Trigger 6 - Diabetes and Islet Transplantation Flashcards
Type 1 diabetes is caused by the autoimmune destruction of the pancreatic islet ______ cells.
β
True or False:
Loss of β-cells/insulin results in hypoglycemia.
False
Explain the main treatment for type 1 diabetes and its frequency.
The main treatment for type 1 diabetes is multiple daily subcutaneous insulin injections or insulin pumps. Generally, individuals may require around 6 injections a day.
What are the consequences of suboptimal blood glucose homeostasis in type 1 diabetes?
a) Respiratory issues
b) Microvascular complications
c) Joint pain
d) Skin disorders
b) Microvascular complications
Define hypoglycemia unawareness.
Hypoglycemia unawareness is a condition where individuals with diabetes are unable to recognize the symptoms of low blood sugar, leading to a lack of awareness and potentially severe consequences.
True or False: Loss of 60% of islet β-cells results in decreased blood glucose concentration.
False
Explain the role of insulin pumps in managing diabetes, highlighting a potential drawback.
Insulin pumps respond to changes in blood glucose, delivering insulin when needed. However, a drawback is that individuals have to wear the technological device continuously.
Which organ in the body produces insulin?
a) Liver
b) Kidney
c) Pancreas
d) Heart
c) Pancreas
What are the Islets of Langerhans?
Islets of Langerhans are highly specialized endocrine organs that make up approximately 2% of the pancreas.
Approximately 60-80% of the cells within the islets are insulin-secreting ______ cells.
β-cells
What is the primary function of alpha cells in the Islets of Langerhans?
a) Produce insulin
b) Secrete glucagon
c) Regulate blood pressure
d) Synthesize enzymes for digestion
b) Secrete glucagon
Explain the paracrine interactions within the Islets of Langerhans.
Important paracrine interactions exist between β-cells and other endocrine non-β-cells within the islets. For example, alpha cells secrete the regulating hormone glucagon.
What role do Islet endothelial cells play in ensuring optimal β-cell function?
Islet endothelial cells play a crucial role in ensuring optimal β-cell function. They contribute to a higher blood flow to the islets, providing high oxygenation and blood supply, allowing β-cells to respond quickly to fluctuations in blood glucose.
True or False:
Approximately 90-95% of cells within the Islets of Langerhans are insulin-secreting β-cells.
False
Why is the high blood flow to the Islets of Langerhans important for their function?
a) Promotes insulin resistance
b) Enhances β-cell response to glucose
c) Increases glucagon production
d) Causes inflammation in the pancreas
b) Enhances β-cell response to glucose
Explain the transplant procedure for Clinical Human Islet Transplantation.
The transplant procedure takes place in the X-Ray department and involves minor surgery. Human islets are transplanted into the portal vein of the liver, where they are dispersed through portal vasculature and embedded in the liver. The procedure is relatively well-functioning, and individuals typically undergo it with local anesthesia, spending only a few days in the hospital.
Where are human islets transplanted in Clinical Human Islet Transplantation?
a) Spleen
b) Kidney
c) Portal vein of the liver
d) Lungs
c) Portal vein of the liver
True or False:
Clinical Human Islet Transplantation involves major surgery.
False
The catheter is inserted into the portal vein via the liver, identified using ________.
ultrasound
Highlight a significant advancement in Clinical Human Islet Transplantation achieved by a group in Canada.
A significant advancement in transplantation was achieved by a group in Canada, involving vast improvements in clinical transplantation by modifying the procedure. They outlined specific immunosuppressive measures to ensure that transplanted islets were not attacked by the body’s immune system, preventing graft rejection.
The group in Canada outlined a minimal dosage of donor islets that need to be transplanted, crucial for ensuring transplanted islets function well and survive for at least a few years to help control poor ________.
glucose
True or False:
Individuals undergoing Clinical Human Islet Transplantation may stay in the hospital for an extended period.
False
What is one advantage of insulin therapy?
a) Increased risk of hypoglycemia
b) Digitalization increasing inefficiency
c) Weight gain
d) Unhealthy weight loss
b) Digitalization increasing efficiency
True or False:
Incorrect insulin injections may lead to high blood sugar levels.
False
Explain a potential consequence of severe hypoglycemia in insulin therapy.
Severe hypoglycemia, which cannot be treated by oneself, may lead to loss of consciousness or coma.
Insulin therapy helps prevent other diabetes complications, such as heart disease, kidney disease, nerve damage, and vision problems, contributing to an ↑ quality of life. However, it does not cure/prevent diabetes; it is only a form of ________.
management
What is a disadvantage of insulin therapy related to weight?
a) Weight loss
b) Unhealthy weight gain
c) Dehydration
d) Increased urination
b) Unhealthy weight gain
True or False:
Insulin therapy provides flexibility with dosage and types of insulin.
True
Despite new technology, insulin therapy requires constant ________ throughout the day.
monitoring
Explain why insulin therapy is considered a form of management rather than a cure for diabetes.
Insulin therapy manages blood sugar levels but does not cure or prevent diabetes.
True or False:
One advantage of insulin therapy is its affordability.
False
Fill in the Gap:
Insulin needs to be stored at temperatures below ________°C and ideally between 2-4°C.
25°C
What is a potential benefit of vaccines in the context of diabetes?
a) Weight loss
b) Prevention of autoimmune response
c) Increased insulin dose
d) Induction of hypoglycemia
b) Prevention of autoimmune response
Explain the potential benefit of novel drugs for insulin therapy.
Novel drugs aim to aid insulin therapy, potentially leading to insulin independence and a decrease in the risk of hypoglycemia.
True or False:
Islet transplantation may eliminate the need for insulin therapy.
True
Metformin reduces insulin dose needed in type 1 diabetics; however, there is no clear evidence to suggest improved ________ control.
glycaemic
Explain the potential benefit of Remygen in diabetes treatment.
Remygen, an investigational Gamma-aminobutyric acid drug, has an immuno-modulatory effect and potentially regenerates β-cells. It works as well as whole pancreas transplantation.
What is a potential advantage of islet transplantation?
a) Constant monitoring
b) Increased risk of hypoglycemia
c) Insulin independence
d) Uncontrolled blood sugar levels
c) Insulin independence
Vaccines targeting coxsackievirus B are well-established, and their long-term effects are known.
False
Highlight a potential benefit of potential new therapies that aim to replace insulin therapy.
Potential new therapies have the potential to be a one-off treatment or infrequent treatments, reducing the need for constant monitoring and injections involved in insulin therapy.
True or False:
Some people have experienced 10 years of clinical benefit from potential new therapies.
True
What is a potential benefit of vaccines targeting enteroviruses in diabetes?
a) Increased insulin dependence
b) Prevention of autoimmune response
c) Weight gain
d) Induction of hypoglycemia
b) Prevention of autoimmune response
True or False:
Metformin has clear evidence indicating improved glycaemic control in type 1 diabetics.
