Clinical Islet Transplantation Research Articles

Biomimetic Hydrogels Promote Pseudoislet Formation to Improve Glycemic Control in Diabetic Mice.

Islet or β-cell transplantation is currently considered to be the ideal treatment for diabetes, and three-dimensional (3D) bioprinting of a bionic pancreas with physiological stiffness is considered to be promising for the encapsulation and transplantation of β-cells. In this study, a 5%GelMA/2%AlgMA hybrid hydrogel with pancreatic physiological stiffness was constructed and used for β-cell encapsulation, 3D bioprinting, and in vivo transplantation to evaluate glycemic control in diabetic mice. The hybrid hydrogel had good cytocompatibility and could induce insulin-producing cells (IPCs) to form pseudoislet structures and improve insulin secretion. Furthermore, we validated the importance of betacellulin (BTC) in IPCs differentiation and confirmed that IPCs self-regulation was achieved by altering the nuclear and cytoplasmic distributions of BTC expression. In vivo transplantation of diabetic mice quickly restored blood glucose levels. In the future, 3D bioprinting of β-cells using biomimetic hydrogels will provide a promising platform for clinical islet transplantation for the treatment of diabetes.

On Chip Sorting of Stem Cell-Derived β Cell Clusters Using Traveling Surface Acoustic Waves.

There is a critical need for sorting complex materials, such as pancreatic islets of Langerhans, exocrine acinar tissues, and embryoid bodies. These materials are cell clusters, which have highly heterogeneous physical properties (such as size, shape, morphology, and deformability). Selecting such materials on the basis of specific properties can improve clinical outcomes and help advance biomedical research. In this work, we focused on sorting one such complex material, human stem cell-derived β cell clusters (SC-β cell clusters), by size. For this purpose, we developed a microfluidic device in which an image detection system was coupled to an actuation mechanism based on traveling surface acoustic waves (TSAWs). SC-β cell clusters of varying size (∼100-500 μm in diameter) were passed through the sorting device. Inside the device, the size of each cluster was estimated from their bright-field images. After size identification, larger clusters, relative to the cutoff size for separation, were selectively actuated using TSAW pulses. As a result of this selective actuation, smaller and larger clusters exited the device from different outlets. At the current sample dilutions, the experimental sorting efficiency ranged between 78% and 90% for a separation cutoff size of 250 μm, yielding sorting throughputs of up to 0.2 SC-β cell clusters/s using our proof-of-concept design. The biocompatibility of this sorting technique was also established, as no difference in SC-β cell cluster viability due to TSAW pulse usage was found. We conclude the proof-of-concept sorting work by discussing a few ways to optimize sorting of SC-β cell clusters for potentially higher sorting efficiency and throughput. This sorting technique can potentially help in achieving a better distribution of islets for clinical islet transplantation (a potential cure for type 1 diabetes). Additionally, the use of this technique for sorting islets can help in characterizing islet biophysical properties by size and selecting suitable islets for improved islet cryopreservation.

Physiomimetic Fluidic Culture Platform on Microwell-Patterned Porous Collagen Scaffold for Human Pancreatic Islets.

Pancreatic islet transplantation is one of the clinical options for certain types of diabetes. However, difficulty in maintaining islets prior to transplantation limits the clinical expansion of islet transplantations. Our study introduces a dynamic culture platform developed specifically for primary human islets by mimicking the physiological microenvironment, including tissue fluidics and extracellular matrix support. We engineered the dynamic culture system by incorporating our distinctive microwell-patterned porous collagen scaffolds for loading isolated human islets, enabling vertical medium flow through the scaffolds. The dynamic culture system featured four 12 mm diameter islet culture chambers, each capable of accommodating 500 islet equivalents (IEQ) per chamber. This configuration calculates > five-fold higher seeding density than the conventional islet culture in flasks prior to the clinical transplantations (442 vs 86 IEQ/cm2). We tested our culture platform with three separate batches of human islets isolated from deceased donors for an extended period of 2 weeks, exceeding the limits of conventional culture methods for preserving islet quality. Static cultures served as controls. The computational simulation revealed that the dynamic culture reduced the islet volume exposed to the lethal hypoxia (< 10 mmHg) to ~1/3 of the static culture. Dynamic culture ameliorated the morphological islet degradation in long-term culture and maintained islet viability, with reduced expressions of hypoxia markers. Furthermore, dynamic culture maintained the islet metabolism and insulin-secreting function over static culture in a long-term culture. Collectively, the physiological microenvironment-mimetic culture platform supported the viability and quality of isolated human islets at high-seeding density. Such a platform has a high potential for broad applications in cell therapies and tissue engineering, including extended islet culture prior to clinical islet transplantations and extended culture of stem cell-derived islets for maturation.

