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Expert Opinion on Biological Therapy Aug 2020Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by... (Review)
Review
INTRODUCTION
Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin.
AREAS COVERED
This review covers the latest advances in cell-based therapies for the treatment and prevention of T1D. Topics include adoptive transfer of cells with increased immunoregulatory potential for β-cell protection, and β-cell replacement strategies such as generation of insulin-producing β-like cells from unlimited sources.
EXPERT OPINION
Cell therapy provides an opportunity to prevent or reverse T1D. Adoptive transfer of autologous cells having enhanced immunomodulatory properties can suppress autoimmunity and preserve β-cells. Such therapies have been made possible by a combination of genome-editing techniques and transplantation of tolerogenic cells. modified autologous hematopoietic stem cells and tolerogenic dendritic cells may protect endogenous and newly generated β-cells from a patient's autoimmune response without hampering immune surveillance for infectious agents and malignant cellular transformations. However, methods to generate cells that meet quality and safety standards for clinical applications require further refinement.
Topics: Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Diabetes Mellitus, Type 1; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Human Embryonic Stem Cells; Humans; Insulin-Secreting Cells; T-Lymphocytes, Regulatory
PubMed: 32299257
DOI: 10.1080/14712598.2020.1748596 -
Journal of Hepatology Oct 2019Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo...
BACKGROUND & AIMS
Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI.
METHODS
The role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion.
RESULTS
In human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis.
CONCLUSION
Our novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, providing evidence of a potential therapeutic target for the management of sterile liver inflammation in transplant recipients.
LAY SUMMARY
In the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult.
Topics: Animals; Apoptosis; Cell Cycle Proteins; Cells, Cultured; Disease Models, Animal; Hippo Signaling Pathway; Humans; Inflammation; Liver; Liver Diseases; Liver Transplantation; Oxidative Stress; Protein Serine-Threonine Kinases; Reperfusion Injury; Shock, Hemorrhagic; Signal Transduction; Transcription Factors; Warm Ischemia
PubMed: 31201834
DOI: 10.1016/j.jhep.2019.05.029 -
Sao Paulo Medical Journal = Revista... 2021
Topics: COVID-19; Humans; Organ Transplantation; SARS-CoV-2
PubMed: 34190892
DOI: 10.1590/1516-3180.2021.139420052021 -
Journal of Hepatology Apr 2022Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses...
BACKGROUND & AIMS
Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied.
METHODS
We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression).
RESULTS
In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers.
CONCLUSION
These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers.
LAY SUMMARY
This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans.
Topics: Animals; Humans; Ikaros Transcription Factor; Inflammasomes; Inflammation; Ischemia; Liver; Liver Diseases; Mice; Mice, Inbred C57BL; Pyroptosis; Reperfusion Injury; Sirtuin 1; Transcription Factors
PubMed: 34871625
DOI: 10.1016/j.jhep.2021.11.026 -
Cold Spring Harbor Perspectives in... Jan 2021Treatment of type 1 diabetes with insulin injection is expensive, complicated, and insufficient. While cadaveric islet transplantations coupled with immunosuppressants... (Review)
Review
Treatment of type 1 diabetes with insulin injection is expensive, complicated, and insufficient. While cadaveric islet transplantations coupled with immunosuppressants can cure diabetes, the scarcity of acceptable islets is problematic. Developmental research on pancreas formation has informed in vitro differentiation of human pluripotent stem cells into functional islets. Although generating β cells from stem cells offers a potential cure for type 1 diabetes, several challenges remain, including protecting the cells from the immune system.
Topics: Animals; Cell Differentiation; Cell Proliferation; Diabetes Mellitus, Type 1; Humans; Immune System; Immunosuppression Therapy; Insulin; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mice; Pancreas; Risk; Stem Cell Transplantation; Stem Cells
PubMed: 32122884
DOI: 10.1101/cshperspect.a035741 -
The Journal of Clinical Investigation Feb 2023Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in...
Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.
Topics: Animals; Humans; Mice; Carcinoembryonic Antigen; Cell Adhesion Molecules; Liver; Liver Transplantation; Neutrophils; Reperfusion Injury; Sphingosine-1-Phosphate Receptors; Transcription Factors
PubMed: 36719377
DOI: 10.1172/JCI162940 -
Frontiers in Clinical Diabetes and... 2024
PubMed: 38711746
DOI: 10.3389/fcdhc.2024.1388904 -
Current Diabetes Reports Nov 2020Human pancreas-on-a-chip (PoC) technology is quickly advancing as a platform for complex in vitro modeling of islet physiology. This review summarizes the current... (Review)
Review
PURPOSE OF REVIEW
Human pancreas-on-a-chip (PoC) technology is quickly advancing as a platform for complex in vitro modeling of islet physiology. This review summarizes the current progress and evaluates the possibility of using this technology for clinical islet transplantation.
RECENT FINDINGS
PoC microfluidic platforms have mainly shown proof of principle for long-term culturing of islets to study islet function in a standardized format. Advancement in microfluidic design by using imaging-compatible biomaterials and biosensor technology might provide a novel future tool for predicting islet transplantation outcome. Progress in combining islets with other tissue types gives a possibility to study diabetic interventions in a minimal equivalent in vitro environment. Although the field of PoC is still in its infancy, considerable progress in the development of functional systems has brought the technology on the verge of a general applicable tool that may be used to study islet quality and to replace animal testing in the development of diabetes interventions.
Topics: Animals; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Lab-On-A-Chip Devices; Pancreas; Technology
PubMed: 33206261
DOI: 10.1007/s11892-020-01357-1 -
Journal of Visceral Surgery Oct 2019The circumportal pancreas (CPP) is a normal though rare anatomical variant of the pancreas resulting from fusion of ventral and dorsal pancreatic buds during...
The circumportal pancreas (CPP) is a normal though rare anatomical variant of the pancreas resulting from fusion of ventral and dorsal pancreatic buds during embryogenesis. Preoperative imaging in a 69-year-old man displayed the presence of a CPP completely encasing the portal vein. For pancreatic resection, missing a CPP is associated with a higher risk of postoperative complications.
Topics: Adenocarcinoma; Aged; Humans; Magnetic Resonance Imaging; Male; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Portal Vein
PubMed: 30773440
DOI: 10.1016/j.jviscsurg.2019.02.001