False
Explain the potential advantage of medications aiming to aid insulin therapy in diabetes treatment.
Medications may provide a one-off treatment or infrequent treatments, reducing the burden of constant monitoring and injections associated with insulin therapy.
True or False:
There is currently no medication available to replace insulin therapy.
True
What is a potential advantage of β-cell replacement therapy?
a) Increased risk of hypoglycemia
b) Constant monitoring
c) Prevention of the need for insulin therapy
d) Uncontrolled blood sugar levels
c) Prevention of the need for insulin therapy
Vaccines targeting coxsackievirus B are currently being developed, but their long-term effects on diabetes remain ________.
unknown
Highlight the potential benefit of digitalization in insulin therapy.
Digitalization has increased the efficiency of insulin therapy, providing improved management and control of blood glucose levels.
What is the Edmonton Protocol (2000) known for in the field of islet transplantation?
The Edmonton Protocol is known for bringing vast improvements to clinical islet transplantation, offering a potential cure for a small subset of patients with Type 1 Diabetes. It allowed individuals to avoid insulin injections or pump therapy for blood glucose control.
What is a major hurdle in islet transplantation due to the shortage of donor islet material?
a) Excessive donor supply
b) Loss during post-transplantation
c) Lack of heterogeneity in donor islets
d) Inadequate donor quality
b) Loss during post-transplantation
True or False:
The Edmonton Protocol has eliminated the need for insulin therapy in all patients with Type 1 Diabetes.
False
The islet isolation process is a complex procedure requiring specialized facilities and expertise. While a donor pancreas contains approximately ∼1 million islets, only ________% are isolated after digestion, purification, and culture.
<50%
Explain a potential solution to the hurdles faced during islet transplantation, particularly the loss of beta cells during pre-transplantation culture.
Mesenchymal Stem Cells (MSCs) stem cells are proposed to help mitigate the loss of beta cells during the pre-transplantation culture period.
True or False:
Ischemia-reperfusion injury is one of the factors contributing to the loss of islets during the post-transplantation period.
True
During the early post-transplantation period (3-7 days), approximately ________% of transplanted islets are lost due to extensive islet cell death.
60-70%
What is the major hurdle known as IBMIR in islet transplantation?
a) Islet Beta-cell Mediated Inflammatory Response
b) Instant Blood-Mediated Immune Rejection
c) Ischemic Blood Mediation in Islet Rejection
d) Islet Beta-cell Mediated Immune Response
b) Instant Blood-Mediated Immune Rejection
Explain the potential benefits and challenges associated with life-long immunosuppression in islet transplantation.
Life-long immunosuppression is necessary to prevent graft rejection but comes with risks, including increased susceptibility to infections, malignancies, and organ damage. New approaches like Etanercept and anakinra show promise in mitigating these risks.
True or False:
Islet graft revascularization takes several weeks, during which post-transplant islets are avascular, leading to poor blood flow and ischemia.
True
Explain the role of pancreatic islet vascularization in transplantation and the challenges associated with it.
Pancreatic islets are highly vascularized, essential for their survival and function. While pancreas transplantation restores blood flow to islets, the isolation process in islet transplantation results in the loss of blood vessel connections. Post-transplant islets, being avascular, rely on the environment for nutrient and oxygen diffusion, affecting their survival and function.
What is the primary source of donor islets for transplantation?
a) Living donors
b) Animal donors
c) Cadaveric pancreases from deceased organ donors
d) Artificially synthesized islets
c) Cadaveric pancreases from deceased organ donors
Loss of islets during the post-transplantation period is due to hypoxic and inflammatory innate immune responses. During the immediate post-transplantation period (first 3-7 days), hurdles include hypoxia causing IBMIR (Instant Blood-Mediated Inflammatory Response) and inflammation leading to the loss of up to ________% of transplanted islets.
70%
Explain the importance of islet secretion of angiogenic factors such as VEGF-A and angiopoietin-1 and how the loss of vascular connections in the isolation process affects islet graft revascularization.
Islets secrete angiogenic factors essential for vascularization. Pancreas transplantation, where vessels remain intact, supports islet survival. However, during islet isolation, blood vessel connections are lost, and islet graft revascularization takes weeks, leading to avascular post-transplant islets, causing poor blood flow and ischemia.
Why is life-long immunosuppression necessary in islet transplantation?
a) To increase the risk of infections
b) To prevent graft survival
c) To enhance the risk of insulin resistance
d) To prevent rejection of transplanted islet cells
d) To prevent rejection of transplanted islet cells
Explain the challenges associated with life-long immunosuppression.
Challenges include patient compliance, healthcare costs for long-term use, and impact on quality of life.
Which existing drugs negatively impact β-cell survival and function in the context of life-long immunosuppression?
a) Etanercept
b) Anakinra
c) Tacrolimus and Sirolimus
d) None of the above
c) Tacrolimus and Sirolimus
What are potential methods of diagnosing allogeneic graft rejection in islet transplantation?
a) Increased insulin production
b) Unexplained hyperglycemia
c) Enhanced C-peptide levels
d) Predisposing events
b) Unexplained hyperglycemia
True or False:
Unexpected decrease in C-peptide is a potential method for diagnosing ongoing allogeneic graft rejection.
True
Explain the significance of chronic islet autoimmunity and its risk level compared to chronic rejection in islet transplantation.
Chronic islet autoimmunity poses a similar risk level to chronic rejection and is a major cause of immunological failure in islet transplantation.
What is a potential consequence of ongoing autoimmunity in islet transplantation?
a) Enhanced islet survival
b) Reduced risk of rejection
c) Improved insulin sensitivity
d) Worsening long-term functioning of transplanted islets
d) Worsening long-term functioning of transplanted islets
Why is vascularization essential for pancreatic islets in transplantation?
a) To increase islet apoptosis
b) To reduce blood flow
c) To restore blood flow to islets
d) To enhance ER stress
c) To restore blood flow to islets
True or False:
Pancreatic islets secrete angiogenic factors such as VEGF-A and angiopoietin-1.
True
Explain the role of stressors and inflammation in the context of inadequate vascular engraftment in islet transplantation.
Stressors and inflammation contribute to the apoptosis of islets in the post-transplant period, where avascular islets are exposed to conditions like hypoxia, ER stress, and ROS.
What do post-transplant islets rely on for diffusion of nutrients and oxygen?
a) Blood vessels
b) Immune cells
c) The surrounding environment
d) Stress responses
c) The surrounding environment
Why is vascularization essential for pancreatic islets in transplantation?
a) To increase islet apoptosis
b) To reduce blood flow
c) To restore blood flow to islets
d) To enhance ER stress
c) To restore blood flow to islets
True or False:
Pancreatic islets secrete angiogenic factors such as VEGF-A and angiopoietin-1.
True
Explain the role of stressors and inflammation in the context of inadequate vascular engraftment in islet transplantation.
