Rat BAT xenotransplantation recovers the fertility and metabolic health of PCOS mice

in Journal of Endocrinology
Authors:
Lei Du State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

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Yang Wang State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Cong-Rong Li State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Liang-Jian Chen State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Jin-Yang Cai State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Zheng-Rong Xia Analysis and Test Center, Nanjing Medical University, Nanjing, Jiangsu, China

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Wen-Tao Zeng Animal Core Facility, Nanjing Medical University, Nanjing, Jiangsu, China

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Zi-Bin Wang Analysis and Test Center, Nanjing Medical University, Nanjing, Jiangsu, China

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Xi-Chen Chen Analysis and Test Center, Nanjing Medical University, Nanjing, Jiangsu, China

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Fan Hu State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Dong Zhang State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
Animal Core Facility, Nanjing Medical University, Nanjing, Jiangsu, China

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Xiao-Wei Xing The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

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Zhi-Xia Yang State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

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Correspondence should be addressed to F Hu or D Zhang or X-W Xing or Z-X Yang: hufan@njmu.edu.cn or dong.ray.zhang@njmu.edu.cn or davy2222@163.com or Yang_zhixa@sina.com

*(L Du, Y Wang, C-R Li, L-J Chen and J-Y Cai contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0068
Volume/Issue:
Volume 248: Issue 2
Article Type:
Research Article
Page Range:
249–264
Online Publication Date:
Feb 2021
Copyright:
© 2021 Society for Endocrinology 2021
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Polycystic ovarian syndrome (PCOS) is a major severe ovary disorder affecting 5–10% of reproductive women around the world. PCOS can be considered a metabolic disease because it is often accompanied by obesity and diabetes. Brown adipose tissue (BAT) contains abundant mitochondria and adipokines and has been proven to be effective for treating various metabolic diseases. Recently, allotransplanted BAT successfully recovered the ovarian function of PCOS rat. However, BAT allotransplantation could not be applied to human PCOS; the most potent BAT is from infants, so voluntary donors are almost inaccessible. We recently reported that single BAT xenotransplantation significantly prolonged the fertility of aging mice and did not cause obvious immunorejection. However, PCOS individuals have distinct physiologies from aging mice; thus, it remains essential to study whether xenotransplanted rat BAT can be used for treating PCOS mice. In this study, rat-to-mouse BAT xenotransplantation, fortunately, did not cause severe rejection reaction, and significantly recovered ovarian functions, indicated by the recovery of fertility, oocyte quality, and the levels of multiple essential genes and kinases. Besides, the blood biochemical index, glucose resistance, and insulin resistance were improved. Moreover, transcriptome analysis showed that the recovered PCOS F0 mother following BAT xenotransplantation could also benefit the F1 generation. Finally, BAT xenotransplantation corrected characteristic gene expression abnormalities found in the ovaries of human PCOS patients. These findings suggest that BAT xenotransplantation could be a novel therapeutic strategy for treating PCOS patients.

