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Microvessel Network Formation and Interactions with Pancreatic Islets in Three-Dimensional Chip Cultures.

ABSTRACT: 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.

SUBMITTER: Rambol MH

PROVIDER: S-EPMC7249478 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Study questionCan we reconstitute physiologically relevant 3-dimensional (3D) microengineered endometrium in-vitro model?Summary answerOur representative microengineered vascularised endometrium on-a-chip closely recapitulates the endometrial microenvironment that consists of three distinct layers including epithelial cells, stromal fibroblasts and endothelial cells in a 3D extracellular matrix in a spatiotemporal manner.What is known alreadyOrgan-on-a-chip, a multi-channel 3D microfluidic cell culture system, is widely used to investigate physiologically relevant responses of organ systems.Study design, size, durationThe device consists of five microchannels that are arrayed in parallel and partitioned by array of micropost. Two central channels are for 3D culture and morphogenesis of stromal fibroblast and endothelial cells. In addition, the outermost channel is for the culture of additional endometrial stromal fibroblasts that secrete biochemical cues to induce directional pro-angiogenic responses of endothelial cells. To seed endometrial epithelial cells, on Day 8, Ishikawa cells were introduced to one of the two medium channels to adhere on the gel surface. After that, the microengineered endometrium was cultured for an additional 5-6 days (total ∼ 14 days) for the purpose of each experiment.Participants/materials, setting, methodsMicrofluidic 3D cultures were maintained in endothelial growth Medium 2 with or without oestradiol and progesterone. Some cultures additionally received exogenous pro-angiogenic factors. For the three distinct layers of microengineered endometrium-on-a-chip, the epithelium, stroma and blood vessel characteristics and drug response of each distinct layer in the microfluidic model were assessed morphologically and biochemically. The quantitative measurement of endometrial drug delivery was evaluated by the permeability coefficients.Main results and the role of chanceWe established microengineered vascularised endometrium-on-chip, which consists of three distinct layers: epithelium, stroma and blood vessels. Our endometrium model faithfully recapitulates in-vivo endometrial vasculo-angiogenesis and hormonal responses displaying key features of the proliferative and secretory phases of the menstrual cycle. Furthermore, the effect of the emergency contraception drug levonorgestrel was evaluated in our model demonstrating increased endometrial permeability and blood vessel regression in a dose-dependent manner. We finally provided a proof of concept of the multi-layered endometrium model for embryo implantation, which aids a better understanding of the molecular and cellular mechanisms underlying this process.Large scale dataN/A.Limitations, reasons for cautionThis report is largely an in-vitro study and it would be beneficial to validate our findings using human primary endometrial cells.Wider implications of the findingsOur 3D microengineered vascularised endometrium-on-a-chip provides a new in-vitro approach to drug screening and drug discovery by mimicking the complicated behaviours of human endometrium. Thus, we suggest our model as a tool for addressing critical challenges and unsolved problems in female diseases, such as endometriosis, uterine cancer and female infertility, in a personalised manner.Study funding/competing interest(s)This work is supported by funding from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) to Y.J.K. (No. 2018R1C1B6003), to J.A. (No. 2020R1I1A1A01074136) and to H.S.K. (No. 2020R1C1C100787212). The authors report no conflicts of interest.

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Microvessel Network Formation and Interactions with Pancreatic Islets in Three-Dimensional Chip Cultures.

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