Stressors and inflammation contribute to the apoptosis of islets in the post-transplant period, where avascular islets are exposed to conditions like hypoxia, ER stress, and ROS.
What do post-transplant islets rely on for diffusion of nutrients and oxygen?
a) Blood vessels
b) Immune cells
c) The surrounding environment
d) Stress responses
c) The surrounding environment
What percentage of transplanted islets are typically lost during the early post-transplantation period (3-7 days)?
a) 20-30%
b) 40-50%
c) 60-70%
d) 80-90%
c) 60-70%
Explain the concept of Instant Blood-Mediated Inflammatory Reactions (IBMIR) and its impact on islet transplantation.
IBMIR is a non-specific inflammatory response occurring immediately after exposure of islet grafts to the recipient’s blood in the portal vein. It involves coagulation, complement activation, and inflammatory cell infiltration, leading to platelet formation, neutrophil infiltration, and the release of proinflammatory cytokines, ultimately causing the destruction of islet cells.
IBMIR is initiated by the activation of thrombosis and coagulation pathways, with the enhancement of tissue factor (TF) expression in islets proposed as the trigger. This leads to thrombin activation and can trigger IBMIR, resulting in platelet formation and neutrophil infiltration of islets, leading to the release of proinflammatory cytokines, including IL-8, ultimately leading to the destruction of ________.
islet cells
True or False:
Autoimmune and alloimmune rejection of islets involve the innate response with macrophages and dendritic cells infiltrating into islet grafts.
True
What is presented on dendritic cells in the context of alloimmune rejection of islets?
a) Insulin
b) Autoantibodies
c) Allo-antigens
d) IL-8
c) Allo-antigens
What contributes to the loss of islets during the immediate post-transplantation period (first 3-7 days)?
a) Hyperglycemia
b) Hypoxia and inflammatory innate immune responses
c) Increased vascularization
d) Reduced inflammation
b) Hypoxia and inflammatory innate immune responses
Explain the concept of Instant Blood-Mediated Inflammatory Response (IBMIR) and its role in the loss of islets during the immediate post-transplantation period.
IBMIR is a clinically significant response where human islets, typically transplanted to the liver via the portal vein, experience up to a 70% loss due to inflammation and innate immune responses during the immediate post-transplantation period (first 3-7 days).
True or False:
Islet graft revascularization is a longer-term hurdle in post-transplantation, contributing to the loss of transplanted islets.
True
What is the primary goal of current research in the field of islet transplantation regarding donor shortage?
a) Increasing donor requirements
b) Utilizing more donors per recipient
c) Improving single donor islet transplantation success rates
d) Reducing the need for islet transplantation
c) Improving single donor islet transplantation success rates
What is the typical duration of the pretransplant culture period for most transplant centers?
a) 1-12 hours
b) 24–72 hours
c) 5-10 days
d) 2-4 weeks
b) 24–72 hours
Explain the factors contributing to the mean reduction in the islet population during the pretransplant culture period.
The mean reduction in the islet population during the pretransplant culture period is influenced by factors such as decreased extracellular matrix (ECM), loss of integrin function and expression leading to apoptosis, increased P38 and JNK phosphorylation, pro-inflammatory cytokines generated by collagenase preparations, and increased ischemia associated with ischemic cell death. Larger islets show greater signs of apoptosis due to their core being more prone to hypoxia in a non-vascularized environment.
During the pretransplant culture period, the mean reduction in the islet population is approximately ________%.
13%
True or False:
Ischemic cell death is one of the factors contributing to the loss of islets during the pretransplant culture period.
True
What do pro-inflammatory cytokines, generated during the isolation process, increase in islets during the pretransplant culture period?
a) Apoptosis and necrosis markers
b) Oxygen levels
c) Vascularization
d) Integrin function
a) Apoptosis and necrosis markers
What is the primary source of donor islet material in the context of islet transplantation?
a) Animal pancreases
b) Human blood
c) Cadaveric pancreases from deceased organ donors
d) Artificially synthesized islets
c) Cadaveric pancreases from deceased organ donors
Explain the challenges associated with the limited supply of donor islet material.
The limited supply of donor islet material is primarily sourced from cadaveric pancreases of deceased organ donors. Challenges include consent issues, logistical challenges in organ retrieval, and a small pool of donors that restrict the supply.
During the islet isolation process, a donor pancreas contains approximately ________ islets, but less than 50% are isolated after digestion, purification, and culture.
∼1 million
True or False: Factors contributing to the quality of donor islets include age, BMI, medical history, and the cause of death.
True
What potential solution is suggested to help address the loss of beta cells in culture during the pre-transplantation period?
a) Increased enzymatic digestion
b) Mechanical stress
c) MSCs Stem cells
d) Isolation process simplification
c) MSCs Stem cells
Where can Mesenchymal Stem/Stromal Cells (MSCs) be derived from?
a) Only from bone marrow
b) Only from adipose tissue
c) Only from pancreases
d) Most vascularized post-natal tissues, including pancreases, bone marrow, and adipose tissue
d) Most vascularized post-natal tissues, including pancreases, bone marrow, and adipose tissue
What is the therapeutic potential of MSCs in the context of islet transplantation?
MSCs have the potential to help islet cells function and survive after transplantation by secreting trophic factors with pro-survival, anti-apoptotic, regenerative, anti-inflammatory, and immunomodulatory properties. They also possess properties for tissue repair and regeneration.
MSCs can be grown and expanded in culture to therapeutically efficacious numbers, gaining plenty of mass for a transplant scenario through their capacity for ________.
self-renewal
True or False:
Over 1300 registered clinical trials use MSCs in a wide range of disease and transplant settings.
True
How can MSCs address the problem of suboptimal islet revascularization in islet transplantation?
a) Secretion of pro-inflammatory cytokines
b) Angiogenic trophic factors
c) Mechanical stress induction
d) Isolation process simplification
b) Angiogenic trophic factors
True or False:
MSC co-transplantation improves islet transplantation outcomes by significantly lowering average blood glucose concentrations compared to islet-alone recipients.
True
What is a significant hurdle to more widespread application of islet transplantation?
a) Islet graft rejection
b) Islet graft revascularization taking 2-4 weeks post-transplantation
c) Hypoxia during transplantation
d) Auto-reactive immune cell responses
b) Islet graft revascularization taking 2-4 weeks post-transplantation
How does MSC co-transplantation improve islet graft revascularization, and what is the associated benefit for islet graft function?
MSC co-transplantation improves islet graft revascularization, both in overall extent and rate. These improvements are associated with enhanced islet graft function, leading to improved glycaemic control and graft curative capacity.
MSCs suppress host T cell proliferation and activity, and their potential for commercial use is due to their ability to be used for ________.
every individual
True or False:
MSCs can modulate the phenotype of macrophages by inducing a shift from M1 to M2, favoring anti-inflammatory responses.
