Dimethyloxaloylglycine-preconditioned human umbilical cord mesenchymal stem cells protect against early pregnancy loss in mice

in Reproduction
Authors:
Anfeng Ning Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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https://orcid.org/0000-0002-3035-6513
,
Nansong Xiao Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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Xiaoqin Yu Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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Hu Wang Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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Chunyi Guan Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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Xu Ma Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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, and
Hong-Fei Xia Reproductive and Genetic Center & NHC Key Laboratory of Reproductive Health Engineering Technology Research, National Research Institute for Family Planning (NRIFP), Beijing, China
Graduate Schools, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

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https://orcid.org/0000-0003-3305-9108

Correspondence should be addressed to X Ma: maxu_ky@nrifp.org.cn or to H-F X: hongfeixia@126.com

(A Ning and N Xiao contributed equally to this study)

DOI:
https://doi.org/10.1530/REP-24-0285
Volume/Issue:
Volume 169: Issue 5
Article ID:
e240285
Article Type:
Research Article
Online Publication Date:
16 Apr 2025
Copyright:
© the author(s) 2025
Restricted access
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In brief

Early pregnancy loss (EPL) is a common pregnancy problem lacking preventive measures. This study shows that DMOG-preconditioned hUC-MSCs can reduce early embryo loss.

Abstract

EPL, a common pregnancy complication, yet has few effective preventive measures currently. To investigate whether dimethyloxaloylglycine (DMOG)-preconditioned human umbilical cord mesenchymal stem cells (hUC-MSCs) can prevent EPL, we initially evaluated the effect of DMOG on hUC-MSCs in vitro. Subsequently, the DMOG-preconditioned hUC-MSCs were transplanted into the lipopolysaccharide (LPS)-induced murine abortion model for intervention, following which we conducted phenotypic analysis. It was found that DMOG treatment enhanced the mRNA expression of HIF1A, H19 and GLUT1 in hUC-MSCs and augmented their migration capability (P < 0.01). Co-culture experiments showed that DMOG-treated hUC-MSCs notably reduced the mRNA levels of IL6, IL1B and TNFA in LPS-induced HTR-8/SVneo cells (P < 0.01). Moreover, DMOG-preconditioned hUC-MSCs remarkably decreased the fetal resorption rate and increased the embryo weight in LPS-induced abortive mice (P < 0.01). Histological analysis indicated that DMOG-preconditioned hUC-MSCs more effectively promoted their homing and inhibited LPS-induced fibrosis at the maternal–fetal interface. Apart from suppressing inflammatory factors in the serum of pregnant mice, DMOG-preconditioned hUC-MSCs can downregulate the mRNA levels of Il2, Il1b, Tnfa, Il5 and Il9 (P < 0.01), which are pro-inflammatory cytokines secreted by M1 macrophages; and simultaneously upregulate the expression of Cd206 and Pparg (P < 0.01), which serve as the cell surface and nuclear receptors of M2 macrophages in the embryos. Immunofluorescence further verified that the transplantation of DMOG-preconditioned hUC-MSCs could increase the expression of CD206 in embryos. Therefore, DMOG-preconditioned hUC-MSCs might prevent EPL by promoting the transformation of M1 into M2 macrophages.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Bandarra D , Biddlestone J , Mudie S , et al. 2015 Hif1a restricts NF-κB-dependent gene expression to control innate immunity signals. Dis Models Mech 8 169–181. (https://doi.org/10.1242/dmm.017285)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • De Nardo D , Labzin LI , Kono H , et al. 2014 High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol 15 152–160. (https://doi.org/10.1038/ni.2784)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dennehy R , Hennessy M , Meaney S , et al. 2022 How we define recurrent miscarriage matters: a qualitative exploration of the views of people with professional or lived experience. Health Expect 25 2992–3004. (https://doi.org/10.1111/hex.13607)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ding H , Gao YS , Wang Y , et al. 2014 Dimethyloxaloylglycine increases the bone healing capacity of adipose-derived stem cells by promoting osteogenic differentiation and angiogenic potential. Stem Cell Dev 23 990–1000. (https://doi.org/10.1089/scd.2013.0486)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ding X , Wu R , Jin B , et al. 2023 Human Wharton's jelly-derived mesenchymal stem cells prevent pregnancy loss in a rat by JAK/STAT-mediated immunomodulation. J Obstet Gynaecol Res 49 2417–2426. (https://doi.org/10.1111/jog.15748)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fan L , Li J , Yu Z , et al. 2014 The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. BioMed Res Int 2014 239356. (https://doi.org/10.1155/2014/239356)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hu S , Zhang C , Ni L , et al. 2020 Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy. Cell Death Dis 11 481. (https://doi.org/10.1038/s41419-020-2680-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li Y , Zhang D , Xu L , et al. 2019 Cell-cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. Cell Mol Immunol 16 908–920. (https://doi.org/10.1038/s41423-019-0204-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu W , Li L , Rong Y , et al. 2020 Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater 103 196–212. (https://doi.org/10.1016/j.actbio.2019.12.020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Müller-Edenborn K , Léger K , Glaus Garzon JF , et al. 2015 Hypoxia attenuates the proinflammatory response in colon cancer cells by regulating IκB. Oncotarget 6 20288–20301. (https://doi.org/10.18632/oncotarget.3961)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nowak-Stępniowska A , Osuchowska PN , Fiedorowicz H , et al. 2022 Insight in hypoxia-mimetic agents as potential tools for mesenchymal stem cell priming in regenerative medicine. Stem Cell Int 2022 8775591. (https://doi.org/10.1155/2022/8775591)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Parasar P , Guru N & Nayak NR 2021 Contribution of macrophages to fetomaternal immunological tolerance. Hum Immunol 82 325–331. (https://doi.org/10.1016/j.humimm.2021.02.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Quenby S , Gallos ID , Dhillon-Smith RK , et al. 2021 Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 397 1658–1667. (https://doi.org/10.1016/S0140-6736(21)00682-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Salek Farrokhi A , Zarnani AH , Rezaei Kahmini F , et al. 2021 Mesenchymal stem cells induce expansion of regulatory T cells in abortion-prone mice. Reproduction 161 477–487. (https://doi.org/10.1530/REP-20-0320)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sayama S , Nagamatsu T , Schust DJ , et al. 2013 Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy. J Reprod Immunol 100 109–117. (https://doi.org/10.1016/j.jri.2013.08.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schumacher A , Sharkey DJ , Robertson SA , et al. 2018 Immune cells at the fetomaternal interface: how the microenvironment modulates immune cells to foster fetal development. J Immunol 201 325–334. (https://doi.org/10.4049/jimmunol.1800058)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shaked I , Hanna RN , Shaked H , et al. 2015 Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nat Immunol 16 1228–1234. (https://doi.org/10.1038/ni.3321)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shao W , Li Z , Wang B , et al. 2023 Dimethyloxalylglycine attenuates steroid-associated endothelial progenitor cell impairment and osteonecrosis of the femoral head by regulating the HIF-1α signaling pathway. Biomedicines 11 992. (https://doi.org/10.3390/biomedicines11040992)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shorter JM , Koelper N , Sonalkar S , et al. 2021 Racial disparities in mental health outcomes among women with early pregnancy loss. Obstet Gynecol 137 156–163. (https://doi.org/10.1097/AOG.0000000000004212)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • The Lancet 2021 Miscarriage: worldwide reform of care is needed. Lancet 397 1597. (https://doi.org/10.1016/S0140-6736(21)00954-5)