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling.

Clinical islet transplantation is limited by ischemia-induced islet cell death. Recently, it has been reported that the absent in melanoma (AIM)2 inflammasome is upregulated by ischemic cell death due to recognition of aberrant cytoplasmic self-dsDNA. However, it is unknown whether AIM2 determines the outcome of islet transplantation. To investigate this, isolated wild type (WT) and AIM2-deficient (AIM2-/-) islets were exposed to oxygen-glucose deprivation to mimic ischemia, and their viability, endocrine function, and interferon (IFN) signaling were assessed. Moreover, the revascularization and endocrine function of grafted WT and AIM2-/- islets were analyzed in the mouse dorsal skinfold chamber model and the diabetic kidney capsule model. Ischemic WT and AIM2-/- islets did not differ in their viability. However, AIM2-/- islets exhibited a higher protein level of p202, a transcriptional regulator of IFN-β and IFN-γ gene expression. Accordingly, these cytokines were upregulated in AIM2-/- islets, resulting in a suppressed gene expression and secretion of insulin. Moreover, the revascularization of AIM2-/- islet grafts was deteriorated when compared to WT controls. Furthermore, transplantation of AIM2-/- islets in diabetic mice failed to restore physiological blood glucose levels. These findings indicate that AIM2 crucially determines the engraftment and endocrine function of transplanted islets by repressing IFN signaling.

337.6: Beta-cell function and insulin sensitivity with islet transplant alone and islet-after-kidney transplantation for type 1 diabetes in the Clinical Islet Transplantation (CIT) Consortium

337.6: Beta-cell function and insulin sensitivity with islet transplant alone and islet-after-kidney transplantation for type 1 diabetes in the Clinical Islet Transplantation (CIT) Consortium

Identification of Compounds Protecting Pancreatic Islets against Oxidative Stress using a 3D Pseudoislet Screening Platform.

Oxidative stress leads to a lower success rate of clinical islet transplantation. Here, FDA-approved compounds are screened for their potential to decrease oxidative stress and to protect or enhance pancreatic islet viability and function. Studies are performed on in vitro "pseudoislet" spheroids, which are pre-incubated with 1280 different compounds and subjected to oxidative stress. Cell viability and oxidative stress levels are determined using a high-throughput fluorescence microscopy pipeline. Initial screening on cell viability results in 59 candidates. The top ten candidates are subsequently screened for their potential to decrease induced oxidative stress, and eight compounds efficient reduction of induced oxidative stress in both alpha and beta cells by 25-50%. After further characterization, the compound sulfisoxazole is found to be the most capable of reducing oxidative stress, also at short pre-incubation times, which is validated in primary human islets, where low oxidative stress levels and islet function are maintained. This study shows an effective screening strategy with 3D cell aggregates based on cell viability and oxidative stress, which leads to the discovery of several compounds with antioxidant capacity. The top candidate, sulfisoxazole is effective after a 30 min pre-incubation, maintains baseline islet function, and may help alleviate oxidative stress in pancreatic islets.

Solubilized Pancreatic Extracellular Matrix from Juvenile Pigs Protects Isolated Human Islets from Hypoxia-Induced Damage: A Viable Option for Clinical Islet Transplantation

The pancreatic extracellular matrix (ECM) is an enormously complex construct. Previous studies underline the challenges to identify the optimal combinations and ratios of individual ECM proteins for promoting survival and function of isolated and transplanted islets. This study aimed on assessing the efficiency of solubilized natural ECM extracted from juvenile pigs, an unlimited donor source. Isolated human islets were cultured under a hypoxic atmosphere (2% oxygen) in media supplemented with either solubilized porcine pancreatic ECM (ppECM) or a mixture of human ECM proteins composed of collagen-IV, laminin-521, and nidogen-1 (hEPM). Control islets were cultured under identical conditions without ECM-compounds. Reactive oxygen species production increased three-fold in controls but was reduced by hEPM or ppECM. Early apoptosis remained on preculture levels when islets were treated with hEPM or ppECM. Preculture viability was preserved when hEPM or ppECM was administered. Whilst controls failed to respond to glucose challenge, treatment with hEPM or ppECM preserved the physiological insulin response. In summary, overall survival was significantly highest in ppECM-treated islets. This study presents a new approach to protect human islets from hypoxia-induced damage by supplementing media with ppECM extracted from an unlimited donor source. The findings may also serve as starting point for a novel encapsulation technique to protect isolated human islets.