True
Which cytokine balance is favorably altered by MSCs during islet transplantation?
a) Th1/Th2
b) Th2/Th3
c) Th3/Th17
d) Th1/Th2/Th17
a) Th1/Th2
True or False:
The therapeutic effects of MSCs in islet transplantation are largely attributed to their secretory products, known as MSC secretome.
True
What is a potential issue with the rapid proliferation of MSCs in culture?
a) Enhanced insulin production
b) Tumorigenicity and cancer risk
c) Improved glucose-stimulated insulin secretion
d) Reduction in inflammatory responses
b) Tumorigenicity and cancer risk
How does co-culturing islets with MSCs improve islet transplantation outcomes, and what are the associated challenges?
Co-culturing islets with MSCs improves the functional ability of islets, making them respond better to blood glucose changes and secrete more insulin. Challenges include issues with MSC heterogeneity, safety concerns, and logistics in scaling up MSC co-culture for clinical islet transplantation.
True or False:
MSCs express a number of protein-coupled receptor ligands, with MSC1 receptor highly expressed in MSC populations.
True
Which MSC-derived secretory factor has been shown to repel pathogenic T cells and attract regulatory T cells to transplanted islets?
a) ANXA1
b) CXCL12/SDF-1
c) C3/C3a
d) MSC1 receptor
b) CXCL12/SDF-1
True or False:
Post-transplantation delivery of MSC-derived secretory products aims to reduce innate immune cell activation, inflammation, and adaptive T cell activation and proliferation.
True
True or False:
Islet transplantation outcomes are hindered by rapid deterioration of islets during the pre-transplant culture period and significant post-transplantation loss of graft function within 24-72 hours due to hypoxia, inflammation, and immunogenicity.
True
How do MSCs influence the host immune response to improve islet transplantation outcomes, particularly in modulating macrophage phenotype?
MSCs influence macrophage phenotype by shifting from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, reducing graft neutrophil infiltration and inflammation post-transplantation.
Co-transplantation of MSCs improves islet revascularization post-transplantation via wnt signaling, promoting the secretion of pro-angiogenic factors such as _________, __________, __________, __________, __________, and __________, resulting in increased extent and rate of graft revascularization.
VEGF-A, VEGF-C, VEGF-D, PIFG, IL8
Which MSC-derived soluble factors contribute to immunosuppression and improved islet function post-transplantation?
a) Interleukin-6 (IL-6)
b) Annexin A1 (ANXA1)
c) Transforming Growth Factor-β (TGF-β)
d) Matrix Metalloproteases (MMPs)
c) Transforming Growth Factor-β (TGF-β)
True or False:
MSCs secrete factors that directly enhance islet function, protect from cytokine-induced apoptosis, and improve in vivo graft function.
True
Which factor is involved in MSCs’ modulation of T-cell mediated immune responses, potentially reducing inflammation post-transplantation?
a) Insulin
b) Annexin A1 (ANXA1)
c) Interferon-gamma (IFN-γ)
d) Epidermal Growth Factor (EGF)
b) Annexin A1 (ANXA1)
MSCs secrete factors like Transforming Growth Factor-β (TGF-β), Hepatocyte Growth Factor (HGF), Interleukin-10 (IL-10), Indoleamine 2,3-Dioxygenase (IDO), Prostaglandin E2 (PGE2), Stromal Cell-Derived Factor-1 (SDF-1), and ________, which contribute to improved islet function post-transplantation.
Matrix Metalloproteases (MMPs)
True or False:
MSCs have been shown to significantly reduce the average blood glucose concentration in mice post-transplantation, indicating improved islet transplantation outcomes.
True
How can MSCs potentially reduce ongoing autoimmunity in the context of islet transplantation?
MSCs can modulate the phenotype of macrophages, induce a shift from pro-inflammatory to anti-inflammatory, and alter the Th1/Th2/Th17 cytokine balance, thereby reducing ongoing autoimmunity.
Which cellular property of MSCs contributes to their potential to become tumorigenic, raising concerns for their safety in transplantation?
a) Anti-inflammatory properties
b) Immunoregulatory properties
c) Angiogenic properties
d) Rapid proliferation capacity
d) Rapid proliferation capacity
Which factor contributes to the enhanced revascularization observed in islet grafts co-transplanted with MSCs?
a) VEGF-B
b) IL-6
c) ANXA1
d) TGF-β
a) VEGF-B
MSCs play a role in altering the Th1/Th2/Th17 cytokine balance, favoring ________ cytokines.
anti-inflammatory
True or False:
Islet transplantation with co-transplanted MSCs creates a systemic immunoprivileged site.
False
What is the main challenge in co-engrafting islets and MSCs, especially in clinical islet transplantation?
Co-engraftment is challenging due to differences in transplantation sites, with clinical islet transplantation mainly occurring through the hepatic portal vein.
What is a potential alternative to co-transplantation for MSCs in clinical islet transplantation?
a) Subcutaneous grafting
b) Intramuscular grafting
c) Cell-free “cocktail” treatment
d) Intraperitoneal grafting
c) Cell-free “cocktail” treatment
Which angiogenic factors are expressed by MSCs to enhance revascularization in co-transplanted islet grafts?
a) VEGF-B
b) IL-6
c) VEGF-A, VEGF-C, VEGF-D, IL-8
d) TGF-β
c) VEGF-A, VEGF-C, VEGF-D, IL-8
MSCs exhibit suppressive effects on host T cell proliferation, contributing to prolonged graft ________.
survival
True or False:
MSC-derived secretory products are administered systemically to improve islet transplantation outcomes.
False
What is the main limitation of using MSCs in clinical islet transplantation?
MSCs must be co-transplanted with islets, which is challenging due to differences in transplantation sites and the difficulty of co-engraftment.
What ligand is associated with delaying TH17 progression and reducing β-cell apoptosis in islet transplantation?
a) VEGF
b) ANXA1
c) SDF-1
d) C3a
b) ANXA1
Definition and Characteristics of MSCs
Mesenchymal Stromal Cells (MSC):
Adult progenitor cells with self-renewal capacity.
Exhibit multilineage differentiation into various mesenchymal cell types.
Isolated from different tissues like umbilical cord, bone marrow, adipose tissue.
Simple collection procedure, making them suitable for experiments and clinical use.
What is the Mesenchymal Stromal Cell (MSC) Secretome?
The MSC Secretome refers to the collection of bioactive molecules secreted by Mesenchymal Stromal Cells, consisting of various proteins, growth factors, and other signaling molecules.
What are the key characteristics of Mesenchymal Stromal Cells (MSCs)?
Mesenchymal Stromal Cells are adult progenitor cells with the ability to self-renew and exhibit multilineage differentiation. They can be isolated from various tissues, such as umbilical cord, endometrial polyps, menses blood, bone marrow, and adipose tissue. MSCs have a simple collection procedure, making them easily usable in experiments and clinical applications.
MSCs promote islet survival and function by enhancing graft ____________.
