Islet Grafts Research Articles

The First Case of Intra-portal Islet Implantation During Liver Machine Perfusion Allowing Simultaneous Islet-liver Transplantation in A Human: A New and Safe Treatment for End-stage Liver Disease Combined With Diabetes Mellitus.

Evaluating the safety and efficacy of implanting a liver with islet grafts into patients with end-stage liver disease and diabetes mellitus (DM). DM and end-stage liver diseases are significant health concern worldwide, often coexisting and mutually influencing each other. Addressing both diseases simultaneously is paramount. We utilized the islet transplantation combined ischemia-free liver transplantation (ITIFLT) technique to treat a patient with hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM). The liver was procured and preserved using the ischemia-free liver transplantation (IFLT) technique, and during normothermic machine perfusion (NMP), isolated and purified islet grafts were transplanted into the liver through the portal vein. Finally, the liver, incorporating with the transplant islet grafts, was implanted into the recipient without interruption of blood supply. The patient received both liver and islet graft from the same donor. The patient achieved insulin-independence by post-transplant day (PTD) 9, and both liver and islet function remained robust. The patient was discharged on PTD 18 and experienced no surgical or transplantation-related complications during the follow-up period. Furthermore, islet grafts presence was observed in liver biopsies after islet transplantation. This landmark case marks the inaugural application of ITIFLT in humans, signifying its potential as a promising treatment modality for end-stage liver disease with DM.

Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells.

Activated beta-cell reactive CD4 + and CD8 + T effector cells undergo a profound DNA-damage response which is targetable by small molecule inhibitors of the p53 and cell cycle pathways that lead to apoptosis. The use of a combination of MDM2 and WEE1 inhibitors, which termed "p53 potentiation with checkpoint abrogation" (PPCA), conferred significant therapeutic efficacy in treating mouse models of new onset T1D. Specific targeting of these T effector cells by PPCA results in a loss of inflammatory T cell subsets, notably proliferation CD4 + Th0 and Th1 subsets and CD8 + T effector memory cells, as determined by single cell RNA-seq studies with the preservation of T regulatory cells. When autologous islet grafts are given to established diabetic NOD mice, a single course of PPCA results in long-term islet graft acceptance, restoration of normoglycemia and loss of beta cell specific CD4 + and CD8 + T cells. PPCA shows promise as a potential means of estimating islet graft tolerance in T1D recipients of islet graft transplantation.

A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation.

For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term. We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγcnull (NOG) mice (Ins1C96Y/C96Y NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice. All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation. The Ins1C96Y/C96Y NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.

Matrix design for optimal pancreatic β cells transplantation

New therapeutic approaches to treat type 1 diabetes mellitus relies on pancreatic islet transplantation. Here, developing immuno-isolation strategies is essential to eliminate the need for systemic immunosuppression after pancreatic islet grafts. A solution is the macro-encapsulation of grafts in semipermeable matrixes with a double function: separating islets from host immune cells and facilitating the diffusion of insulin, glucose, and other metabolites.This study aims to synthesize and characterize different types of gelatin-collagen matrixes to prepare a macro-encapsulation device for pancreatic islets that fulfill these functions. While natural polymers exhibit superior biocompatibility compared to synthetic ones, their mechanical properties are challenging to reproduce. To address this issue, we conducted a comparative analysis between photo-crosslinked gelatin matrixes and chemically crosslinked collagen matrixes. We show that the different crosslinkers and polymerization methods influence the survival and glucose-stimulated insulin production of pancreatic β cells (INS1) in vitro, as well as the in vitro and in vivo stability of the matrix and the immuno-isolation in vivo.Among the matrixes, the stiff multilayer GelMA matrixes (8.5 kPa), fabricated by digital light processing, were the best suited for pancreatic β cells macro-encapsulation regarding these parameters. Within the alveoli of this matrix, pancreatic β cells spontaneously formed aggregates.

α- or β-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (β-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor β-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or β-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor β-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system.

Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.

