In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR.
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ABSTRACT:
SUBMITTER: Charbord J
PROVIDER: S-EPMC9756392 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR.
Charbord Jérémie J Ren Lipeng L Sharma Rohit B RB Johansson Anna A Ågren Rasmus R Chu Lianhe L Tworus Dominika D Schulz Nadja N Charbord Pierre P Stewart Andrew F AF Wang Peng P Alonso Laura C LC Andersson Olov O
Nature metabolism 20210520 5
It is known that β cell proliferation expands the β cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β cell regeneration in diabetes. Here, through a new high-throughput screen using a luminescence ubiquitination-based cell cycle indicator (LUCCI) in zebrafish, we identify HG-9-91-01 as a driver of proliferation and confirm this effect in mouse and human β cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and o ...[more]
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Project description:Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes.
2025-02-28 | GSE256517 | GEO
Project description:Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes. Loss of functional β-cells is a pivotal event in the dysregulation of glucose homeostasis observed in diabetes. While the plasticity of β-cells in response to increased metabolic demand has been extensively studied, the common drivers of β-cell proliferation and the molecular mechanisms governing regeneration in humans remain elusive. Here, we investigated the proliferative response following targeted chemical ablation of β-cells using diphtheria toxin (DT) and streptozotocin (STZ) in mice. Hemizygous expression of the RIP-DTR transgene enabled efficient partial ablation of β-cells, leading to close to 50% β-cell loss five days post ablation, stabilizing at this level up to 10 weeks post ablation. Transcriptomic analysis revealed a dynamic molecular landscape following ablation, with early activation of tissue remodeling and clearance of dead cells, followed by transient activation of regenerative signaling pathways. Furthermore, we observed a distinct proliferative boost in the immediate aftermath of ablation, characterized by upregulation of cell cycle progression markers. Interestingly, long-term follow-up revealed compound stress from partial β-cell loss and high-fat diet feeding induced a robust proliferative response, albeit with a negative impact on β-cell signature. Additionally, single low-dose STZ injections induced partial β-cell loss and compensatory proliferation, with the regulatory landscape deregulated by STZ injection in the long term. The compound stress of high-fat diet and STZ ablation further altered the islet transcriptional landscape, particularly affecting metabolic pathways. Overall, our study provides insights into the dynamic response of β-cells to partial ablation and highlights the impact of compound stressors on islet function and metabolism, shedding light on potential strategies for promoting β-cell regeneration in diabetes.
2025-02-28 | GSE256518 | GEO
Project description:BackgroundThe death of epithelial cells in the proximal tubules is thought to be the primary cause of AKI, but epithelial cells that survive kidney injury have a remarkable ability to proliferate. Because proximal tubular epithelial cells play a predominant role in kidney regeneration after damage, a potential approach to treat AKI is to discover regenerative therapeutics capable of stimulating proliferation of these cells.MethodsWe conducted a high-throughput phenotypic screen using 1902 biologically active compounds to identify new molecules that promote proliferation of primary human proximal tubular epithelial cells in vitro.ResultsThe primary screen identified 129 compounds that stimulated tubular epithelial cell proliferation. A secondary screen against these compounds over a range of four doses confirmed that eight resulted in a significant increase in cell number and incorporation of the modified thymidine analog EdU (indicating actively proliferating cells), compared with control conditions. These eight compounds also stimulated tubular cell proliferation in vitro after damage induced by hypoxia, cadmium chloride, cyclosporin A, or polymyxin B. ID-8, an inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), was the top candidate identified as having a robust proproliferative effect in two-dimensional culture models as well as a microphysiologic, three-dimensional cell culture system. Target engagement and genetic knockdown studies and RNA sequencing confirmed binding of ID-8 to DYRK1A and upregulation of cyclins and other cell cycle regulators, leading to epithelial cell proliferation.ConclusionsWe have identified a potential first-in-class compound that stimulates human kidney tubular epithelial cell proliferation after acute damage in vitro.
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Project description:Partial beta cell loss induces transient compensatory proliferation I
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Project description:Partial beta cell loss induces transient compensatory proliferation II
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