Patients' opinions 10 years after receiving encapsulated porcine islet xenotransplantation without immunosuppression.

Previously we performed clinical encapsulated neonatal porcine islet transplantation under comprehensive regulation, and demonstrated the efficacy and safety. To analyze the patients' quality of life (QOL), we assessed patients' opinions 10 years after islet xenotransplantation. Twenty-one type 1 diabetic patients received microencapsulated neonatal porcine islet transplants in Argentina were enrolled. Seven patients were enrolled in efficacy and safety study and 14 patients were enrolled in safety studies. Patients' opinions related to the current and pre-transplant status of diabetes control, blood glucose levels, severe hypoglycemia, and hyperglycemia required hospitalization were analyzed. In addition, opinions related to islet xenotransplantation were assessed. At the time of this survey, average HbA1c was still significantly lower compared to pre-transplantation (8.5±0.9 (%) at pre-transplant and 7.4±0.5(%) at the survey, p<.05) and average insulin dose were also lower (0.95±0.32 (IU/kg) at pre-transplant and 0.73±0.27 (IU) at the survey). The majority of patients improved diabetes control (71%), blood glucose levels (76%), severe hypoglycemia (86%) and hyperglycemia required hospitalization (76%), and no patients deteriorated in all of the categories when compared with pre-transplantation. No patients had cancer, or psychological problem, and one patient had a serious adverse event. The majority of patients wanted to recommend this treatment to other patients (76%) and receive booster transplantation (85.7%). The majority of patients had positive opinions related to the encapsulated porcine islet xenotransplantation 10 years after transplantation.

Evaluating the Potential for ABO-incompatible Islet Transplantation: Expression of ABH Antigens on Human Pancreata, Isolated Islets, and Embryonic Stem Cell-derived Islets.

ABO-incompatible transplantation has improved accessibility of kidney, heart, and liver transplantation. Pancreatic islet transplantation continues to be ABO-matched, yet ABH antigen expression within isolated human islets or novel human embryonic stem cell (hESC)-derived islets remain uncharacterized. We evaluated ABH glycans within human pancreata, isolated islets, hESC-derived pancreatic progenitors, and the ensuing in vivo mature islets following kidney subcapsular transplantation in rats. Analyses include fluorescence immunohistochemistry and single-cell analysis using flow cytometry. Within the pancreas, endocrine and ductal cells do not express ABH antigens. Conversely, pancreatic acinar tissues strongly express these antigens. Acinar tissues are present in a substantial portion of cells within islet preparations obtained for clinical transplantation. The hESC-derived pancreatic progenitors and their ensuing in vivo-matured islet-like clusters do not express ABH antigens. Clinical pancreatic islet transplantation should remain ABO-matched because of contaminant acinar tissue within islet preparations that express ABH glycans. Alternatively, hESC-derived pancreatic progenitors and the resulting in vivo-matured hESC-derived islets do not express ABH antigens. These findings introduce the potential for ABO-incompatible cell replacement treatment and offer evidence to support scalability of hESC-derived cell therapies in type 1 diabetes.

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for β cell replacement including the use of SC-islets or other types of novel cells in clinical settings.

Micropyramid-patterned, oxygen-permeable bottomed dish for high density culture of pancreatic islets

The need for maintaining cell-spheroid viability and function within high-density cultures is unmet for various clinical and experimental applications, including cell therapies. One immediate application is for transplantation of pancreatic islets, a clinically recognized treatment option to cure type 1 diabetes; islets are isolated from a donor for subsequent culture prior to transplantation. However, high seeding conditions cause unsolicited fusion of multiple spheroids, thereby limiting oxygen diffusion to induce hypoxic cell death. Here we introduce a culture dish incorporating a micropyramid-patterned surface to prevent the unsolicited fusion and oxygen-permeable bottom for optimal oxygen environment. A 400 µm-thick, oxygen-permeable polydimethylsiloxane sheet topped with micropyramid pattern of 400 µm-base and 200 µm-height was fabricated to apply to the 24-well plate format. The micropyramid pattern separated the individual pancreatic islets to prevent the fusion of multiple islets. This platform supported the high oxygen demand of islets at high seeding density at 260 islet equivalents cm−2, a 2–3-fold higher seeding density compared to the conventional islet culture used in a preparation for the clinical islet transplantations, demonstrating improved islet morphology, metabolism and function in a 4 d-culture. Transplantation of these islets into immunodeficient diabetic mice exhibited significantly improved engraftment to achieve euglycemia compared to islets cultured in the conventional culture wells. Collectively, this simple design modification allows for high-density cultures of three-dimensional cell spheroids to improve the viability and function for an array of investigational and clinical replacement tissues.

