Recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening are highlighted while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential.
Abstract
Type 1 diabetes (T1D) impacts more than 9 million individuals globally. Despite a century since the isolation and clinical introduction of insulin, exogenous insulin injections remain the primary form of treatment for T1D. While continuous glucose monitoring systems and optimized insulin delivery reduce life-threatening hypoglycemic events, they do not provide a permanent cure. Transplantation of pancreatic islets offers a potential long-term solution. Recent advances in stem cell–derived islets (SC-islets) have shown remarkable promise in both clinical and research settings. This article highlights recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential. We also discuss exciting emerging approaches that expand investigations beyond pancreatic endocrine cells to encompass nonendocrine cell types in the pancreas, offering a unique bird’s-eye view into pancreatic biology and insights into cellular cross talk in health and disease. Our aim is for this article to serve as a resource for up-to-date advances in SC-islet research and to highlight novel platforms for studying diabetes pathogenesis in unprecedented ways, accelerating progress toward a permanent cure. Article Highlights Stem cell–derived islets provide a renewable source of insulin-producing cells for studying diabetes and developing regenerative therapies. Stem cell–derived islets are still functionally immature in comparison with primary human islets, underscoring the need for deeper insights into β-cell biology to improve their fidelity. Nonetheless, they serve as a powerful platform for diabetes disease modeling. Emerging technological advances, including spatial multiomics and multicellular organoid development, are revealing key roles for non–β-cell and nonislet cell types in pancreatic diseases. Integrating these emerging tools is critical for broadening our understanding of diabetes pathophysiology and may enable us to view the disease from previously unexplored perspectives.
Type 1 diabetes (T1D) is a selective autoimmune loss of insulin-secreting pancreatic β-cells and lifelong replacement with exogenous insulin. The disease remains incurable despite extensive research. New therapies, such as stem cell replacement, have been developed as the leading β-cell replacement modality. Pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) have been established as insulin-secreting cells, a theoretically unlimited reservoir for transplantation. Defective β-cell function, immune rejection, and ethical issues still exist. New immunosuppressive measures such as costimulation blockade therapy or regulatory T cell (Treg)-based therapy have been proposed to optimize graft survival with fewer side effects. Bioengineered islet grafting, xenograft transplantations, and gene editing tools are also analyzed in order to improve the effectiveness of β-cell replacement. Therapeutic advances in target immunomodulation and islet encapsulation are also enhancing survival and functionality of transplanted cells. This article provides a pharmaceutical review of emerging β-cell replacement therapies including stem cell-derived therapy, immunotherapy, and innovative biotechnologybased solutions. Breaking through current limitations of these therapies is crucial to achieving long-term insulin independence for T1D patients. Refining differentiation protocols, improving immune evasion strategies, and merging paradigms of personalized medicine are essential to achieving maximal therapeutic benefit in future studies.
Dushyant, Smita Narwal, Gurvirender Singh et al.· Recent advances in inflammat...· 0 citations
Abstract Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic β cells, leading to lifelong insulin dependence and an increased risk of severe complications. Three-dimensional stem cells (3D SCs) culture systems have emerged as a superior alternative by more accurately mimicking the in vivo microenvironment and enhancing stemness maintenance, regenerative efficiency, and paracrine secretion. However, studies exploring the application of 3D SCs in T1D remain limited. Here, we developed a novel serum- and cytokine-free orbital-shaking system. It enables efficient and large-scale reprogramming of somatic cells into 3D embryonic-like stem cell spheroids (Sph-Es) characterized by robust pluripotency and improved safety. To enhance therapeutic utility, Sph-Es were irradiated and transduced with INS-expressing adenoviral vectors to generate Sph-R-Ins, allowing transient insulin production without permanent genomic modification. In STZ-induced T1D mice, Sph-R-Ins improved glycemic control and glucose tolerance and increased mouse insulin and C-peptide responses, indicating improved endogenous islet function. Donor-cell tracking analyses showed no pancreatic engraftment, supporting an indirect mode of action. Additional transcriptomic, immunological, and ex vivo studies indicated that the therapeutic benefit was accompanied by ECM-related signaling changes, reduced inflammatory infiltration, enhanced M2 macrophage polarization and Treg-associated immune regulation, improved metabolic signaling, and spheroid-derived paracrine support of islet function. Together, these findings establish a mechanically guided 3D stem cell–gene therapy platform with both endocrine and immunometabolic benefits in T1D.
AIMS
Islet transplantation offers the potential of a cure for type 1 diabetes (T1D), but the limited availability of human donor islets means that this therapy is currently only available to a small group of people with T1D who have intractable hypoglycaemia. The shortage of donor human islets has driven extensive research efforts to generate human islets from pluripotent stem cells (SC-islets), and current protocols are producing SC-islets which are showing promising results in early clinical trials. As part of our T1D Grand Challenge research programme, we set up a Patient and Public Involvement (PPI) Steering Group with a diverse range of members with lived experience of T1D to interact with us and provide advice. The aim of this study was to explore how perceptions of human islet transplantation differ between people with lived experience of T1D and diabetes researchers.
