New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

Abstract

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that affects female fertility. However, with the lack of a corresponding research model, the pathology mechanism of PCOS is poorly understood. Induced pluripotent stem cell (iPSC) technology has been recognized as means to generate patient-specific stem cells for disease modeling.MethodsThe mRNA abundance of iPSCs was analyzed by RNA microarray and real-time polymerase chain reaction (RT-PCR). Karyotyping of iPSCs was performed with cytogenetic analysis. The mitochondrial respiration ability and glycolytic function were measured by the Seahorse Bioscience XF extracellular flux analyzer. The expression of iPSC-associated markers was identified by immunofluorescence and RT-PCR. The teratoma formation of iPSCs was studied using immunochemistry.ResultsA PCOS patient-derived iPSC model was established from somatic cells of PCOS patients. Through comprehensive transcriptional profiling analysis of the RNA microarray, PCOS patient-derived iPSCs showed metabolic abnormalities and mitochondrial dysfunction compared with non-PCOS patient-derived iPSCs in vitro. Specifically, a total of 2904 genes were differentially expressed between the two iPSC populations, of which 1416 genes were upregulated and 1488 genes were downregulated (fold change > 2, p < 0.01). Gene Ontology (GO) term enrichment results showed that upregulated genes were enriched in metabolic processes and mitochondrial activities which participated in the tricarboxylic acid (TCA) cycle, the respiratory electron transport chain (ETC), and glycogenolysis. On the other hand, the downregulated genes were related to cell communication, glucose transport, and uptake. The differentially expressed genes were verified by RT-PCR in PCOS patient-derived iPSCs and granulosa cells from PCOS patients. The PCOS patient-derived iPSCs demonstrated decreased mitochondrial respiration ability and glycolytic function (p < 0.05) but increased mitochondrial copy numbers and biogenesis (p < 0.05). Subsequently, some genes related to glucose metabolism were rescued by treating with metformin in PCOS patient-derived iPSCs. Meanwhile, the ATP production ability of mitochondria and the glycolysis ability of PCOS patient-derived iPSCs also partially returned to normal levels. However, metformin had little effect on mitochondrial maximal respiration ability and maximal glycolytic capacity.ConclusionsWe measured differences in iPSCs from women with and without PCOS in gene transcription and mitochondrial respiratory function. PCOS patient-derived iPSCs showed abnormal expression of metabolic genes and mitochondrial dysfunction in vitro. The study provides a novel cell model in vitro for studying the clinical causes and molecular mechanisms of PCOS.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0950-x) contains supplementary material, which is available to authorized users.

Mitochondrial DNA 4977 bp Deletion in Peripheral Blood Is Associated With Polycystic Ovary Syndrome

“…Consistent with our study, Min et al. detected increased mtDNA CN and increased expression levels of mtDNA replication-related factors in PCOS-patient-derived induced pluripotent stem cells ( 31 ). This inconsistency may be attributed to participant preferences or the different sample size of the studied population.…”

Is there any association between vitamin D levels and polycystic ovary syndrome (PCOS) phenotypes?

“…Research has found a correlation between PCOS and other metabolic problems, including high blood pressure, depression and anxiety, dyslipidemia, and chronic inflammation. It has also been verified that metabolic disorders are common in women with PCOS (23). Hang Wun and cols., in their study, stated that vitamin D deficiency was highly prevalent in women with PCOS in Scotland, with this rate having been higher than that of ovulatory control women and the general UK population.…”

Polycystic ovary syndrome and mitochondrial dysfunction

“…Therefore, decreased expression of GLUTs and related mitochondrial dysfunction may be associated with IR in PCOS. Mitochondrial biogenesis may be increased to compensate for the disruption of the functional integrity of mitochondria and the mitochondrial dysfunction of iPSCs from patients with PCOS [88]. In my opinion, these paradoxical results may be induced by different stages of disease manifestation.…”