Zheng-Yi; Cheng, R Holland; Clark, Karl J; Curiel, David T; Dahlman, James E; Deverman, Benjamin E; Dickinson, Mary E; Doudna, Jennifer A; Ekker, Stephen C; Emborg, Marina E; Feng, Guoping; Freedman, Benjamin S; Gamm, David M; Gao, Guangping; Ghiran, Ionita C; Glazer, Peter M; Gong, Shaoqin; Heaney, Jason D; Hennebold, Jon D; Hinson, John T; Khvorova, Anastasia; Kiani, Samira; Lagor, William R; Lam, Kit S; Leong, Kam W; Levine, Jon E; Lewis, Jennifer A; Lutz, Cathleen M; Ly, Danith H; Maragh, Samantha; McCray, Paul B; McDevitt, Todd C; Mirochnitchenko, Oleg; Morizane, Ryuji; Murthy, Niren; Prather, Randall S; Ronald, John A; Roy, Subhojit; Roy, Sushmita; Sabbisetti, Venkata; Saltzman, W Mark; Santangelo, Philip J; Segal, David J; Shimoyama, Mary; Skala, Melissa C; Tarantal, Alice F; Tilton, John C; Truskey, George A; Vandsburger, Moriel; Watts, Jonathan K; Wells, Kevin D; Wolfe, Scot A; Xu, Qiaobing; Xue, Wen; Yi, Guohua; and, Jiangbing Zhou
The NIH Somatic Cell Genome Editing program Journal Article
In: Nature, vol. 592, no. 7853, pp. 195–204, 2021, ISSN: 1476-4687.
@article{pmid33828315,
title = {The NIH Somatic Cell Genome Editing program},
author = {Krishanu Saha and Erik J Sontheimer and P J Brooks and Melinda R Dwinell and Charles A Gersbach and David R Liu and Stephen A Murray and Shengdar Q Tsai and Ross C Wilson and Daniel G Anderson and Aravind Asokan and Jillian F Banfield and Krystof S Bankiewicz and Gang Bao and Jeff W M Bulte and Nenad Bursac and Jarryd M Campbell and Daniel F Carlson and Elliot L Chaikof and Zheng-Yi Chen and R Holland Cheng and Karl J Clark and David T Curiel and James E Dahlman and Benjamin E Deverman and Mary E Dickinson and Jennifer A Doudna and Stephen C Ekker and Marina E Emborg and Guoping Feng and Benjamin S Freedman and David M Gamm and Guangping Gao and Ionita C Ghiran and Peter M Glazer and Shaoqin Gong and Jason D Heaney and Jon D Hennebold and John T Hinson and Anastasia Khvorova and Samira Kiani and William R Lagor and Kit S Lam and Kam W Leong and Jon E Levine and Jennifer A Lewis and Cathleen M Lutz and Danith H Ly and Samantha Maragh and Paul B McCray and Todd C McDevitt and Oleg Mirochnitchenko and Ryuji Morizane and Niren Murthy and Randall S Prather and John A Ronald and Subhojit Roy and Sushmita Roy and Venkata Sabbisetti and W Mark Saltzman and Philip J Santangelo and David J Segal and Mary Shimoyama and Melissa C Skala and Alice F Tarantal and John C Tilton and George A Truskey and Moriel Vandsburger and Jonathan K Watts and Kevin D Wells and Scot A Wolfe and Qiaobing Xu and Wen Xue and Guohua Yi and Jiangbing Zhou and },
doi = {10.1038/s41586-021-03191-1},
issn = {1476-4687},
year = {2021},
date = {2021-04-01},
journal = {Nature},
volume = {592},
number = {7853},
pages = {195--204},
abstract = {The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.