Revascularization
What is one of the functional properties of MSCs in the context of islet transplantation?
a) Increasing islet apoptosis
b) Suppressing immune responses
c) Reducing graft revascularization
d) Inhibiting insulin secretion
b) Suppressing immune responses
True or False: The MSC Secretome includes molecules that have anti-inflammatory effects.
True
What is the primary value of Mesenchymal Stromal Cells in Islet Transplantation?
MSCs play a valuable role in islet transplantation by improving graft survival, enhancing revascularization, and suppressing immune and inflammatory responses, thereby enhancing the overall transplantation outcome.
How do MSCs influence angiogenesis in the context of islet transplantation?
MSCs influence angiogenesis by promoting the formation of new blood vessels, providing necessary oxygen for islet survival and function during transplantation.
What is C3a in the context of islet transplantation?
C3a, or complement component 3a, is an anaphylatoxin (complement peptide) that plays a crucial role in β-cell survival. It exerts various effects by binding to receptor C3aR and is protective against the autoimmune attack that causes Type 1 diabetes.
How does C3a contribute to β-cell survival, and what happens in its deficiency?
C3a promotes islet survival and function by preventing β-cell apoptosis. C3a deficiency activates the mitochondrial pathway of apoptosis, leading to decreased AKT phosphorylation and lower P-BAD levels, contributing to β-cell apoptosis.
SDF-1 is a pro-survival factor for _______ cells.
Beta
What is the functional importance of CXCL12/CXC receptor type 4 in the context of islet transplantation?
a) MSC homing to injured tissues
b) Inducing apoptosis in beta cells
c) Activating cytotoxic CD8+ T cells
d) Enhancing allogenic graft rejection
a) MSC homing to injured tissues
True OR False: Annexin A1 (ANXA1) is an immunomodulatory molecule expressed by pancreatic islets.
False
What is the primary anti-inflammatory property associated with ANXA1 in the context of islet transplantation?
ANXA1, or Annexin A1, has anti-inflammatory properties and reduces proinflammatory responses via protein kinase C, protecting against damage to the heart and kidneys.
How does pre-culturing MSCs with ANXA1 affect cytokine-induced apoptosis?
Pre-culturing MSCs with ANXA1 protects against cytokine-induced apoptosis, showcasing its anti-inflammatory effects and potential for improving blood glucose control.
What does SDF-1 stand for, and what is its role in islet transplantation?
SDF-1 stands for Stromal cell-derived factor 1. In islet transplantation, SDF-1 acts as a pro-survival factor for beta cells, attracting immune-suppressive regulatory T cells and preventing infiltration of cytotoxic CD8+ T cells into the islet graft.
What are the key characteristics of ANXA1 in terms of calcium ion and phospholipid binding?
ANXA1, belonging to the calcium ion and phospholipid binding protein annexin superfamily, stabilizes the MAPK pathway in Type 1 Diabetes (T1D) and activates the pro-survival Akt pathway, contributing to its anti-inflammatory properties.
ANXA1 binds to formyl peptide receptor 2 (FPR2), reducing proinflammatory responses via __________.
Protein kinase C
What is the primary effect of C3a deficiency in beta cells during islet transplantation?
a) Increased AKT phosphorylation
b) Enhanced graft revascularization
c) Activation of the mitochondrial pathway of apoptosis
d) Improved insulin secretory activity
c) Activation of the mitochondrial pathway of apoptosis
True or False: SDF-1 has been shown to delay allogenic graft rejection when directly coated onto islets.
True
What is AKT, and how is it related to beta-cell survival in the context of islet transplantation?
AKT is a protein kinase associated with cell survival. In islet transplantation, decreased AKT phosphorylation in C3-inhibited cells contributes to beta-cell apoptosis, highlighting its significance in promoting beta-cell survival.
How does SDF-1 influence T-cell-mediated immune responses in islet transplantation?
SDF-1 prevents the infiltration of cytotoxic CD8+ T cells into the islet graft and attracts immune-suppressive regulatory T cells, modulating T-cell-mediated immune responses and improving islet transplantation outcomes.
What are Mesenchymal Stem/Stromal Cells (MSCs) and how do they contribute to islet transplantation?
MSCs are adult progenitor cells capable of proliferating in vitro and giving rise to differentiated mesenchymal cell types. In islet transplantation, MSCs play a major role in co-transplantation through direct and indirect mechanisms, promoting islet survival by enhancing tissue repair, graft revascularization, and exerting immunosuppressive effects.
How do MSCs protect islets in co-culture studies, and what are the protective effects of MSCs?
MSCs in co-culture studies enhance B cell viability and function, contributing to islet graft survival. The protective effects of MSCs include paracrine factor secretion, self-renewal capacity, potential for differentiation, and immunomodulatory properties.
What is the primary role of MSC-mediated mitochondrial transfer in islet β‐cells?
a) Regulating insulin synthesis
b) Promoting cellular repair
c) Controlling glucose metabolism
d) Enhancing mitochondrial ATP generation
d) Enhancing mitochondrial ATP generation
What are the three main mechanisms of mitochondrial transfer from MSCs to damaged cells?
The three main mechanisms are tunneling nanotubes (TNTs), extracellular vesicles (EVs), and through cell fusion.
What are the advantages of MSC-mediated mitochondrial transfer?
Advantages include mitochondrial repair, a cellular energy boost leading to enhanced cellular energy production, and therapeutic potential for various diseases associated with mitochondrial dysfunction.
What are some advantages and disadvantages of MSC-mediated mitochondrial transfer?
Advantages:
Mitochondrial Repair
Cellular Energy Boost
Therapeutic Potential
Disadvantages:
Variable Efficacy
Regulatory Challenges
Limited Understanding
What is the role of the extracellular matrix (ECM) in the context of isolated islets?
Isolated islets are metabolically fragile due to the loss of an ECM, reducing the chances of a successful transplantation and insulin secretion. Co-transplantation with Mesenchymal Stromal Cells (MSCs) can reverse these effects by providing a repair scaffold and reservoir for biologically active molecules.
How do MSCs contribute to tissue repair, and what is the significance of MSC-derived ECM in islet transplantation?
MSCs play a major role in tissue repair by migrating to the site of injury and depositing ECM, which acts as a repair scaffold and reservoir for biologically active molecules. MSC-derived ECM, containing molecules like Annexin 1 and collagen, has anti-inflammatory, immunomodulatory, and angiogenic properties, enhancing the functional survival of islet grafts and increasing insulin secretion.
Collagen 3A1, present in MSC-derived ECMs, induces insulin secretion through activation of the β-cell GPCR 56, which is the most commonly expressed GPCR in mouse and human ___________.
Islets
What is the mechanism through which collagen 3A1 in MSC-derived ECM induces insulin secretion in islet cells?
a) Activation of PKB/Akt
b) Inhibition of Erk1/2
c) Suppression of integrin expression
d) Reduction in GPCR 56 levels
a) Activation of PKB/Akt
True or False: MSCs can secrete matrix metalloproteases (MMP1 and MMP13) involved in ECM remodelling.
