Diabetes & Metabolism Journal

Original Articles

Basic Research
Differentiation of Microencapsulated Neonatal Porcine Pancreatic Cell Clusters in Vitro Improves Transplant Efficacy in Type 1 Diabetes Mellitus Mice: Gyeong-Jin Cheon, Heon-Seok Park, Eun-Young Lee, Min Jung Kim, Young-Hye You, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon; Diabetes Metab J. 2022;46(5):677-688. Published online February 7, 2022; DOI: https://doi.org/10.4093/dmj.2021.0202

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Background
Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC’s clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by in vitro chemical treatment and microencapsulation.
Methods
NPCCs isolated from 3-day-old piglets were cultured in F-10 media and then microencapsulated with alginate on day 5. Differentiation of NPCCs is facilitated by media supplemented with activin receptor-like kinase 5 inhibitor II, triiodothyronine and exendin-4 for 2 weeks. Marginal number of microencapsulated NPCCs to cure diabetes with and without differentiation were transplanted into diabetic mice and observed for 8 weeks.
Results
The proportion of insulin-positive cells and insulin mRNA levels of NPCCs were significantly increased in vitro in the differentiated group compared with the undifferentiated group. Blood glucose levels decreased eventually after transplantation of microencapsulated NPCCs in diabetic mice and normalized after 7 weeks in the differentiated group. In addition, the differentiated group showed nearly normal glucose tolerance at 8 weeks after transplantation. In contrast, neither blood glucose levels nor glucose tolerance were improved in the undifferentiated group. Retrieved graft in the differentiated group showed greater insulin response to high glucose compared with the undifferentiated group.
Conclusion
in vitro differentiation of microencapsulated immature NPCCs increased the proportion of insulin-positive cells and improved transplant efficacy in diabetic mice without immune rejection.

Citations

Citations to this article as recorded by

Dual-targeted nano-encapsulation of neonatal porcine islet-like cell clusters with triiodothyronine-loaded bifunctional polymersomes
Sang Hoon Lee, Minse Kim, Eun-Jin Lee, Sun Mi Ahn, Yu-Rim Ahn, Jaewon Choi, Jung-Taek Kang, Hyun-Ouk Kim
Discover Nano.2024;[Epub] CrossRef
Long‐term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits
Heon‐Seok Park, Eun Young Lee, Young‐Hye You, Marie Rhee, Jong‐Min Kim, Seong‐Soo Hwang, Poong‐Yeon Lee
Journal of Diabetes Investigation.2024;[Epub] CrossRef

Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model: Jin-Sun Chang, Young-Hye You, Shin-Young Park, Ji-Won Kim, Hun-Sung Kim, Kun-Ho Yoon, Jae-Hyoung Cho; Diabetes Metab J. 2013;37(6):475-483. Published online December 12, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.6.475

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Background

We aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes.

Methods

To load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation. We induced type 1 diabetes model (T1D) for ten Sprague-Dawley rats using streptozotocin and used five Otsuka Long-Evans Tokushima Fatty rats as obese type 2 diabetes model (OT2D) and 10 Goto-Kakizaki rats as nonobese type 2 diabetes model (NOT2D). We performed the stress loading test in both the normal and diabetic states and compared patterns of glucose fluctuation among the three models. We classified the pattern of glucose fluctuation into A, B, and C types according to speed of change in glucose level.

Results

Increase in glucose, total amount of hyperglycemic exposure, time of stress-induced hyperglycemia, and speed of glucose increase were significantly increased in all models compared to the normal state. While the early increase in glucose after exposure to stress was higher in T1D and NOT2D, it was slower in OT2D. The rate of speed of the decrease in glucose level was highest in NOT2D and lowest in OT2D.

Conclusion

The diabetic state was more vulnerable to stress compared to the normal state in all models, and the pattern of glucose fluctuation differed among the three types of diabetes. The study provides basic evidence for stress-induced hyperglycemia patterns and characteristics used for the management of diabetes patients.

