Biofabrication of a vascularized islet organ for type 1 diabetes

Citro, Antonio; Moser, Philipp T.; Dugnani, Erica; Rajab, Taufiek Konrad; Ren, Xi; Evangelista-Leite, Daniele; Charest, Jonathan M.; Peloso, Andréa; Podesser, Bruno K.; Manenti, Fabio; Pellegrini, Silvia; Piemonti, Lorenzo; Ott, Harald C.

doi:10.1016/j.biomaterials.2019.01.035

Cited by 71 publications

(54 citation statements)

References 53 publications

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“…Current research on T1D focuses on the understanding of b-cell re-establishment by the investigation of complex cellular organoids, such as heterotypic cell aggregates from b-cells and ECs, 9,18 so-called pseudo-islets. Bioengineered prevascularized grafts combining b-cells and ECs ex vivo have been reported, [21][22][23][24] potentially reducing the required time to develop angiogenesis and revascularization in vivo, facilitating graft survival after transplantation. 13,25 Apart from the aspect of increased survival, 22 distinct groups have shown that b-cell and EC cocultures impact graft vascularization and increase b-cell functionality.…”

Section: Introductionmentioning

confidence: 99%

Controlled Heterotypic Pseudo-Islet Assembly of Human β-Cells and Human Umbilical Vein Endothelial Cells Using Magnetic Levitation

Urbanczyk

Zbinden

Layland

et al. 2020

Tissue Engineering Part A

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b-Cell functionality and survival are highly dependent on the cells' microenvironment and cell-cell interactions. Since the pancreas is a highly vascularized organ, the crosstalk between b-cells and endothelial cells (ECs) is vital to ensure proper function. To understand the interaction of pancreatic b-cells with vascular ECs, we sought to investigate the impact of the spatial distribution on the interaction of human cell line-based b-cells (EndoC-bH3) and human umbilical vein endothelial cells (HUVECs). We focused on the evaluation of three major spatial distributions, which can be found within human islets in vivo, in tissue-engineered heterotypic cell spheroids, socalled pseudo-islets, by controlling the aggregation process using magnetic levitation. We report that heterotypic spheroids formed by spontaneous aggregation cannot be maintained in culture due to HUVEC disassembly over time. In contrast, magnetic levitation allows the formation of stable heterotypic spheroids with defined spatial distribution and significantly facilitated HUVEC integration. To the best of our knowledge, this is the first study that introduces a human-only cell line-based in vitro test system composed of a coculture of b-cells and ECs with a successful stimulation of b-cell secretory function monitored by a glucose-stimulated insulin secretion assays. In addition, we systematically investigate the impact of the spatial distribution on cocultures of human b-cells and ECs, showing that the architecture of pseudo-islets significantly affects b-cell functionality.

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Section: Introductionmentioning

confidence: 99%

Controlled Heterotypic Pseudo-Islet Assembly of Human β-Cells and Human Umbilical Vein Endothelial Cells Using Magnetic Levitation

Urbanczyk

Zbinden

Layland

et al. 2020

Tissue Engineering Part A

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“…Once generated, regardless of their origin, insulin‐producing organoids can be used as building blocks, assembled and incorporated into a scaffold, to construct a bioartificial pancreas. Over the past decades, a broad variety of naturally derived and synthetic polymers, collagen gels, with or without pores, and decellularized biological matrices have been proposed for scaffold construction [96–99]. While synthetic materials can be manufactured with consistent composition and can be easily fine‐tuned according to needs [97], biological scaffolds are biocompatible, and can recreate the microenvironment of the islets due to the similar composition of the ECM.…”

Section: Assembling Organoids Into a Bioartificial Pancreasmentioning

confidence: 99%

Generation of insulin‐secreting organoids: a step toward engineering and transplanting the bioartificial pancreas

et al. 2020

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Summary Diabetes is a major health issue of increasing prevalence. ß‐cell replacement, by pancreas or islet transplantation, is the only long‐term curative option for patients with insulin‐dependent diabetes. Despite good functional results, pancreas transplantation remains a major surgery with potentially severe complications. Islet transplantation is a minimally invasive alternative that can widen the indications in view of its lower morbidity. However, the islet isolation procedure disrupts their vasculature and connection to the surrounding extracellular matrix, exposing them to ischemia and anoikis. Implanted islets are also the target of innate and adaptive immune attacks, thus preventing robust engraftment and prolonged full function. Generation of organoids, defined as functional 3D structures assembled with cell types from different sources, is a strategy increasingly used in regenerative medicine for tissue replacement or repair, in a variety of inflammatory or degenerative disorders. Applied to ß‐cell replacement, it offers the possibility to control the size and composition of islet‐like structures (pseudo‐islets), and to include cells with anti‐inflammatory or immunomodulatory properties. In this review, we will present approaches to generate islet cell organoids and discuss how these strategies can be applied to the generation of a bioartificial pancreas for the treatment of type 1 diabetes.

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“…To address this issue, a number of experimental approaches are being tested to provide rapid or immediate vascular supply in the subcutaneous space. These include strategies to prevascularize the subcutaneous space [28,29,30▪,31], co-transplant endothelial cells along with β cells to induce vascularization at the time of transplant [32–34,35▪], or provide oxygen via oxygen-generating biomaterials [36,37]. A variety of promising encapsulation (macro and micro) techniques have been tested in small and large animals with promising results [38–41].…”

Section: Stem Cell-derived Islet Transplant Sitementioning

confidence: 99%

Mimicking nature-made beta cells: recent advances towards stem cell-derived islets

Tremmel

Mitchell

Sackett

et al. 2019

Current Opinion in Organ Transplantation

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Purpose of review Stem cell-derived islets are likely to be useful as a future treatment for diabetes. However, the field has been limited in the ability to generate β-like cells with both phenotypic maturation and functional glucose-stimulated insulin secretion that is similar to primary human islets. The field must also establish a reliable method of delivering the cells to patients while promoting rapid in-vivo engraftment and function. Overcoming these barriers to β cell differentiation and transplantation will be key to bring this therapy to the clinic. Recent findings The ability to generate stem cell-derived β-like cells capable of dynamic glucose-responsive insulin secretion, as well as β-like cells expressing key maturation genes has recently been demonstrated by several groups. Other groups have explored the potential of vascularized subcutaneous transplant sites, as well as endothelial cell co-transplant to support β cell survival and function following transplantation. Summary The generation of stem cell-derived islets with dynamic glucose-responsive insulin secretion has brought the field closer to clinical translation, but there is still need for improving insulin content and secretory capacity, as well as understanding the factors affecting variable consistency and heterogeneity of the islet-like clusters. Other questions remain regarding how to address safety, immunogenicity and transplantation site moving forward.

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Biofabrication of a vascularized islet organ for type 1 diabetes

Cited by 71 publications

References 53 publications

Controlled Heterotypic Pseudo-Islet Assembly of Human β-Cells and Human Umbilical Vein Endothelial Cells Using Magnetic Levitation

Controlled Heterotypic Pseudo-Islet Assembly of Human β-Cells and Human Umbilical Vein Endothelial Cells Using Magnetic Levitation

Generation of insulin‐secreting organoids: a step toward engineering and transplanting the bioartificial pancreas

Mimicking nature-made beta cells: recent advances towards stem cell-derived islets

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