True
What is Annexin 1, and how does it contribute to the anti-inflammatory effects of MSC-derived ECM?
Annexin 1 is an anti-inflammatory molecule highly expressed in MSC populations and localized to MSC-derived ECMs. Its presence contributes to the anti-inflammatory effects of the ECM on islet cells.
What is the main mechanism of action for ECM in mediating the beneficial effects of MSCs on islet function?
ECM-integrin interactions play a crucial role in mediating the beneficial effects of MSCs on islet function. Integrins are transmembrane glycoproteins that, upon binding to the ECM, activate signaling cascades such as PKB/Akt and Erk1/2, improving islet function and survival, and promoting increased insulin secretion.
What is a common issue in islet transplantation related to immune rejection, and how can Mesenchymal Stromal Cells (MSCs) address this problem?
Immune rejection leading to graft failure is a common issue. MSCs can possess immunomodulatory properties, potentially suppressing the immune response and promoting graft survival. This might eliminate the need for immunosuppressant drugs.
What challenge is associated with the limited availability of donor islets for transplantation, and how can MSCs provide a solution?
The limited availability of donor islets is a challenge. MSCs can proliferate in vitro, offering an unlimited cell source to support islet transplantation.
What issues may impact islet function and viability during isolation and transplantation, and how can MSCs contribute to addressing these issues?
Islet function and viability may be impacted during isolation and transplantation. MSCs can provide a supportive microenvironment, enhancing the survival and function of islet cells.
What problem is associated with insufficient vascularization around transplanted islets, and how can MSCs contribute to addressing this issue?
Insufficient vascularization leading to inadequate blood supply is a concern. MSCs promote angiogenesis, improving vascularization around transplanted islets and addressing hypoxia-related challenges.
What challenge may islets face due to hypoxia-induced stress, and how can MSCs potentially mitigate this stress?
Islets may encounter hypoxia-induced stress due to insufficient oxygen supply. MSCs possess anti-inflammatory properties, potentially mitigating post-transplantation inflammation associated with hypoxia.
How can inflammation at the transplantation site negatively impact graft survival, and what role can MSCs play in addressing this issue?
Post-transplantation inflammation can negatively impact graft survival through immune rejection. MSCs possess immunomodulatory properties, potentially reducing inflammation and improving graft survival.
What are Mesenchymal Stromal Cells (MSCs), and what is their primary characteristic?
MSCs are multipotent stem cells capable of self-renewal and differentiation into multiple cell types.
Why might insulin treatment fail to maintain tight glycemic control, and what alternative was introduced?
Insulin treatment may fail to maintain tight glycemic control, leading to the introduction of islet treatments as a non-invasive, safe alternative to pancreatic treatments.
What challenges are associated with islet treatments, and why were MSCs introduced?
Challenges include a shortage of tissue donors and the rapid deterioration of islets. MSCs were introduced to address these challenges.
What is one of the primary roles of MSCs in islet transplantation?
a) Increasing tissue donor availability
b) Promoting islet deterioration
c) Improving vascularization
d) Suppressing graft survival
c) Improving vascularization
True or False: MSCs have the ability to influence both innate and adaptive immune systems in islet transplantation.
True
How do MSCs contribute to improving graft functional survival in islet transplantation?
MSCs contribute to improving graft functional survival by addressing the challenges associated with islet treatments, such as the shortage of tissue donors and the rapid deterioration of islets, through mechanisms like enhancing vascularization and influencing the immune systems.
How does the upregulation of VEGFR contribute to oxygenation in islet transplantation?
Upregulation of VEGFR leads to increased expression of VEGF-A, promoting revascularization, angiogenesis, and endothelial cell proliferation after transplantation. VEGF-A is expressed in islets from as early as 1 day to 28 days, enhancing oxygenation.
hat is the role of Hepatocyte Growth Factor (HGF) in oxygenation, and how does it work in tandem with VEGFR upregulation?
HGF increases endothelial permeability and inhibits endothelial cell apoptosis, enhancing angiogenesis. It works in tandem with VEGFR upregulation to improve oxygenation over time.
How does the increase in Angiopoietin 1 (Ang-1) contribute to oxygenation in islet transplantation?
Increased Ang-1 binds to Tie-2, promoting the survival and integrity of blood vessels. While the expression of Tie-2 is not affected, phosphorylated Tie-2 increases, potentially having a cytoprotective effect on islets and improving oxygenation.
How do Mesenchymal Stromal Cells (MSCs) increase oxygenation through mitochondrial transfer, and what are the two mechanisms involved?
MSCs transfer mitochondria to islet cells through both tunneling nanotubes (TNTs) and extracellular vesicles (EVs), enhancing oxygenation.
What is the role of TNTs in mitochondrial transfer from MSCs to islet cells?
TNTs, cytoskeletal structures made of F-actin, extend from MSCs towards islets, allowing for mitochondrial transfer and enhancing oxygenation.
How do MSC-derived extracellular vesicles contribute to mitochondrial transfer and oxygenation?
MSCs are in direct contact with islet cells, forming macrovesicles that carry mitochondria. This mechanism is crucial for mitochondrial transfer from MSCs to cocultured islet beta-cells, promoting oxygenation.
Why are isolated islets metabolically fragile, and how do MSCs contribute to tissue repair and improved function?
Isolated islets are metabolically fragile due to the loss of the extracellular matrix. MSCs aid in tissue repair by migrating to the injury site and depositing ECM, contributing to improved glycaemic control and insulin secretory function.
How do MSCs support islet cell function through the extracellular matrix?
MSCs secrete matrix metalloproteases (MMP1 and MMP3), involved in the reproduction of the extracellular matrix. The ECM acts as a scaffold containing growth factors and cytokines, regulating islet survival, insulin secretion, proliferation, and preserving the spherical morphology of islets.
What are two main issues associated with islet cell transplantation, and how do MSCs address these issues?
The rejection of islet cells and the need for lifelong immunosuppressive treatments are main issues. MSCs inhibit T-cell proliferation, promote regulatory T-cell function and generation, potentially preventing the rejection of islet cells.
What was observed in the graft area of recipients treated with MSCs in the experiment?
The graft area of recipients treated with MSCs showed preserved islet structure and positive insulin staining. CD4+ and CD8+ T-cells were present at the border of the islets, with only a small amount of infiltration of the islet cell graft. Islet grafts were more preserved compared to the untreated islet cell alone group.
How do MSCs reduce the production of T helper 1 cytokines and increase the secretion of T helper 2 or regulatory cytokines in the context of mixed-lymphocyte reaction (MLR) cultures?
MSCs can reduce the production of T helper 1 cytokines (e.g., IFN-γ/TNFα) and increase the secretion of T helper 2 or regulatory cytokines in MLR cultures, potentially suppressing pathological T-cell responses and exerting positive effects on β-cell function.