On the path to a diabetes cure: a critical appraisal of developments in pancreatic beta cell encapsulation and implantation

Microencapsulation of β-cells is a rapidly growing field that offers broad potential for the therapy and possible cure of diabetes, especially type 1 diabetes, thanks to the immunization of the engrafted tissue that increases its long-term efficacy and decreases the risk of immunogenicity. Despite the promising results obtained in human and animal studies, important challenges need to be addressed. The structure and composition of the microspheres and the site where they are implanted can affect the effectiveness of the treatment, and associated immunogenicity problems have been reported. To improve the safety of the encapsulated islet graft system, new efforts are being made in the bioengineering of the capsules and the production of insulin-producing cells within the capsular membranes. These critical advances in cell encapsulation technology are expected to enable broader and more effective human application of this system. In this review, the great potential of encapsulated pancreatic islet transplantation to provide a cure for type 1 diabetes is highlighted. The advantages and disadvantages of this therapeutic strategy are also outlined, as well as key advances made in cellular microencapsulation research for treating diabetes.

Pancreatic stellate cells support human pancreatic β-cell viability in vitro and enhance survival of immunoisolated human islets exposed to cytokines

Pancreatic islet transplantation is proposed as a cure for type 1 diabetes mellitus (T1D). Despite its success in optimal regulation of glucose levels, limitations in longevity of islet grafts still require innovative solutions. Inflammatory stress post-transplantation and loss of extracellular matrix attribute to the limited β-cell survival. Pancreatic stellate cells (PSCs), identified as pancreatic-specific stromal cells, have the potential to play a crucial role in preserving islet survival. Our study aimed to determine the effects of PSCs co-cultured with human CM β-cells and human islets under inflammatory stress induced by a cytokine cocktail of IFN-γ, TNF-α and IL-1β. Transwell culture inserts were utilized to assess the paracrine impact of PSCs on β-cells, alongside co-cultures enabling direct interaction between PSCs and human islets. We found that co-culturing PSCs with human CM β-cells and human cadaveric islets had rescuing effects on cytokine-induced stress. Effects were different under normoglycemic and hyperglycemic conditions. PSCs were associated with upregulation of β-cell mitochondrial activity and suppression of inflammatory gene expression. The rescuing effects exist both in indirect and direct co-culture methods. Furthermore, we tested whether PSCs have rescuing effects on human islets in conventional alginate-based microcapsules and in composite microcapsules composed of alginate-pectin collagen type IV, laminin sequence RGD, Nec-1, and amino acid. PSCs partially prevented cytokine-induced stress in both systems, but beneficial effects were stronger in composite capsules. Our findings show novel effects of PSCs on islet health. Islets and PSCs coculturing or co-transplantation might mitigate the inflammation stress and improve islet transplantation outcomes.

Immunoprotection Strategies in β-Cell Replacement Therapy: A Closer Look at Porcine Islet Xenotransplantation.

Type 1 diabetes mellitus (T1DM) is characterized by absolute insulin deficiency primarily due to autoimmune destruction of pancreatic β-cells. The prevailing treatment for T1DM involves daily subcutaneous insulin injections, but a substantial proportion of patients face challenges such as severe hypoglycemic episodes and poorly controlled hyperglycemia. For T1DM patients, a more effective therapeutic option involves the replacement of β-cells through allogeneic transplantation of either the entire pancreas or isolated pancreatic islets. Unfortunately, the scarcity of transplantable human organs has led to a growing list of patients waiting for an islet transplant. One potential alternative is xenotransplantation of porcine pancreatic islets. However, due to inter-species molecular incompatibilities, porcine tissues trigger a robust immune response in humans, leading to xenograft rejection. Several promising strategies aim to overcome this challenge and enhance the long-term survival and functionality of xenogeneic islet grafts. These strategies include the use of islets derived from genetically modified pigs, immunoisolation of islets by encapsulation in biocompatible materials, and the creation of an immunomodulatory microenvironment by co-transplanting islets with accessory cells or utilizing immunomodulatory biomaterials. This review concentrates on delineating the primary obstacles in islet xenotransplantation and elucidates the fundamental principles and recent breakthroughs aimed at addressing these challenges.

Non-invasive quantification of stem cell-derived islet graft size and composition.

Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [18F]F-dibenzocyclooctyne-exendin-4 ([18F]exendin) and the dopamine precursor 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm3 in size, [18F]exendin having a better detection rate than [18F]FDOPA (69% vs 44%, <1 mm3; 96% vs 85%, >1 mm3). Graft volume quantified with [18F]exendin (r2=0.91) and [18F]FDOPA (r2=0.86) strongly correlated with actual graft volume. [18F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r2=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r2=0.52). [18F]exendin and [18F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes.

