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Kim W.J.,Inha University | Lee S.-W.,Innovative Research Institute for Cell Therapy | Lee S.-W.,Seoul National University | Kim K.-W.,Research Institute of Pharmaceutical science | Kim K.-W.,Seoul National University
International Journal of Molecular Medicine | Year: 2014

Lately, the importance of the communication between different cell types and the understanding of the cell communication pathway has been emphasized, as it may provide a novel therapeutic strategy for the regeneration of damaged tissue. In the present study, we suggest that sonic hedgehog (Shh) is a mediator of cell communication between neurons and fibroblasts. Recombinant Shh (rShh) affected the expression of the angiogenic factors, angiopoietin (Ang)-1 and Ang-2, in fibroblasts, but not in neurons or neural progenitor cells (NPCs). The expression of the Shh downstream transcription factor, Gli1, was markedly increased in neurons and NPCs, indicating that neurons and NPCs responded to rShh. However, rShh did not affect Ang-1 and Ang-2 expression in neurons and NPCs. It should be noted that Shh was strongly expressed in neurons, but that Shh expression was undetectable in fibroblasts. We performed a co-culture assay using neurons and fibroblasts to investigate whether the expression of Ang-1 and Ang-2 is regulated by cell communication, without rShh treatment. Ang-1 expression in fibroblasts was markedly upregulated by co-culture with neurons, whereas Ang-2 expression was decreased by co-culture with neurons. Moreover, when an Shh-neutralizing antibody was added, this effect was diminished. Collectively, our data suggest that Shh-expressing neurons regulate angiopoietin expression in neighboring fibroblasts in a paracrine manner.


Lee S.E.,NICHE | Lee S.E.,Innovative Research Institute for Cell Therapy | Lee S.E.,Seoul National University | Kim H.-S.,NICHE | And 2 more authors.
Journal of Smooth Muscle Research | Year: 2012

An adipokine, resistin, was first discovered as a potential mediator of obesity related insulin resistance in rodents. However, the relevance of resistin in human obesity and insulin resistance has been challenged by the difference between human and rodent resistin and the controversies in human epidemiologic studies. Instead, recent human clinical studies and experiments support the idea that human resistin is an inflammatory mediator and a biomarker of cardiovascular diseases, especially in atherosclerosis and heart failure. Thus, we focused on the recent evidence of the role of human resistin in cardiovascular disease. © 2012 The Japan Society of Smooth Muscle Research.


Kim M.J.,Seoul National University | Kim M.J.,Korea Cancer Center Hospital | Choi O.K.,Innovative Research Institute for Cell Therapy | Chae K.S.,Innovative Research Institute for Cell Therapy | And 9 more authors.
Islets | Year: 2015

Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7Δβ cell) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7Δβ cell mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7Δb cell mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process. © Min Joo Kim, Ok Kyong Choi, Kyung Sil Chae, Hakmo Lee, Sung Soo Chung, Dong-Sik Ham, Ji-Won Kim, Kun-Ho Yoon, Kyong Soo Park, and Hye Seung Jung.


Kim M.J.,Seoul National University | Kim M.J.,Korea Cancer Center Hospital | Choi O.K.,Innovative Research Institute for Cell Therapy | Chae K.S.,Innovative Research Institute for Cell Therapy | And 10 more authors.
Endocrinology and Metabolism | Year: 2015

Damaged mitochondria are removed by autophagy. Therefore, impairment of autophagy induces the accumulation of damaged mitochondria and mitochondrial dysfunction in most mammalian cells. Here, we investigated mitochondrial function and the expression of mitochondrial complexes in autophagy-related 7 (Atg7)-deficient β-cells. Methods: To evaluate the effect of autophagy deficiency on mitochondrial function in pancreatic β-cells, we isolated islets from Atg7F/F:RIP-Cre+ mice and wild-type littermates. Oxygen consumption rate and intracellular adenosine 5'-triphosphate (ATP) content were measured. The expression of mitochondrial complex genes in Atg7-deficient islets and in β-TC6 cells transfected with siAtg7 was measured by quantitative real-time polymerase chain reaction. Results: Baseline oxygen consumption rate of Atg7-deficient islets was significantly lower than that of control islets (P<0.05). Intracellular ATP content of Atg7-deficient islets during glucose stimulation was also significantly lower than that of control islets (P<0.05). By Oxygraph-2k analysis, mitochondrial respiration in Atg7-deficient islets was significantly decreased overall, although state 3 respiration and responses to antimycin A were unaffected. The mRNA levels of mitochondrial complexes I, II, III, and V in Atg7-deficient islets were significantly lower than in control islets (P<0.05). Down-regulation of Atg7 in β-TC6 cells also reduced the expression of complexes I and II, with marginal significance (P<0.1). Conclusion: Impairment of autophagy in pancreatic β-cells suppressed the expression of some mitochondrial respiratory complexes, and may contribute to mitochondrial dysfunction. Among the complexes, I and II seem to be most vulnerable to autophagy deficiency. ©2015 Korean Endocrine Society.

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