Characterization of human islet function in a convection-driven intravascular bioartificial pancreas.

Clinical islet transplantation for treatment of type 1 diabetes (T1D) is limited by the shortage of pancreas donors and need for lifelong immunosuppressive therapy. A convection-driven intravascular bioartificial pancreas (iBAP) based on highly permeable, yet immunologically protective, silicon nanopore membranes (SNM) holds promise to sustain islet function without the need for immunosuppressants. Here, we investigate short-term functionality of encapsulated human islets in an iBAP prototype. Using the finite element method (FEM), we calculated predicted oxygen profiles within islet scaffolds at normalized perifusion rates of 14-200 nl/min/IEQ. The modeling showed the need for minimum in vitro and in vivo islet perifusion rates of 28 and 100 nl/min/IEQ, respectively to support metabolic insulin production requirements in the iBAP. In vitro glucose-stimulated insulin secretion (GSIS) profiles revealed a first-phase response time of <15 min and comparable insulin production rates to standard perifusion systems (~10pg/min/IEQ) for perifusion rates of 100-200 nl/min/IEQ. An intravenous glucose tolerance test (IVGTT), performed at a perifusion rate of 100-170 nl/min/IEQ in a non-diabetic pig, demonstrated a clinically relevant C-peptide production rate (1.0-2.8pg/min/IEQ) with a response time of <5min.

Generation of Insulin-Producing Multicellular Organoids.

Clinical islet transplantation (CIT) is an established noninvasive treatment for type I diabetes (T1D) and has demonstrated improved glycemic control, preventing the occurrence of severe hypoglycemia. However, CIT has several limitations, such as the need for multiple donors, lifelong immunosuppression, and suboptimal long-term graft function. Most of the transplanted islets are lost due to inflammation, ischemic damage, and delayed revascularization.Generation of organoids have gained increasing interest in regenerative medicine in recent years. In the context of beta-cell replacement, it offers a possibility to address limitations of CIT by allowing to produce uniform organoids from single or multiple cell types facilitating revascularization and anti-inflammatory and/or immunomodulatory protection. We have previously generated multicellular insulin-secreting organoids composed of islet cells and the human amniotic epithelial cells (hAECs). These 3D insulin-secreting structures demonstrated improved viability and function both in vitro and in vivo. Here we detail a stepwise methodology to generate insulin-secreting organoids using two different methods. In addition, quality assessment in vitro tests are also described.

Isolation of Human Pancreatic Islets from the Indian Population - Unveiling the Synergistic Interplay between different blends of Collagenases and Neutral Proteases

Innovative and effective therapeutic approaches for diabetes such as islet cell transplantation are much needed as diabetes increases the risk of heart failure. In India, the success rate of human clinical islet transplantation (allo-or auto-) mandates sufficiency of functional islets from the pancreas of either brain-dead or chronic pancreatitis donors. Human islet transplantation outcome is significantly affected by collagenases, which decides the yield and quality of isolated pancreatic islet cells. Comparison of collagenase blends carried out in a few islet transplantation centers yields conflicting results for islet quantity and quality. Therefore, we have researched on the right blend of enzymes to achieve an efficient pancreatic islet release, first-ever in Indian population. Our prospective approach evaluated the outcome of islet isolations performed in humans with three different collagenases, namely Serva Collagenase NB1, Roche Liberase and Vitacyte supplemented with Neutral Protease NB. Eight brain-dead humans served as organ donors for pancreatic islet isolation. We modified the islet isolation method to test these three new enzymes using the traditional split pancreas methodology. The islet isolation outcomes were compared for morphological differences, yield, and viability. This was correlated statistically with the donor characteristics using graph-pad prism analysis. Islet yield was substantial in all the three enzyme blends. But post-purification of islets in the Indian population, we found that the yield was better in Serva collagenase NB1 compared to Vitacyte and Roche liberase. For every gram of pancreas, the islet yield, proportion and morphology of islet cells (both free and intact) were higher in Serva collagenase compared to the other two enzyme blends.

