Dataset Information

IPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets.

ABSTRACT: Islet transplantation is an effective therapy for achieving and maintaining normoglycemia in patients with type 1 diabetes mellitus. However, the supply of transplantable human islets is limited. Upon removal from the pancreas, islets rapidly disintegrate and lose function, resulting in a short interval for studies of islet biology and pretransplantation assessment. Here, we developed a biomimetic platform that can sustain human islet physiology for a prolonged period ex vivo. Our approach involved the creation of a multichannel perifusion system to monitor dynamic insulin secretion and intracellular calcium flux simultaneously, enabling the systematic evaluation of glucose-stimulated insulin secretion under multiple conditions. Using this tool, we developed a nanofibrillar cellulose hydrogel-based islet-preserving platform (iPreP) that can preserve islet viability, morphology, and function for nearly 12 weeks ex vivo, and with the ability to ameliorate glucose levels upon transplantation into diabetic hosts. Our platform has potential applications in the prolonged maintenance of human islets, providing an expanded time window for pretransplantation assessment and islet studies.

SUBMITTER: Chen YJ

PROVIDER: S-EPMC6948755 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets.

Chen Yi-Ju YJ Yamazoe Taiji T Leavens Karla F KF Cardenas-Diaz Fabian L FL Georgescu Andrei A Huh Dongeun D Gadue Paul P Stanger Ben Z BZ

JCI insight 20191101 21

Islet transplantation is an effective therapy for achieving and maintaining normoglycemia in patients with type 1 diabetes mellitus. However, the supply of transplantable human islets is limited. Upon removal from the pancreas, islets rapidly disintegrate and lose function, resulting in a short interval for studies of islet biology and pretransplantation assessment. Here, we developed a biomimetic platform that can sustain human islet physiology for a prolonged period ex vivo. Our approach invol ...[more]

PMID: 31672937

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Project description:Although the application of human embryonic stem cells (hESCs) in stem cell-replacement therapy remains promising, its potential is hindered by a low cell survival rate in post-transplantation within the inner ear. Here, we aim to enhance the in vitro and in vivo survival rate and neuronal differentiation of otic neuronal progenitors (ONPs) by generating an artificial stem cell niche consisting of three-dimensional (3D) hESC-derived ONP spheroids with a nanofibrillar cellulose hydrogel and a sustained-release brain-derivative neurotrophic factor delivery system. Our results demonstrated that the transplanted hESC-derived ONP spheroids survived and neuronally differentiated into otic neuronal lineages in vitro and in vivo and also extended neurites toward the bony wall of the cochlea 90 days after the transplantation without the use of immunosuppressant medication. Our data in vitro and in vivo presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear. Using our protocol to create an artificial stem cell niche in the inner ear, it is now possible to work on integrating transplanted hESC-derived ONPs further and also to work toward achieving functional auditory neurons generated from hESCs. Our findings suggest that the provision of an artificial stem cell niche can be a future approach to stem cell-replacement therapy for inner-ear regeneration. STATEMENT OF SIGNIFICANCE: Inner ear regeneration utilizing human embryonic stem cell-derived otic neuronal progenitors (hESC-derived ONPs) has remarkable potential for treating sensorineural hearing loss. However, the local environment of the inner ear requires a suitable stem cell niche to allow hESC-derived ONP engraftment as well as neuronal differentiation. To overcome this obstacle, we utilized three-dimensional spheroid formation (direct contact), nanofibrillar cellulose hydrogel (extracellular matrix), and a neurotrophic factor delivery system to artificially create a stem cell niche in vitro and in vivo. Our in vitro and in vivo data presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear.

Project description:The pancreatic islet is a highly vascularized micro-organ, and rapid revascularization postislet transplantation is important for islet survival and function. However, the various mechanisms involved in islet revascularization are not fully understood, and we currently lack good in vitro platforms to explore this. Our aim for this study was to generate perfusable microvascular networks in a microfluidic chip device, in which islets could be easily integrated, to establish an in vitro platform for investigations on islet-microvasculature interactions. We compared the ability of mesenchymal stem cells (MSCs) and fibroblasts to support microvascular network formation by human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial colony-forming cell in two-dimensional and three-dimensional models of angiogenesis, and tested the effect of different culture media on microvessel formation. HUVECs that were supported by MSCs formed patent and perfusable networks in a fibrin gel, whereas networks supported by fibroblasts rapidly regressed. Network morphology could be controlled by adjusting relative cell numbers and densities. Incorporation of isolated rat islets demonstrated that islets recruit local microvasculature in vitro, but that the microvessels did not invade islets, at least during the course of these studies. This in vitro microvascularization platform can provide a useful tool to study how various parameters affect islet integration with microvascular networks and could also be utilized for studies of vascularization of other organ systems. Impact statement To improve pancreatic islet graft survival and function posttransplantation, rapid and adequate revascularization is critical. Efforts to improve islet revascularization are demanding due to an insufficient understanding of the mechanisms involved in the process. We have applied a microfluidics platform to generate microvascular networks, and by incorporating pancreatic islets, we were able to study microvasculature-islet interactions in real time. This platform can provide a useful tool to study islet integration with microvascular networks, and could be utilized for studies of vascularization of other organ systems. Moreover, this work may be adapted toward developing a prevascularized islet construct for transplantation.

Dataset Information

IPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets.

Publications

iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets.

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