Abstract:Producing a sufficient number of cardiomyocytes from pluripotent stem cells has been of great demand for cardiac regeneration therapy. However, it remains challenging to efficiently differentiate cardiomyocytes with low costs. Reportedly, granulocyte colony-stimulating factor (G-CSF) receptor (GCSFR) signaling activates signal transducers and activators of transcription (STAT) signaling and enhances cardiac differentiation from embryonic stem cells or induced pluripotent stem cells (iPSCs). To economically and… Show more
“…Thus, cytokines stimulation via receptors is critical for the activation of JAK-STAT. For instance, G-CSF prevented cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes 39 . The IL-10 receptor signaling through JAK-STAT pathway was also reported 40 .…”
Background
Ischemia-reperfusion is frequently occurred in ischemic cerebral vascular disease, during which process the inflammatory signaling played essential roles. The aim of study was to discover the efficacy of the antibody to a key immune cytokine IL-23 (anti-IL-23) for the therapy of cerebral ischemia-reperfusion injury.
Methods
We established the cerebral ischemia-reperfusion injury model by middle cerebral artery occlusion (MCAO). Anti-IL-23 injection attenuated the lesions indicated by histology study. RT-PCR and Western blot were employed to detect the mRNA and protein expression of JAK2 and STAT3 after anti-IL-23 treatment. ELISA was utilized to measure the levels of MDA (malondialdehyde) and superoxide dismutase (SOD). Moreover, curcumin and IL-6 were implicated in the endogenous intervention of IL-23/IL-23R signaling in vivo.
Results
Our data demonstrated that the treatment of anti-IL-23 might transcriptionally activate the classic immune pathway in the brain. Anti-IL-23 augment the phosphorylation levels of both JAK2 and STAT3, suggesting the amplification signaling of JAK/STAT after exogenous IL-23 intervention. Anti-IL-23 reduced the ROS molecules of STAT downstream in the serum and brain. It also alleviated the injury by lowering the levels of MDA and SOD in the serum. JAK2 inhibitor could abolish the effect of anti-IL-23 whereas JAK3 ameliorated the injury. The combination of anti-IL-23 and JAK3 displayed synergetic results.
Conclusions
In summary, this study indicated that anti-IL-23 had protection effects against cerebral ischemia-reperfusion injury by targeting the immune specific JAK2-STAT3 in JAK/STAT pathway.
“…Thus, cytokines stimulation via receptors is critical for the activation of JAK-STAT. For instance, G-CSF prevented cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes 39 . The IL-10 receptor signaling through JAK-STAT pathway was also reported 40 .…”
Background
Ischemia-reperfusion is frequently occurred in ischemic cerebral vascular disease, during which process the inflammatory signaling played essential roles. The aim of study was to discover the efficacy of the antibody to a key immune cytokine IL-23 (anti-IL-23) for the therapy of cerebral ischemia-reperfusion injury.
Methods
We established the cerebral ischemia-reperfusion injury model by middle cerebral artery occlusion (MCAO). Anti-IL-23 injection attenuated the lesions indicated by histology study. RT-PCR and Western blot were employed to detect the mRNA and protein expression of JAK2 and STAT3 after anti-IL-23 treatment. ELISA was utilized to measure the levels of MDA (malondialdehyde) and superoxide dismutase (SOD). Moreover, curcumin and IL-6 were implicated in the endogenous intervention of IL-23/IL-23R signaling in vivo.
Results
Our data demonstrated that the treatment of anti-IL-23 might transcriptionally activate the classic immune pathway in the brain. Anti-IL-23 augment the phosphorylation levels of both JAK2 and STAT3, suggesting the amplification signaling of JAK/STAT after exogenous IL-23 intervention. Anti-IL-23 reduced the ROS molecules of STAT downstream in the serum and brain. It also alleviated the injury by lowering the levels of MDA and SOD in the serum. JAK2 inhibitor could abolish the effect of anti-IL-23 whereas JAK3 ameliorated the injury. The combination of anti-IL-23 and JAK3 displayed synergetic results.
Conclusions
In summary, this study indicated that anti-IL-23 had protection effects against cerebral ischemia-reperfusion injury by targeting the immune specific JAK2-STAT3 in JAK/STAT pathway.
“…In addition, JAK Inhibitor I perturbed BSA-FL-mediated increases in the STAT3 phosphorylation and myocardial differentiation efficiency. These findings suggest that the artificial GCSFR-mediated signal transduction in response to a surrogate ligand activates the JAK/STAT pathway, contributing to differentiation preferential to cardiomyocytes rather than to other cell types [122]. Therefore, the artificial GCSFR we constructed would be a favorable and economical tool to enhance the cardiomyocyte creation from PSCs (Table 1).…”
Section: Stat3 Activation Through Artificial Receptors For Myocardial Differentiationmentioning
confidence: 96%
“…Using the above technologies, we recently reported a novel strategy to improve the differentiation efficiency from miPSCs to cardiomyocytes by the economical activation of G-CSF/STAT3 signaling in response to a surrogate ligand [122]. As mentioned in the previous section, G-CSF is a well-known hematopoietic cytokine that regulates stem cell mobilization and anti-apoptosis via JAK/STAT signal activation [42,43,129,130].…”
Section: Stat3 Activation Through Artificial Receptors For Myocardial Differentiationmentioning
confidence: 99%
“…Although recombinant G-CSF is clinically used for chemo-associated neutropenia treatment in cancer patients, G-CSF is expensive for repetitive usages. Thus, we constructed a chimeric antigen/GCSFR responsive to cognate artificial antigens, fluorescein-conjugated bovine serum albumin (BSA-FL) [122]. BSA-FL is inexpensive, chemically stable, and physiologically inactive compared to recombinant G-CSF, and it is expected to bind to this artificial receptor, specifically activating the downstream signaling pathways in the targeted cells.…”
Section: Stat3 Activation Through Artificial Receptors For Myocardial Differentiationmentioning
Heart disease is the most common cause of death in developed countries, but the medical treatments for heart failure remain limited. In this context, the development of cardiac regeneration therapy for severe heart failure is important. Owing to their unique characteristics, including multiple differentiation and infinitive self-renewal, pluripotent stem cells can be considered as a novel source for regenerative medicine. Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling plays critical roles in the induction, maintenance, and differentiation of pluripotent stem cells. In the heart, JAK/STAT3 signaling has diverse cellular functions, including myocardial differentiation, cell cycle re-entry of matured myocyte after injury, and anti-apoptosis in pathological conditions. Therefore, regulating STAT3 activity has great potential as a strategy of cardiac regeneration therapy. In this review, we summarize the current understanding of STAT3, focusing on stem cell biology and pathophysiology, as they contribute to cardiac regeneration therapy. We also introduce a recently reported therapeutic strategy for myocardial regeneration that uses engineered artificial receptors that trigger endogenous STAT3 signal activation.
“…A great example will be of hiPSCs with engineered artificial receptors and surrogate antigens (low cost) that can trigger endogenous signal transduction pathways in a dose-dependent manner. STAT3 was activated through signal cascade by an engineered artificial receptor which prevented heart failure and guided hiPSC-CMs into more mature CMs upon doxorubicin administration [ 113 ]. Fig.…”
Section: The Future Of Modeling Using Hipscsmentioning
Purpose of Review
Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient’s unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology.
Recent Findings
Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology.
Summary
When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals’ treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.
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