True or false: MSCs, in the experiment, completely prevented the infiltration of CD4+ and CD8+ T-cells into the islet cell graft.
False
How do MSCs contribute to preventing the rejection of islet cells in transplantation?
MSCs inhibit T-cell proliferation, promote regulatory T-cell function and generation, and reduce the production of T helper 1 cytokines, potentially preventing the rejection of islet cells in transplantation.
What are Mesenchymal Stromal Cells (MSCs), and what are the three criteria for their classification?
MSCs are pluripotent cells capable of differentiating into various cell types. The three criteria for MSC classification include being plastic-adherent, expressing CD105, CD73, and CD90 (and lacking hematopoietic antigens), and having standard trilineage differentiation potential.
Where are MSCs typically extracted from, and what is a significant characteristic related to immune recognition?
MSCs are extracted from the bone marrow, adipose tissue, placenta, and cord blood. MSCs do not express significant histocompatibility complexes and immune-stimulating molecules, making them undetected by immune surveillance and preventing graft rejection after transplantation.
How do MSCs contribute to tissue repair, and what is their role as a repair scaffold?
MSCs migrate to the site of injury, depositing extracellular matrix (ECM) that acts as a repair scaffold and reservoir for MSC-derived molecules, facilitating tissue repair.
Why are MSCs considered an ideal cell source for tissue regeneration, and provide three key examples of their applications.
MSCs are considered ideal for tissue regeneration due to their presence in almost all tissues, ease of extraction, and ability to differentiate into various cell types. Three key examples of their applications include bone regeneration, wound healing, and immunomodulation.
How do MSCs contribute to bone regeneration?
MSCs can differentiate into osteoblasts, promoting the formation of new bone tissues, making them valuable for bone regeneration.
How do MSCs contribute to wound healing, and what specific process do they promote?
MSCs promote angiogenesis and accelerate the healing process, making them valuable for treating inflammatory and autoimmune diseases.
What immunomodulatory properties do MSCs possess, and how can they contribute to controlling the immune response?
MSCs possess anti-inflammatory, immunoregulatory, and immunosuppressive capacities, contributing to their potential role as immune-tolerant agents. They can suppress excessive immune responses and promote an anti-inflammatory environment.
What are MHC molecules, and why are they crucial for the immune system’s function?
MHC (Major Histocompatibility Complex) molecules are crucial for the immune system’s function as they play a key role in presenting peptides to T cells, allowing the immune system to monitor cell health and respond to infections or cancerous changes.
What is the role of MHC Class I molecules, where are they present, and what can foreign MHC Class I lead to in transplants?
MHC Class I molecules are present on almost all body cells and display internal peptides to CD8+ T cells. In transplants, foreign MHC Class I can cause recipient CD8+ T cells to attack the graft, leading to rejection.
Where are MHC Class II molecules found, and what role do they play in triggering immune responses in transplant rejection?
MHC Class II molecules are found on antigen-presenting cells (APCs) like dendritic cells and macrophages. They present external peptides from pathogens to CD4+ T cells, triggering immune responses crucial in transplant rejection.
What is the role of T Cell Receptor (TCR), and how does it contribute to the immune response in transplantation?
Each T cell has a unique T Cell Receptor (TCR) that is specific to a certain peptide-MHC complex. When TCRs bind to their specific peptide-MHC complex, they activate the T cell, leading to an immune response. This system is vital for distinguishing self from non-self, especially in transplantation.
What is the timing, mechanism, pathology, and management of hyperacute rejection?
Timing: Minutes to hours
Mechanism: Pre-existing antibodies against the graft
Pathology: Blood clot formation, immediate organ failure
Management: Pre-transplant blood tests (cross-matching)
What is the timing, mechanism, pathology, and management of acute rejection?
Timing: Days to months
Mechanism: T-cell mediated
Pathology: Cellular - direct T-cell destruction; Humoral - antibody-mediated inflammation and tissue damage
Management: Immunosuppressive drugs
What is the timing, mechanism, pathology, and management of accelerated acute rejection?
iming: Within days
Mechanism: Similar to acute rejection but in highly sensitized patients
Pathology: Similar to acute rejection but more rapid
Management: Aggressive immunosuppressive therapy
What is the timing, mechanism, pathology, and management of chronic rejection?
Timing: Months to years
Mechanism: Cellular and humoral immune response
Pathology: Scarring, fibrosis, blood vessel narrowing, ischemia, organ failure
Management: Prolonging graft function, managing complications
How do MSCs influence dendritic cells, and what is the consequence for T cell activation and adaptive immune responses?
MSCs can inhibit the maturation of dendritic cells, reducing their ability to activate T cells and initiate adaptive immune responses.
What cytokines and growth factors do MSCs secrete, and how do they collectively contribute to dampening inflammatory responses?
MSCs secrete TGF-β, IL-10, and PGE2, collectively contributing to dampening inflammatory responses.
How do MSCs affect the lifespan and inflammatory mediator release of neutrophils, and what is the balancing effect they achieve?
MSCs prolong the lifespan of neutrophils while modulating their release of inflammatory mediators, balancing the need for pathogen defense with the prevention of excessive inflammation.
How do MSCs modify NK cell phenotype, and what effects do they have on NK cell proliferation, cytotoxicity, and cytokine secretion?
MSCs modify NK cell phenotype, reducing NK cell proliferation, cytotoxic effects, and secretion of pro-inflammatory cytokines.
How do MSCs respond to the inflammatory environment, and what is an example of their adjustment in immunomodulatory activities?
MSCs respond to the inflammatory environment by adjusting their immunomodulatory activities. For example, the presence of pro-inflammatory cytokines like TNF-α and IFN-γ can enhance the immunosuppressive functions of MSCs.
How does MSCs’ ability to interact with other immune cells at different stages contribute to reducing early immune responses in the context of grafts?
MSCs’ ability to interact with various immune cells is fundamental for reducing early immune responses in the context of grafts, as shown in various trials.
How do Mesenchymal Stromal Cells (MSCs) contribute to tissue repair?
A) By direct destruction of damaged cells
B) By promoting inflammation at the injury site
C) By migrating to the site of injury and depositing extracellular matrix (ECM)
D) By inducing immune responses against damaged tissues
C) By migrating to the site of injury and depositing extracellular matrix (ECM)
What is the primary role of MSCs in co-transplantation with islets?
A) Inducing apoptosis in islet cells
B) Enhancing graft revascularization and promoting tissue repair
C) Suppressing insulin secretion in islet cells
D) Increasing inflammation at the transplantation site
B) Enhancing graft revascularization and promoting tissue repair
In the context of graft rejection, what is the primary mechanism of hyperacute rejection?
A) T-cell mediated destruction
B) Pre-existing antibodies against the graft
C) Chronic immune responses
D) Inadequate blood supply to the transplanted tissue
B) Pre-existing antibodies against the graft
How do MSCs modulate NK cell phenotype?
