Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus

Uhlemeyer, Celina; Müller, Nadine; Rieck, Michael; Kuboth, Jennifer; Schlegel, Caroline; Griess, Kerstin; Dorweiler, Tim Florian; Heiduschka, Sonja; Eckel, Jürgen; Roden, Michael; Lammert, Eckhard; Stoffel, Markus; Belgardt, Bengt F.

doi:10.1016/j.molmet.2022.101650

Cited by 8 publications

(6 citation statements)

References 52 publications

(76 reference statements)

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“…Previous studies reported conflicting results on the role of p53 in pancreatic β-cells. It has been demonstrated that p53 target genes are upregulated in diabetic mice [ 30 ] and p53 deletion does not change the insulin secretion or the number of β-cells in diabetes mouse models [ 31 ]. In contrast, another report showed that a specific deletion of p53 in mouse β-cells protects them against cell death induced by glucokinase mutation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

p53 Inhibition in Pancreatic Progenitors Enhances the Differentiation of Human Pluripotent Stem Cells into Pancreatic β-Cells

Aigha

Abdelalim

2023

Stem Cell Rev and Rep

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The multipotent pancreatic progenitor cells (MPCs) co-expressing the transcription factors, PDX1 and NKX6.1, are the source of functional pancreatic β-cells. The aim of this study was to examine the effect of p53 inhibition in MPCs on the generation of PDX1+/NKX6.1+ MPCs and pancreatic β-cell generation. Human embryonic stem cells (hESCs) were differentiated into MPCs and β-cells. hESC-MPCs (stage 4) were treated with different concentrations of p53 inhibitors, and their effect was evaluated using different approaches. NKX6.1 was overexpressed during MPCs specification. Inhibition of p53 using pifithrin-μ (PFT-μ) at the MPC stage resulted in a significant increase in the number of PDX1+/NKX6.1+ cells and a reduction in the number of CHGA+/NKX6.1− cells. Further differentiation of MPCs treated with PFT-μ into pancreatic β-cells showed that PFT-μ treatment did not significantly change the number of C-Peptide+ cells; however, the number of C-PEP+ cells co-expressing glucagon (polyhormonal) was significantly reduced in the PFT-μ treated cells. Interestingly, overexpression of NKX6.1 in hESC-MPCs enhanced the expression of key MPC genes and dramatically suppressed p53 expression. Our findings demonstrated that the p53 inhibition during stage 4 of differentiation enhanced MPC generation, prevented premature endocrine induction and favored the differentiation into monohormonal β-cells. These findings suggest that adding a p53 inhibitor to the differentiation media can significantly enhance the generation of monohormonal β-cells. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

p53 Inhibition in Pancreatic Progenitors Enhances the Differentiation of Human Pluripotent Stem Cells into Pancreatic β-Cells

Aigha

Abdelalim

2023

Stem Cell Rev and Rep

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“…For instance, mice harboring knock-out of the DNA ligase Lig4 (leading to increased endogenous unrepaired DNA strand breaks) and a point mutation in Tp53 (R172P) that mitigates p53-induced apoptosis, leads to very early onset of diabetes, involving both senescent β-cells and progressive loss of β-cell mass due to p53-independent apoptosis ( 100 ). In line with these findings, selective ablation of Tp53 failed to ameliorate dysglycemia induced by genetic modifications, diet, or pharmacologic agents ( 103 ), however β-cell senescence was not addressed. Similarly, deletion of the chromosome licensing factor Pttg1 (encoding the protein Securin), leads to a mixture of both senescent and apoptotic β-cells ( 99 ).…”

Section: Lessons On β-Cell Senescence From Genetic Modelsmentioning

confidence: 96%

Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies

Cha,

Aguayo-Mazzucato,

Thompson

2023

Front. Endocrinol.

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Cellular senescence is a response to a wide variety of stressors, including DNA damage, oncogene activation and physiologic aging, and pathologically accelerated senescence contributes to human disease, including diabetes mellitus. Indeed, recent work in this field has demonstrated a role for pancreatic β-cell senescence in the pathogenesis of Type 1 Diabetes, Type 2 Diabetes and monogenic diabetes. Small molecule or genetic targeting of senescent β-cells has shown promise as a novel therapeutic approach for preventing and treating diabetes. Despite these advances, major questions remain around the molecular mechanisms driving senescence in the β-cell, identification of molecular markers that distinguish senescent from non-senescent β-cell subpopulations, and translation of proof-of-concept therapies into novel treatments for diabetes in humans. Here, we summarize the current state of the field of β-cell senescence, highlighting insights from mouse models as well as studies on human islets and β-cells. We identify markers that have been used to detect β-cell senescence to unify future research efforts in this field. We discuss emerging concepts of the natural history of senescence in β-cells, heterogeneity of senescent β-cells subpopulations, role of sex differences in senescent responses, and the consequences of senescence on integrated islet function and microenvironment. As a young and developing field, there remain many open research questions which need to be addressed to move senescence-targeted approaches towards clinical investigation.

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“…In apparent contrast with these results, studies using models of type 1 (autoimmune) or type 2 (non-autoimmune) diabetes revealed that deletion of Bax alone or combined loss of Bax and Bak1 [421,422], deletion of the gene encoding BIM, alone or together with the gene encoding PUMA [418,[423][424][425] as well as the loss of BMF [426], protect pancreatic β cells from autoimmune destruction. Moreover, the absence of BIM prevents the emergence of type 1 diabetes in non-obese diabetic (NOD) mice [418,423], while ablation of Trp53 in pancreatic β cells failed to halt cell death in multiple experimental models of diabetes [427].…”

Section: Autoimmune and Inflammatory Diseasesmentioning

confidence: 99%

Apoptotic cell death in disease—Current understanding of the NCCD 2023

et al. 2023

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Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

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Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus

Cited by 8 publications

References 52 publications

p53 Inhibition in Pancreatic Progenitors Enhances the Differentiation of Human Pluripotent Stem Cells into Pancreatic β-Cells

p53 Inhibition in Pancreatic Progenitors Enhances the Differentiation of Human Pluripotent Stem Cells into Pancreatic β-Cells

Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies

Apoptotic cell death in disease—Current understanding of the NCCD 2023

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