Caspase 9-induced apoptosis for efficient fetal cell ablation and disease modeling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1187456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31375092_1.fastq.gz | Fastqsanger.gz | |||
| SRR31375092_2.fastq.gz | Fastqsanger.gz | |||
| SRR31375093_1.fastq.gz | Fastqsanger.gz | |||
| SRR31375093_2.fastq.gz | Fastqsanger.gz | |||
| SRR31375094_1.fastq.gz | Fastqsanger.gz |
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Project description:Animal models for targeted cell ablation are invaluable in the field of biology and medicine. Specifically, fetal targeted cell ablation has the potential for organ regeneration and xenotransplantation. Previous methods involve conventional knockout models, which offers limited control over severity, or conditional ablation models, which use inducers that are harmful to fetuses. In this study, we apply the inducible caspase 9 (iC9) system to target mouse fetal nephron progenitor cells. It triggers specific, rapid, and efficient target cell ablation through the intrinsic apoptosis pathway by the administration of a safe, placental-permeable inducer. This feature allowed for precise adjustment of severity based on the timing of administration, enabling the creation of a viable severe kidney failure model. We also demonstrate that cells with low iC9 expression levels and those in the solid organ state are less susceptible to apoptosis induction. RNA-seq of wild type mouse fetal kidneys revealed that DNA damage response is enhanced after dissociation, suggesting that it is the underlying mechanism for the reduced susceptibility to apoptosis in solid-state cells compared to single-cell states. Apoptosis can still be triggered in these conditions by the combined inhibition of X-linked inhibitor of apoptosis protein. This approach will not only facilitate the study of mechanisms involved in induced cell death but also enhance its utility as a research tool, including for fetal organ transplantation models.
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Project description:Fetal cell ablation models are crucial for studying congenital diseases, organ regeneration, and xenotransplantation. However, conventional knockout models offer limited control over disease severity, while conditional ablation models often require fetus-harming inducers. In the present study, we demonstrate that the inducible caspase 9 system enables precise targeting of fetal nephron progenitor cells in mice through the intrinsic apoptotic pathway. Using a safe, placenta-permeable inducer, this system facilitates specific, rapid, and efficient cell ablation. The system's temporal control allows precise adjustment of disease severity, generating reproducible models ranging from congenital kidney deficiency to severe chronic kidney disease. Cells with low expression levels of inducible caspase 9 and those in solid organs are less susceptible to apoptosis. However, this limitation can be overcome by inhibiting the X-linked inhibitor of apoptosis protein, thereby expanding the system's applicability. Additionally, this model provides a developmental environment suitable for chimeric kidney regeneration. This system advances understanding of induced cell death mechanisms, enhances pathological research tools, and supports therapeutic development in kidney disease and xenotransplantation applications.
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Project description:Apoptosis and autophagy are programs of controlled cellular suicide or survival, closely interconnected at multiple levels to ensure balanced answers to stress signals, and often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end–directed transport of autophagic and endosomal vesicles as molecular interaction partner of activated caspase 8. The absence of FYCO1 sensitized cells to basal and TRAIL induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC), caused by defective interaction with the CCZ1-MON1A complex, necessary to activate RAB7A and allow proper endosome/autophagosome maturation and fusion with lysosomes. We demonstrated that FYCO1 is a novel and specific caspase 8 substrate, and that the cleavage at aspartate 1306 inactivates its function, allowing for the progression of apoptosis. Furthermore, a lack of FYCO1 resulted in a more efficient and prolonged formation of the TNF-R signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a natural control mechanism that fine tunes both apoptotic and inflammatory answers.
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Project description:Neurobrucellosis is a serious complication of brucellosis, which poses a significant threat to human health and quality of life. The origin of this phenomenon is that the patients are more vulnerable to the development of chronic Brucella infection, which is also an important clinical problem. The regulation of Brucella on microglia apoptosis is a primary contributor to chronic neurobrucellosis, nevertheless, the precise molecular mechanism remains incompletely understood. In our research, human microglial clone 3 (HMC3) cells were infected with Brucella suis vaccine strain S2 (B. suis S2) at different MOI for different times to evaluate the influences of B. suis S2 on the IRE1/Caspase-12/Caspase-3 pathway. Subsequently, under the conditions of IRE1/Caspase-12/Caspase-3 pathway was suppressed by B. suis S2, CALR protein was screened by ubiquitin-modified proteomics. Eventually, we infected CALR-overexpression and -knockdown HMC3 cell lines with B. suis S2 to elucidate the molecular mechanism by which the B. suis S2 inhibited HMC3 cells apoptosis. In summary, we confirm that B. suis S2 inhibits apoptosis in HMC3 cells mediated by the IRE1/Caspase-12/Caspase-3 pathway through modulation of CALR ubiquitination. Our study establishes the theoretical foundation for investigating the mechanisms underlying neurobrucellosis and provides a guidance for the clinical treatment of neurobrucellosis.
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Project description:Cell death is a fundamental process for health and disease. Emerging research unveiled numerous distinct cell death modalities with similar and intertwined signaling pathways, but different outcomes, rising the need to understand the decision points during cell death signaling. Paracetamol (Acetaminophen, APAP)-induced hepatocyte death includes several apoptotic processes, but eventually ends as oncotic necrosis without any caspase activation. Here, we studied this paradoxical form of cell death and revealed that APAP not only fails to activate caspases, but also strongly impedes their activation upon classical apoptosis induction. We explored different hypotheses and deciphered that high oxidative stress consistently blocks caspase activity. Importantly, caspase inhibition and the associated switch from apoptotic to necrotic cell death is reversible through the administration of antioxidants. Thus, exemplified by APAP-induced cell death, our study stresses that the cellular redox status is a critical decision maker between different forms of cell death as it directly affects caspase activity.
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Project description:Jörg W. Stucki & Hans-Uwe Simon. Mathematical modeling of the regulation of caspase-3 activation and degradation. Journal of Theoretical Biology 234, 1 (2005).
Caspases are thought to be important players in the execution process of apoptosis. Inhibitors of apoptosis (IAPs) are able to block caspases and therefore apoptosis. The fact that a subgroup of the IAP family inhibits active caspases implies that not each caspase activation necessarily leads to apoptosis. In such a scenario, however, processed and enzymically active caspases should somehow be removed. Indeed, IAP–caspase complexes covalently bind ubiquitin, resulting in degradation by the 26S proteasome. Following release from mitochondria, IAP antagonists (e.g. second mitochondrial activator of caspases (Smac)) inactivate IAPs. Moreover, although pro-apoptotic factors such as irradiation or anti-cancer drugs may release Smac from mitochondria in tumor cells, high cytoplasmic survivin and ML-IAP levels might be able to neutralize it and, consequently, IAPs would further be able to bind activated caspases. Here, we propose a simple mathematical model, describing the molecular interactions between Smac deactivators, Smac, IAPs, and caspase-3, including the requirements for both induction and prevention of apoptosis, respectively. In addition, we predict a novel mechanism of caspase-3 degradation that might be particularly relevant in long-living cells.
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