Supplementary Materials

    • Supplementary Figure 1. Verification of xenotransplanted rat BAT A and B. Paraffin sections of BAT showed that tomato fluorescence (red) was readily visible in the RTM group, but not in the MTM group. The lower panel shows that, following PCR amplification of rat and mouse UCP1 using specific primers, DNA sequencing proved the identity of rat BAT and mouse BAT.
    • Supplementary Figure 2. Xenotransplanted rat BAT corrected the expression of multiple BAT marker genes A–G. Th results of real-time PCR show that the mRNA levels of seven BAT marker genes, i.e., AdipoQ, PGC-1α, PGC-1ß, UCP1, PPAR1α, MCAD, and Dio2, were altered in PCOS mouse ovary. The changes were largely corrected following rat BAT xenotransplantation. Different lowercase alphabets above the columns in the graphs indicate significant difference between groups.
    • Supplementary Figure 3. Xenotransplanted rat BAT improved the distribution of biochemical blood indexes of F0 PCOS mice A–D. Measurement of the biochemical blood indexes and kernel density curves for ALT, AST, HDL-C, and BUN, respectively. The results from three mice were plotted for each index. The curves show that the distribution of these indexes in the RTM, MTM, and control groups was closer to each other and distributed within a much narrower region than in the PCOS group.
    • Supplementary Figure 4. Xenotransplanted rat BAT improved the estrus cycles of PCOS mic Plots of estrus cycle curves within 21 test days are shown. Four mice were included in each group. There were fewer and irregular cycles in the PCOS group than in the control group. Improvements in estrus cycle abnormality were observed in the RTM and MTM groups.
    • Supplementary Figure 5. Xenotransplanted rat BAT restored the expression of genes indicative of follicle and oocyte quality A. The results of real-time PCR show that BMP15 mRNA levels were markedly decreased in the PCOS group, but were restored to levels close to that of the control group after rat BAT xenotransplantation. B–F. The expression of five granular cell–expressed, steroidogenesis-related genes were significantly lower (AMHr and aromatase, B and C) or higher (Cyp17a, Cyp19a, FSHr, D–F) in the PCOS group, but the changes were largely restored in the RTM group. G. Immunohistochemistry shows that Cyp19a levels in granular cells were increased in the PCOS group, but were reduced to the same level as the control group after rat BAT xenotransplantation. Different lowercase alphabets above the columns in the graphs indicate significant difference between groups.
    • Supplementary Figure 6. Rat BAT xenotransplantation in F0 PCOS mice had a positive effect on the mRNA expression profiles in F1 offspring A. Venn diagrams show that, in comparison with the PCOS group, the control, PCOS+RTM, and PCOS+MTM groups have 126 DEGs sharing similar expression profiles. B. Heat map of overlapping DEGs from (A) showing the profile similarity among the control, RTM, and MTM groups. C–G. The results of real-time PCR for selected overlapping genes confirmed the mRNA sequencing findings. H. KEGG analysis shows that these genes are involved in multiple signal pathways essential for the quality and survival of follicles and oocytes (red arrows), such as ovarian steroidogenesis, oxidative phosphorylation, the MAPK pathway, the VEGF signaling pathway, and the oxytocin signaling pathway. Other pathways (black arrows) were also found, including that for arachidonic acid metabolism, aldosterone synthesis and secretion, linoleic acid metabolism, lipid metabolism, thyroid hormone synthesis, and drug metabolism. Different lowercase alphabets above the columns in the graphs indicate significant difference between groups.
    • Supplementary Figure 7. Rat BAT xenotransplantation improved the distribution of biochemical blood indexes in F1 PCOS mice A–F. Measurement of serum biochemical indexes and kernel density curves in F1 mice. (A) ALT, (B) CHOL, (C) ALT/AST ratio, (D) UA, (E) CK, (F) BUN. The results from three different mice were plotted for each index. The RTM, MTM, and Young groups had similar curves, and the indexes were distributed within a much narrower region than in the PCOS group.
    • Supplementary table 1 Primers used in this study.
    • Supplementary table 2 This table lists overlapped DEGs (among RTM, MTM, and control group compared with the PCOS group) corresponding to KEGG pathways important for quality and survival of the follicle and oocytes (Fig 6H, red arrow-pointed), and metabolism (Fig 6H, black arrow-pointed) in F0 model mice.
    • Supplementary table 3 This table, stemming from supplementary dataset 2 and 3, lists DEGs in multiple human PCOS transcriptome studies that overlapped with DEGs from current study. From left to right, column 1 are published human PCOS transcritptome study and data source in the publication; column 2 are upregulated and overlaping DEGs; column 3 are down-regulated and overlaping DEGs; column 4 are metabolism-related overlapping DEGs.
    • Supplementary table 4 This table lists overlapped DEGs (among RTM, MTM, and control group compared with the PCOS group) according to KEGG pathways important for quality and survival of the follicle and oocytes (Supplementary Fig 6H, red arrow-pointed), and metabolism (Supplementary Fig 6H, black arrow-pointed) in F1 model mice
    • Supplementary dataset 1 This file contains datasets for all 230 overlapped DEGs (Fig. 6A and B) among RTM, MTM, and control group compared with the PCOS group in F0 model mice. It has two sheets: "F0 up-regulated DEGs" contained all DEGs that have significantly higher (｜log2｜ > 1) expression levels in RTM, MTM, and control group than PCOS group; "F0 down-regulated DEGs" contained all DEGs that have significantly lower (｜log2｜ > 1) expression level in RTM, MTM, and control group than PCOS group. For each gene, both FPKM of each repeat and the average FPKM of three repeats are shown.
    • Supplementary dataset 2 This file, corresponding to Fig. 7, contains 4 sheets of datasets for all DEGs that overlapped between human PCOS studies and corrent study. From left to right, in sheet 1, the datasets from column A-AB are for the DEGs in current study; the datasets from column AD-BL are for the DEGs in Lan et al (36). In sheet 2, the datasets from column A-AA are for the DEGs in our study; the datasets from column AC-AI are for the DEGs in Wissing et al (37). In sheet 3, the datasets from column A-AB are for the DEGs in our study; the datasets from column AD-AL are for the DEGs in Lu et al (38). In sheet 4, the datasets from column A-AB are for the DEGs in our study; the datasets from column AD-AG are for the DEGs in Kaur et al (39). For a clear distinguishment between our data and the reference data, column AC in sheet 1, column AB in sheet 2, column AC in sheet 3, and column AC in sheet 4 are left blank and highlighted in green; Two columns with title "symbol" and red typed in each sheet list all overlapping DEGs between our data and reference data.
    • Supplementary dataset 3 This file contains 4 sheets. Each sheet includes KEGG information for the DEGs that overlapped between human PCOS studies and current study.
    • Supplementary dataset 4 This dataset contains all 126 overlapped DEGs (Supplementary Fig. 6A and B) among RTM, MTM, and control group compared with the PCOS group in F1 model mice. It has two sheets: "F1 up-regulated DEGs" contained all DEGs that have significantly higher (｜log2｜ > 1) expression level in RTM, MTM, and control group than in PCOS group; "F1 down-regulated DEGs" contained all DEGs that have significantly lower (｜log2｜ > 1) expression level in RTM, MTM, and control group than in PCOS group. For each gene, both FPKM of each repeat and the average FPKM of three repeats are shown.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
16
Article Type:
Research Article
Received Date:
20 Nov 2020
Accepted Date:
08 Dec 2020
Print Publication Date:
01 Feb 2021
Online Publication Date:
Feb 2021
Keywords:
rat; mouse; xenotransplantation; fertility; metabolic health; PCOS

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