Citations

Citations to this article as recorded by

Stress hyperglycemia as first sign of asymptomatic type 1 diabetes: an instructive case
Wei-De Wang, Chun-Hao Chu, Chiung-Hsi Tien, Shuo-Yu Wang, Shih-Yao Liu, Chien-Ming Lin
BMC Pediatrics.2021;[Epub] CrossRef
Genetic determinants of obesity heterogeneity in type II diabetes
Somayeh Alsadat Hosseini Khorami, Mohd Sokhini Abd Mutalib, Mohammad Feili Shiraz, Joseph Anthony Abdullah, Zulida Rejali, Razana Mohd Ali, Huzwah Khaza’ai
Nutrition & Metabolism.2020;[Epub] CrossRef
Sex Dimorphic Responses of the Hypothalamus–Pituitary–Thyroid Axis to Maternal Separation and Palatable Diet
Lorraine Jaimes-Hoy, Fidelia Romero, Jean-Louis Charli, Patricia Joseph-Bravo
Frontiers in Endocrinology.2019;[Epub] CrossRef
Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats
Shimaa M. Elshazly, Dalia M. Abd El Motteleb, Islam A.A.E-H. Ibrahim
Chemico-Biological Interactions.2018; 291: 153. CrossRef
Physiology and Neurobiology of Stress and the Implications for Physical Health
B Sivaprakash
Annals of SBV.2014; 3(1): 25. CrossRef

Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells: Young-Hye You, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon; Diabetes Metab J. 2011;35(2):119-129. Published online April 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.2.119

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Background

A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.

Methods

Adult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.

Results

The adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.

Conclusion

These data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.

Citations

Citations to this article as recorded by

The pig pangenome provides insights into the roles of coding structural variations in genetic diversity and adaptation
Zhengcao Li, Xiaohong Liu, Chen Wang, Zhenyang Li, Bo Jiang, Ruifeng Zhang, Lu Tong, Youping Qu, Sheng He, Haifan Chen, Yafei Mao, Qingnan Li, Torsten Pook, Yu Wu, Yanjun Zan, Hui Zhang, Lu Li, Keying Wen, Yaosheng Chen
Genome Research.2023; 33(10): 1833. CrossRef
Improvement of the therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet
Yu Na Lee, Hye-Jin Yi, Eun Hye Seo, Jooyun Oh, Song Lee, Sarah Ferber, Teruo Okano, In Kyong Shim, Song Cheol Kim
Stem Cell Research & Therapy.2021;[Epub] CrossRef
Generation of iPSC-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with healthy control
Min Jung Kim, Eun Young Lee, Young-Hye You, Hae Kyung Yang, Kun-Ho Yoon, Ji-Won Kim
Stem Cell Research.2020; 48: 101958. CrossRef
Effect of FIGF overexpression on liver cells transforming to insulin-producing cells
Yaqin He, Xiaoliang Xie, Xiaoyan Li, Shikuo Rong, Yukui Li, Zhenhui Lu
Journal of Biosciences.2019;[Epub] CrossRef
Generation of Insulin-Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD
So-Hyun Lee, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes & Metabolism Journal.2017; 41(5): 405. CrossRef
Quantitative Raman spectral changes of the differentiation of mesenchymal stem cells into islet-like cells by biochemical component analysis and multiple peak fitting
Xin Su, Shaoyin Fang, Daosen Zhang, Qinnan Zhang, Yingtian He, Xiaoxu Lu, Shengde Liu, Liyun Zhong
Journal of Biomedical Optics.2015; 20(12): 125002. CrossRef
Generation of Functional Insulin-Producing Cells from Neonatal Porcine Liver-Derived Cells by PDX1/VP16, BETA2/NeuroD and MafA
Dong-Sik Ham, Juyoung Shin, Ji-Won Kim, Heon-Seok Park, Jae-Hyoung Cho, Kun-Ho Yoon, Kathrin Maedler
PLoS ONE.2013; 8(11): e79076. CrossRef
PPARγ Activation Attenuates Glycated-Serum Induced Pancreatic Beta-Cell Dysfunction through Enhancing Pdx1 and Mafa Protein Stability
Yunxia Zhu, Ai Ma, Hongxiu Zhang, Chaojun Li, Rebecca Berdeaux
PLoS ONE.2013; 8(2): e56386. CrossRef
β‐Cell differentiation and regeneration in type 1 diabetes
L. Ding, C. Gysemans, C. Mathieu
Diabetes, Obesity and Metabolism.2013; 15(s3): 98. CrossRef

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