Low-Nutrient Environment-Induced Changes in Inflammation, Cell Proliferation, and PGC-1α Expression in Stromal Cells with Ovarian Endometriosis

Although nutrient status plays an important role in cell metabolism, its significance in endometriosis is obscure. Herein, we investigated the effects of a low-nutrient microenvironment on endometriosis. Stromal cells (SCs) from ovarian endometrioma (OESCs) or normal endometrium without endometriosis (NESCs) were isolated and cultured. A low-nutrient microenvironment was replicated by replacing the culture medium with Hank’s balanced salt solution. OESC and NESC proliferation under the low-nutrient condition was measured. The expression of exacerbating factors in endometriosis under the low-nutrient condition was examined at the mRNA and protein levels. OESCs showed higher proliferation than NESCs under the low-nutrient condition. In OESCs, the low-nutrient condition upregulated the mRNA expression of vascular endothelial growth factor (VEGF), interleukin-6 and -8, aromatase, Bcl-2, and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and downregulated that of BAX and induced transcription of PI.3, PII, and exon II. Western blotting revealed elevated VEGF and PGC-1α expression under the low-nutrient condition in OESCs. These changes coincided with the elevated expression of PGC-1α, which was reduced at the mRNA level upon nutrient status rescue. Endometriosis is exacerbated by altered angiogenesis, inflammation, anti-apoptosis, and local estrogen production while trying to survive under a low-nutrient microenvironment; it may be attributed to PGC-1α-mediated metabolic mechanisms. Similar content being viewed by others Data Availability The data underlying this article will be shared at reasonable request to the corresponding author. Code Availability Not applicable.

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We thank Ms. Ayaka Miura and Ms. Makoto Kazui for providing technical assistance. Funding This work was supported partially by Grants-in-Aid for Scientific Research under Grant number [21K09523] from the Ministry of Education, Culture, Sports, Science, and Technology (Japan). Author information Authors and Affiliations Contributions K.S., T.M., and J.K. designed the study. K.S., Y.T., M.F., K.O., E.M., Y.T., H.O., H.K., O.T., and Y.T. conceived and carried out experiments. K.S., T.M., F.I., A.K., K.K., and I.K. contributed to the interpretation of the results. K.S. and T.M. wrote the article. All authors were involved in writing the paper and had final approval of the submitted and published version. Corresponding author Ethics declarations Ethics Approval All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine (ERB-C-855–1). Consent to Participate Informed consent was obtained from all patients for being included in the study. Consent for Publication All agreed to publish this article. Competing Interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file2 (download PNG ) Supplementary Fig. 1 TUNEL staining of ovarian endometrioma stromal cell (OESC) and normal endometrium stromal cell (NESC) under low-nutrient conditions. TUNEL staining was performed after 24 h of incubation in low-nutrient medium, respectively. a, NESCs; b, OESCs; arrows, positive cells; bar, 200 μm. (PNG 2930 kb) Supplementary file3 (download PNG ) Supplementary Fig. 2 Expression of IL-1β and TNF-α in ovarian endometrioma stromal cell (OESC) under low-nutrient conditions. The expression of them in OESCs (n=6) was measured using real-time polymerase chain reaction (PCR) after incubation with control (Cont) or low-nutrient (Low) medium for 24 h. *P < 0.05 versus Cont (Wilcoxon signed-rank test). Abbreviations: TNF-α, tumor necrosis factor-α (PNG 112 kb) Rights and permissions Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Shimura, K., Tarumi, Y., Fujii, M. et al. Low-Nutrient Environment-Induced Changes in Inflammation, Cell Proliferation, and PGC-1α Expression in Stromal Cells with Ovarian Endometriosis. Reprod. Sci. 30, 1094–1102 (2023). https://doi.org/10.1007/s43032-022-01089-5 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-022-01089-5