METHODS
To determine how perceptions of human islet transplantation may differ between people with lived experience of T1D and researchers, two islet transplant recipients recounted their experiences to members of the PPI group and the science researchers.
RESULTS
We subsequently asked both groups for individual, anonymised responses to the presentations, and we here present an analysis of that survey.
CONCLUSIONS
Overall, this exercise highlights different approaches to islet/SC-islet transplantation between people with lived experience of T1D and basic science diabetes researchers. This emphasises the continued need for open lines of communication between the two groups so each can benefit from the other's experience.
P. M. Jones, Sarah Gatward, Lesley Beadle et al.· Diabetic Medicine· 0 citations
ABSTRACT Type 1 Diabetes (T1D) is an autoimmune disorder marked by the immune‐mediated destruction of pancreatic β‐cells, resulting in insulin deficiency and dysregulated glucose control. Current therapies—such as insulin replacement and artificial pancreas systems—manage symptoms but fail to restore endogenous β‐cell function or halt disease progression. Transplantation strategies, including islet allo‐ and xenotransplantation, offer potential cures but remain limited by immune rejection, donor scarcity, and the adverse effects of systemic immunosuppression. Within the framework of predictive, preventive, and personalised medicine (3 PM), T1D management requires a paradigm shift towards early detection, targeted prevention, and individualised therapy. Predictive biomarkers and molecular phenotyping can identify high‐risk individuals and forecast graft outcomes, while preventive strategies—such as localised immunomodulation, bioenergetic support, and control of systemic inflammation—improve tolerance and graft longevity. Personalised interventions, including patient‐specific biomaterials, immunoprotective encapsulation, and regulatory T cell–based or stem‐cell–derived β‐cell replacement, address immune and metabolic heterogeneity. Recent progress in biomaterials, encapsulation, and 3D bioprinting enables the practical implementation of this 3 PM approach by enhancing oxygenation, vascular integration, and specific scaffold design. Integration of AI‐driven analytics, digital health monitoring, and multi‐modal diagnostics further supports predictive control of transplant outcomes. This review highlights advances in islet transplantation and regenerative biomaterial engineering as key enablers of the transition from reactive treatment to 3 PM‐guided, patient‐tailored therapy for T1D.
Fatemeh Sabet Sarvestani, R. Yaghobi, Mohsen Khosravi Maharlooei et al.· Diabetes/Metabolism Research...· 0 citations
Diabetes mellitus (DM) is a multifactorial metabolic disorder in which chronic hyperglycemia arises alongside adipose-tissue dysfunction, ectopic lipid accumulation, endothelial injury, and progressive multiorgan damage. These processes form an interconnected network, and because lowering glucose or blocking any single pathway leaves the other nodes active, the disease continues to advance even when glycemic targets are met. Therapies that act on several nodes at once are therefore conceptually attractive. Mesenchymal stem cell (MSC) therapy fits this requirement, engaging the immune, vascular, and metabolic arms of the disease at the same time through a shared paracrine program. Here, we analyze 107 registered interventional trials, drawn from 124 screened records, that evaluate MSC-based therapies across type 1 diabetes, type 2 diabetes, and a range of diabetic complications. Autologous bone marrow-derived MSCs (BMMSCs) and adipose-derived MSCs (AdMSCs) featured in the earliest trials, and registration has since shifted toward standardized allogeneic umbilical cord-derived MSCs (UCMSCs) and cell-free derivatives. The strongest and most consistent benefits appear in ischemic and wound-healing complications, particularly diabetic foot ulcers, whereas metabolic outcomes remain variable. Together, current early-phase evidence supports MSC therapy as a safe and potentially disease-modifying adjunct, although larger randomized trials with harmonized endpoints are needed to confirm efficacy.
Pancreatic beta cells are dedicated factories in the production, storage and secretion of impressive amounts of insulin. In the human pancreas, beta cells are found in clusters known as islets of Langerhans which vary in cell quantity and endocrine cell types, including glucagon-producing alpha cells and somatostatin-producing delta cells. Major progress has been made in recent years in understanding beta cell physiology and pathology, with a particular focus on the mechanisms of beta cell destruction in type 1 diabetes and potential approaches for restoring beta cell function. In this review, we have selected recent examples that highlight the progress made in understanding human islets and beta cell biology. Specifically, we (1) concentrated on new discoveries in beta cells, both within and outside of the islets of Langerhans; (2) evaluated whether more understanding of basic beta cell biology is needed; (3) discussed whether more tools are needed to provide answers to our key questions; as an example, we highlighted the progress made in the development of human beta cell lines and in the imaging tools for studying human beta cells; (4) questioned why there is still a gap in knowledge regarding beta cell destruction in type 1 diabetes, despite hundreds of thousands of published studies. We conclude with our vision of beta and islet cell biology.
R. Scharfmann, Arnaud Zaldumbide· Diabetologia· 0 citations
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