A) By promoting NK cell proliferation
B) By enhancing NK cell cytotoxic effects
C) By reducing NK cell proliferation, cytotoxic effects, and secretion of pro-inflammatory cytokines
D) By activating the inflammatory response in NK cells
C) By reducing NK cell proliferation, cytotoxic effects, and secretion of pro-inflammatory cytokines
What is the role of MHC Class I molecules in graft rejection?
A) They present external peptides to CD4+ T cells
B) They are found on antigen-presenting cells (APCs)
C) They are crucial for graft survival
D) They can cause rejection if foreign MHC Class I is present in transplants
D) They can cause rejection if foreign MHC Class I is present in transplants
How do MSCs exert immunosuppression on T cells, and what signaling pathways are affected?
MSCs exert immunosuppression on T cells by blocking the IL-2 cytokine signaling pathway, essential for T cell activation, proliferation, and differentiation. This reduces the production of effector cytokines, such as IFN-γ and TNFα.
How do MSCs influence CD8+CD28− T cells and their impact on CD4+ T cells?
MSCs upregulate the number of CD8+CD28− T cells, inhibiting the proliferation and activation of CD4+ T cells via downregulation of IFN-γ and enhancing the apoptosis of activated CD4+ T cells.
How do MSCs stimulate Tregs differentiation, and what is the result in terms of inhibiting graft-destructive T-cell responses?
MSCs stimulate Tregs differentiation by inducing the production of IL-10, leading to an overall inhibition of graft-destructive T-cell responses.
What inhibitory effects do MSCs have on B cells, and what soluble factors contribute to this effect?
MSCs inhibit B cell proliferation, differentiation, and chemotactic cytokine production. Soluble factors such as TGF-β, HGF, PGE2, and IDO contribute to this inhibitory effect.
How do human MSCs affect B cells’ chemokine receptor expression, and what role do Bregs play in immunosuppression?
Human MSCs inhibit the expression of chemokine receptors (CXCR4, CXCR5, and CCR7) on B cells. Bregs exhibit immunosuppressive effects mainly mediated by IL-10, contributing to immunological tolerance.
How do MSCs contribute to the survival time of patients with refractory chronic graft-versus-host disease, and what factors are involved?
MSCs increase survival time through IDO-induced IL-10 secretion and Breg proliferation.
What is the in vivo and in vitro evidence for the role of MSCs in regulating adaptive immunity, and under what conditions did MSCs prevent a Th17 response?
Co-transplanting C57BL/6 rats with MSCs prevented a Th17 response, particularly when MSCs were administered beneath the kidney capsule, not when administered systemically.
Why is oxidative phosphorylation and ATP generation crucial in islet β-cells, and what is the significance of a high number of mitochondria in these cells?
Oxidative phosphorylation and ATP generation are pivotal for rapid responses to fluctuations in blood glucose. Islet β-cells have a high number of mitochondria to ensure quick responses, sensing glucose, and producing insulin.
How do MSCs directly influence islet β-cells to improve glucose-stimulated insulin secretion, and what is the significance of co-culturing islets with MSCs in vitro?
MSCs improve insulin secretion by interacting with beta cells. Co-culturing islets with MSCs in vitro enhances this process, leading to improved insulin secretion.
Name the mechanisms involved in intercellular mitochondrial transfer from MSCs to islet β-cells, and briefly describe one of them.
Mechanisms include Cytoplasmic Bridges/Tunnelling nanotubes, MSC-derived extracellular vesicles (EVs), Gap junctional complex connexins, Mitochondrial ejection, and Cytoplasmic fusion. Tunnelling nanotubes are ultrastructures composed of actin filaments, extending from MSCs to neighboring cells for mitochondrial transfer
What analytical technique is used for measuring glucose-stimulated oxidative consumption rate (OCR), and why is it preferred over traditional approaches?
he Seahorse XF24 analyzer is used. This technique avoids issues associated with mitochondrial membrane potential-dependent dyes and potential leakage, providing a genetic approach for accurate measurements without toxicity concerns.
How do MSCs transfer mitochondria to islet β-cells, and what is the role of extracellular vesicles (EVs) in this process?
MSCs transfer mitochondria through tunnelling nanotubes and EVs. EVs, crucial components of the MSC secretome, can contain organelles like mitochondria and anti-inflammatory factors such as Annexin A1.
What is the primary function of MSCs in the context of islet transplantation?
a. Insulin production
b. Immune rejection
c. Tissue repair and regeneration
d. Blood clot formation
c. Tissue repair and regeneration
Which component of the MSC secretome is associated with repair of damaged tissue and modulation of immune responses?
a. Annexin A1
b. Stromal cell-derived factor 1 (SDF-1)
c. Complement component 3a (C3a)
d. Hepatocyte growth factor (HGF)
b. Stromal cell-derived factor 1 (SDF-1)
What is the mechanism through which MSCs influence islet insulin secretory function in co-culture studies?
a. Cellular fusion
b. Mitochondrial transfer
c. Extracellular matrix production
d. Immune suppression
b. Mitochondrial transfer
How do MSCs contribute to improving islet oxygenation and function when co-transplanted with islets?
a. By inducing hyperacute rejection
b. By promoting inflammation
c. By inhibiting angiogenesis
d. By enhancing vascularization
d. By enhancing vascularization
Which type of rejection occurs within minutes to hours and involves pre-existing antibodies against the graft?
a. Acute rejection
b. Chronic rejection
c. Hyperacute rejection
d. Accelerated acute rejection
c. Hyperacute rejection
What is the primary role of MSCs in interactions with dendritic cells in innate immunity?
a. Promoting dendritic cell maturation
b. Inhibiting T cell activation
c. Inducing inflammatory responses
d. Enhancing graft rejection
b. Inhibiting T cell activation
Which extracellular structure is involved in the intercellular mitochondrial transfer from MSCs to islet β-cells?
a. Gap junctions
b. Tunneling nanotubes
c. Extracellular vesicles
d. Matrix metalloproteases
b. Tunneling nanotubes
What is the primary purpose of using the Seahorse XF24 analyzer in measuring islet β-cell functions?
a. To induce oxidative stress
b. To measure cytokine secretion
c. To assess mitochondrial membrane potential
d. To measure glucose-stimulated oxidative consumption rate (OCR)
d. To measure glucose-stimulated oxidative consumption rate (OCR)
Which cytokine signaling pathway is blocked by MSCs to exert immunosuppression on T cells?
a. IL-10
b. IFN-γ
c. IL-2
d. TNF-α
c. IL-2
What inhibitory effect do MSCs have on B cells in adaptive immunity?
a. Inducing chemotactic cytokine production
b. Promoting immunoglobulin production
c. Suppressing B cell proliferation
d. Enhancing chemokine receptor expression on B cells
c. Suppressing B cell proliferation
