scholarly journals Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation

2016 ◽  
Vol 115 (04) ◽  
pp. 781-788 ◽  
Author(s):  
Jong-Hyung Lim ◽  
Ioannis Mitroulis ◽  
Anaisa Ferreira ◽  
Lan-Sun Chen ◽  
Bettina Gercken ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Islet Transplantation ◽  
Inflammatory Reaction ◽  
Aggregate Formation ◽  
Pancreatic Islet Transplantation ◽  
Inflammatory Injury ◽  
Novel Approach ◽  
Peptide Release ◽  
Pre Treatment ◽  
And Function

SummaryPlatelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood–islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Role of Exosomes in Islet Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jordan Mattke ◽  
Srividya Vasu ◽  
Carly M. Darden ◽  
Kenjiro Kumano ◽  
Michael C. Lawrence ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Graft Function ◽  
Pancreatic Islet Transplantation ◽  
Complex Molecules ◽  
Wide Range ◽  
And Function ◽  
Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

scholarly journals 307.8: Novel Approach in Pancreatic Islet Transplantation: Acellular Vessel

2021 ◽  
Vol 105 (12S1) ◽  
pp. S26-S26
Author(s):  
Jeffrey H. Lawson ◽  
Juan Wang ◽  
Edward X. Han ◽  
Mehmet Kural ◽  
Bo Jiang ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Pancreatic Islet ◽  
Pancreatic Islet Transplantation ◽  
Novel Approach

scholarly journals Protection of pancreatic islets using theranostic silencing nanoparticles in a baboon model of islet transplantation

2020 ◽  
Author(s):  
Ada Admin ◽  
Thomas Pomposelli ◽  
Ping Wang ◽  
Kazuhiro Takeuchi ◽  
Katsunori Miyake ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
In Vivo Studies ◽  
Pancreatic Islet Transplantation ◽  
Insulin Requirements ◽  
Novel Approach ◽  
Apoptotic Effect ◽  
Novel Strategy ◽  
Interfering Rna

The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation and other factors continues to limit its efficacy. In this project we demonstrate a novel approach aimed at protection of islets prior to Tx in non-human primates (NHP, baboons) by silencing a gene (caspase 3) responsible for induction of apoptosis. This was done using small interfering RNA (siRNA, siCas-3) conjugated to magnetic nanoparticles (MN). In addition to serving as carriers for siCas-3 these nanoparticles also act as reporters for magnetic resonance imaging so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the anti-apoptotic effect of MN-siCas-3 on islets in culture resulting in a minimal islet loss. For in vivo studies donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted even with a marginal number of labeled islets compared to controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaver or living donor.

scholarly journals Islet transplantation tolerance in animals with defined histocompatibility and diabetes

2021 ◽  
Author(s):  
Preksha Bhagchandani ◽  
Charles Chang ◽  
Weichen Zhao ◽  
Luiza Ghila ◽  
Pedro L. Herrera ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Transplantation Tolerance ◽  
Pancreatic Islet Transplantation ◽  
Β Cell ◽  
Specific Expression ◽  
Additional Advantage ◽  
Cell Ablation ◽  
High Affinity Receptor ◽  
And Function ◽  
Diabetes Induction

Advances in organ transplantation benefit from development of genetically inbred animal strains with defined histocompatibility and cell-specific markers to distinguish donor and host cell subsets. For studies of pancreatic islet transplantation tolerance in diabetes, an invariant method to ablate host β cells and induce diabetes would provide an immense additional advantage. Here we detail development and use of B6 RIP-DTR mice , an immunocompetent line permitting diabetes induction with 100% penetrance. This inbred line is homozygous for the C57BL/6J major histocompatibility complex (MHC) haplotype and expresses the mutant CD45.1 allele in the hematopoietic lineage. β cell-specific expression of a high-affinity receptor for diphtheria toxin (DT) permits experimental β cell ablation and diabetes induction after DT administration. Diabetes reversal for over one year was achieved after transplantation with congenic C57BL/6J islets, but not with MHC-mismatched BALB/c islets, which were rapidly rejected. In summary, the generation of a C57BL/6J congenic line harboring the CD45.1 allele and Ins2-HBEGF transgene should advance studies of islet transplantation tolerance and mechanisms to improve islet engraftment and function, thereby optimizing development of cell replacement strategies for diabetes mellitus.

scholarly journals Protection of pancreatic islets using theranostic silencing nanoparticles in a baboon model of islet transplantation

2020 ◽  
Author(s):  
Ada Admin ◽  
Thomas Pomposelli ◽  
Ping Wang ◽  
Kazuhiro Takeuchi ◽  
Katsunori Miyake ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
In Vivo Studies ◽  
Pancreatic Islet Transplantation ◽  
Insulin Requirements ◽  
Novel Approach ◽  
Apoptotic Effect ◽  
Novel Strategy ◽  
Interfering Rna

The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation and other factors continues to limit its efficacy. In this project we demonstrate a novel approach aimed at protection of islets prior to Tx in non-human primates (NHP, baboons) by silencing a gene (caspase 3) responsible for induction of apoptosis. This was done using small interfering RNA (siRNA, siCas-3) conjugated to magnetic nanoparticles (MN). In addition to serving as carriers for siCas-3 these nanoparticles also act as reporters for magnetic resonance imaging so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the anti-apoptotic effect of MN-siCas-3 on islets in culture resulting in a minimal islet loss. For in vivo studies donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted even with a marginal number of labeled islets compared to controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaver or living donor.

scholarly journals In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo

2018 ◽  
Vol 315 (4) ◽  
pp. E650-E661 ◽  
Author(s):  
Clarissa Hernandez Stephens ◽  
Kara S. Orr ◽  
Anthony J. Acton ◽  
Sarah A. Tersey ◽  
Raghavendra G. Mirmira ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Cellular Therapy ◽  
Foreign Body Response ◽  
Type I ◽  
Pancreatic Islet Transplantation ◽  
And Function

Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 –3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.

Sign in / Sign up

Export Citation Format

Share Document