Exploring Local Immune Modulation With Rapamycin-eluting Micelles to Preserve Islet Graft Function in Mice

Islet transplantation is an effective means for a subset of people with type 1 diabetes to achieve insulin independence; however, lifelong systemic immunosuppression required to subvert the immune response remains a major barrier in patient inclusion. Herein, we explore the use of a localized drug delivery system to preserve islet allograft function, reducing the need for toxic systemic immunosuppression. Rapamycin (rapa), an immunosuppressant used in clinical islet transplantation, was encapsulated in Food and Drug Administration-approved poly(lactide-co-glycolide) (PLGA) micelles.

Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study.

To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c <7.0%), freedom from severe hypoglycemia, and insulin independence. Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c <7.0% (P = 0.0017); freedom from severe hypoglycemia was maintained at >90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation. Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.

From islet of Langerhans transplantation to the bioartificial pancreas

Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity.A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage.This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.

P12.06: Effect of Supplementing Taurine to the Developed Lowtemperature Islet Preservation Solution

Introduction: Pancreatic islet transplantation has recently emerged as one of the most promising therapeutic approaches for improving glycemic control in type 1 diabetes patients. However, one of the problems with islet transplantation is that it is impossible to culture the isolated islet for extended periods to while recipients are selected, tested and prepared for surgery. To address this problem, we developed the islet preservation solution, and to improve the function of the preservation solution, we added taurine and conducted a preservation experiment. Taurine is antioxidant activity and it is not a classical free radical scavenger. Therefore, its mechanism remains unclear but it controls osmotic pressure. Our hypothesis is that taurine supplementation can improve islet recovery and enhance islet function after low temperature preservation. Methods: CMRL 1066 medium (Corning) was used as a control group, and a comparison group was prepared some compounds OPTI(Optipharm presevation) solution (with taurine) and OPTI-T solution (without taurine). To confirm the preservation effect of these solutions, we isolated islet from adult Yucatan pig’s pancreas using standard enzymatic digestion (Nordmark) followed by Ficoll purification, these islets were preserved in a humidified tissue culture incubator with preservation solutions and preserved in 4℃ for up to 4 weeks. We compared islet survival in groups of islets. To islet viability and islet functionality, we utilized Glucose Stimulated Insulin Secretion (GSIS) for measuring insulin release, calculated stimulation index (SI) and AO/PI viability staining for during the preservation period. Results: Highest islet recovery was preserved in the group of pig islets cultured with Taurine as compared to the group of islets hypothermically preserved in standard tissue culture media over the 4 week preservation period (p<0.001 using ANOVA). The porcine islet viability/cell number ratio in the OPTI solution maintained a high survival rate for up to 2 weeks (94%). In contrast, porcine islet in OPTI-T solution and CMRL 1066 supplemented media significantly reduced viability after 1 weeks. OPTI solution (with taurine) was significantly higher than OPTI-T solution (without taurine) and CMRL 1066 during 4 weeks after preservation. Glucose stimulation insulin secretion test was performed for functional analysis. As a result, a level of porcine insulin was higher during 2 weeks in the OPTI solution than OPTI-T solution and CMRL 1066. But after 3 weeks preservation, insulin level in high glucose, significantly decreased. Therefore, the viability and functionality of islets were improved by adding taurine to the developed preservation solution. Conclusion: Taurine supplementation has been shown to highest islet recovery, viability and insulin secretion level for 2 weeks. Based on this data, we have performed 2 weeks cold storage of isolated islets for current clinical islet transplantation. Ministry of trade industry and energy, KEIT 20011276, NTIS 1415172664.

Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression.

Islet transplantation has been established as a viable treatment modality for type 1 diabetes. However, the side effects of the systemic immunosuppression required for patients often outweigh its benefits. Here, we engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein–modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression. Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact.

Advances in islet organoids

<p indent="0mm">Diabetes mellitus is a major public health issue and has an increasing pandemic prevalence. There is no existing treatment or medication that can cure the disease. Clinical islet transplantation has the potential to cure diabetes, yet the profound donor shortage hinders the widespread implementation of this therapy. Therefore, generating β cells <italic>in vitro</italic> represents an area of increasing interest. Advances in stem cell culture have made it possible to derive <italic>in vitro</italic> 3D tissues, called organoids. Organoid technology can be used to model organ development and diseases, and it also opens up new avenues for regenerative medicine, providing a new cell source for islet transplantation. Here, we describe current efforts aimed at generating β-like cells and islet organoids using embryonic stem cells, induced pluripotent stem cells, transdifferentiated cells, and adult stem cells. In addition, we discuss the remaining hurdles and optimization strategies for the clinical application of islet organoids.