1506-P: Genomic Monitoring of Islet Graft Injury in Type 1 Diabetic Patients after Islet Transplantation

1506-P: Genomic Monitoring of Islet Graft Injury in Type 1 Diabetic Patients after Islet Transplantation

Skeletal Myoblast Cells Enhance the Function of Transplanted Islets in Diabetic Mice.

Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1α (SDF-1α)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.

Efficient Vascular and Neural Engraftment of Stem Cell-Derived Islets.

Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at three months post-transplantation, and observed that the cell apoptosis rates were lower, but the vascular density was similar in SC-islets to that of human islets. While the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. The oxygenation of the SC-islet grafts was twice as high as in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, also the reinnervation of the SC-islets was four- to five-fold higher than the human islets. Both SC-islets and the human islets contained amyloid at one and three months post-transplantation. We conclude that the vascular and neural engraftment of SC-islets is superior to human islets, but that grafts of both origins develop amyloid with potential long-term consequences.

Advancing diabetes treatment: the role of mesenchymal stem cells in islet transplantation.

Diabetes mellitus, a prevalent global health challenge, significantly impacts societal and economic well-being. Islet transplantation is increasingly recognized as a viable treatment for type 1 diabetes that aims to restore endogenous insulin production and mitigate complications associated with exogenous insulin dependence. We review the role of mesenchymal stem cells (MSCs) in enhancing the efficacy of islet transplantation. MSCs, characterized by their immunomodulatory properties and differentiation potential, are increasingly seen as valuable in enhancing islet graft survival, reducing immune-mediated rejection, and supporting angiogenesis and tissue repair. The utilization of MSC-derived extracellular vesicles further exemplifies innovative approaches to improve transplantation outcomes. However, challenges such as MSC heterogeneity and the optimization of therapeutic applications persist. Advanced methodologies, including artificial intelligence (AI) and single-cell RNA sequencing (scRNA-seq), are highlighted as potential technologies for addressing these challenges, potentially steering MSC therapy toward more effective, personalized treatment modalities for diabetes. This review revealed that MSCs are important for advancing diabetes treatment strategies, particularly through islet transplantation. This highlights the importance of MSCs in the field of regenerative medicine, acknowledging both their potential and the challenges that must be navigated to fully realize their therapeutic promise.

A Recombinant Peptide Device Combined with Adipose Tissue-Derived Stem Cells Enhances Subcutaneous Islet Engraftment.

Subcutaneous space has been considered an attractive site for islet graft transplantation; however, the oxygen tension and vascularization are insufficient for islet graft survival. We investigated whether subcutaneous pre-implantation of a recombinant peptide (RCP) device with adipose tissue-derived stem cells (ADSCs) enhanced subcutaneous islet engraftment. RCP devices with/without syngeneic ADSCs were pre-implanted into the subcutaneous space of C57BL/6 mice. Syngeneic islets (300 or 120 islet equivalents (IEQs)) were transplanted into the pre-treated space after diabetes induction using streptozotocin. The cure rates of groups in which RCP devices were implanted four weeks before transplantation were significantly better than the intraportal transplantation group when 300 IEQs of islets were transplanted (p < 0.01). The blood glucose changes in the RCP+ADSCs-4w group was significantly ameliorated in comparison to the RCP-4w group when 120 IEQs of islets were transplanted (p < 0.01). Immunohistochemical analyses showed the collagen III expression in the islet capsule of the RCP+ADSCs-4w group was significantly enhanced in comparison to the RCP-4w and RCP+ADSCs-d10 groups (p < 0.01, p < 0.01). In addition, the number of von Willebrand factor-positive vessels within islets in the RCP+ADSCs-4w group was significantly higher than the RCP-4w group. These results suggest that using ADSCs in combination with an RCP device could enhance the restoration of the extracellular matrices, induce more efficient prevascularization within islets, and improve the graft function.

Intragraft memory-like CD127hiCD4+Foxp3+ Tregs maintain transplant tolerance.

CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in suppressing transplant rejection, but their role within the graft and heterogeneity in tolerance are poorly understood. Here, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid organs and grafts in an islet xenotransplant model of tolerance. We showed Tregs were essential for tolerance induction and maintenance. Tregs demonstrated heterogeneity within the graft and lymphoid organs of tolerant mice. A subpopulation of CD127hi Tregs with memory features were found in lymphoid organs, presented in high proportions within long-surviving islet grafts, and had a transcriptomic and phenotypic profile similar to tissue Tregs. Importantly, these memory-like CD127hi Tregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag-/- hosts, than naive Tregs or unselected Tregs from tolerant mice. Administration of IL-7 to the CD127hi Treg subset was associated with a strong activation of phosphorylation of STAT5. We proposed that memory-like CD127hi Tregs developed within the draining lymph node and underwent further genetic reprogramming within the graft toward a phenotype that had shared characteristics with other tissue or tumor Tregs. These findings suggested that engineering Tregs with these characteristics either in vivo or for adoptive transfer could enhance transplant tolerance.

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

Islet transplantation is a curative treatment for patients suffering from type 1 diabetes and has the potential to replace current treatment strategies involving the exogenous administration of insulin. Despite this potential, there are many hurdles in achieving successful long‐term graft survival due to autoimmune and foreign body reactions leading to graft rejection coupled with donor shortage and potential adverse effects from the need for long‐term administration of immunosuppressive drugs. As a result, various approaches have been proposed to increase the viability and function of islet grafts during isolation and ex vivo culture with the use of growth factors, hormones, and other therapeutic agents. In addition, other strategies have addressed how to enhance or maintain islet graft performance after implantation with improvements on immunosuppressive drug regimens and the use of biomaterials to encapsulate and protect the cells from graft rejection. This review focuses on the recent advances in strategies to improve islet viability and function with the addition of exogenous compounds and the implementation of conformal coating as a promising tool for immunoprotection of islet transplants.

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression.

Cell-based therapies hold promise for many chronic conditions; however, the continued need for immunosuppression along with challenges in replacing cells to improve durability or retrieving cells for safety are major obstacles. We subcutaneously implanted a device engineered to exploit the innate transcapillary hydrostatic and colloid osmotic pressure generating ultrafiltrate to mimic interstitium. Long-term stable accumulation of ultrafiltrate was achieved in both rodents and nonhuman primates (NHPs) that was chemically similar to serum and achieved capillary blood oxygen concentration. The majority of adult pig islet grafts transplanted in non-immunosuppressed NHPs resulted in xenograft survival >100 days. Stable cytokine levels, normal neutrophil to lymphocyte ratio, and a lack of immune cell infiltration demonstrated successful immunoprotection and averted typical systemic changes related to xenograft transplant, especially inflammation. This approach eliminates the need for immunosuppression and permits percutaneous access for loading, reloading, biopsy, and recovery to de-risk the use of "unlimited" xenogeneic cell sources to realize widespread clinical translation of cell-based therapies.

Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes.

Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.

Reversal of Hyperglycemia by Subcutaneous Islet Engraftment Using an Atelocollagen Sponge as a Scaffold.

Type 1 diabetes mellitus (T1DM) affects 8.4 million people worldwide, with patients primarily relying on exogenous insulin injections to maintain blood glucose levels. Islet transplantation via the portal vein has allowed for the direct internal release of insulin by glucose-sensitive islets. However, this method might not be desirable for future cell therapy transplanting pluripotent stem cell-derived β cells, facing challenges including difficulties in cell retrieval and graft loss due to the instant blood-mediated inflammatory reaction (IBMIR). Here, we established a subcutaneous transplantation protocol using an atelocollagen sponge as a scaffold. While the subcutaneous site has many advantages, the lack of a vascular bed limits its application. To address this issue, we performed angiogenesis stimulation at the transplantation site using bFGF absorbed in a gelatin sponge (Spongel), significantly improving the microvascular area. Our in vivo experiments also revealed angiogenesis stimulation is crucial for reversing hyperglycemia in streptozotocin (STZ)-induced diabetic mice. In addition to the angiogenic treatment, an atelocollagen sponge is used to carry the islets and helps avoid graft leakage. With 800 mouse islets delivered by the atelocollagen sponge, the STZ-induced diabetic mice showed a reversal of hyperglycemia and normalized glucose intolerance. Their normoglycemia was maintained until the graft was removed. Analysis of the harvested islet grafts exhibited a high vascularization and preserved morphologies, suggesting that using an atelocollagen sponge as a scaffold helps maintain the viability of the islet grafts.