  • Walter K 2023 Early pregnancy loss. JAMA 329 1426. (https://doi.org/10.1001/jama.2023.4973)

  • Wang X , Chen C , Wang L , et al. 2003 Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 79 577–584. (https://doi.org/10.1016/s0015-0282(02)04694-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang L , Wang H , Luo J , et al. 2022 Decorin promotes decidual M1-like macrophage polarization via mitochondrial dysfunction resulting in recurrent pregnancy loss. Theranostics 12 7216–7236. (https://doi.org/10.7150/thno.78467)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wilcox AJ , Weinberg CR , O'Connor JF , et al. 1988 Incidence of early loss of pregnancy. N Engl J Med 319 189–194. (https://doi.org/10.1056/NEJM198807283190401)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu C , Zhou Y , Chang J , et al. 2013 Delivery of dimethyloxallyl glycine in mesoporous bioactive glass scaffolds to improve angiogenesis and osteogenesis of human bone marrow stromal cells. Acta Biomater 9 9159–9168. (https://doi.org/10.1016/j.actbio.2013.06.026)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wynn TA & Vannella KM 2016 Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44 450–462. (https://doi.org/10.1016/j.immuni.2016.02.015)

  • Yeung YT , Aziz F , Guerrero-Castilla A , et al. 2018 Signaling pathways in inflammation and anti-inflammatory therapies. Curr Pharm Des 24 1449–1484. (https://doi.org/10.2174/1381612824666180327165604)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yuk JM , Kim TS , Kim SY , et al. 2015 Orphan nuclear receptor ERRα controls macrophage metabolic signaling and A20 expression to negatively regulate TLR-induced inflammation. Immunity 43 80–91. (https://doi.org/10.1016/j.immuni.2015.07.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang L , Li Y , Guan CY , et al. 2018 Therapeutic effect of human umbilical cord-derived mesenchymal stem cells on injured rat endometrium during its chronic phase. Stem Cell Res Ther 9 36. (https://doi.org/10.1186/s13287-018-0777-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y , Han F , Gu L , et al. 2020 Adipose mesenchymal stem cell exosomes promote wound healing through accelerated keratinocyte migration and proliferation by activating the AKT/Hif1a axis. J Mol Histol 51 375–383. (https://doi.org/10.1007/s10735-020-09887-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang L , Ye C , Li P , et al. 2022 ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome. Stem Cell Res Ther 13 448. (https://doi.org/10.1186/s13287-022-03132-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao QY , Li QH , Fu YY , et al. 2022 Decidual macrophages in recurrent spontaneous abortion. Front Immunol 13 994888. (https://doi.org/10.3389/fimmu.2022.994888)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhou F , Wang Y , Tan Y , et al. 2021 HMGB1 regulates lipopolysaccharide-induced cellular dysfunction in HTR8/SVneo cells: implications for the role of HMGB1 in unexplained spontaneous miscarriage. Placenta 112 16–22. (https://doi.org/10.1016/j.placenta.2021.06.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zinaman MJ , Clegg ED , Brown CC , et al. 2019 Reprint of: estimates of human fertility and pregnancy loss. Fertil Steril 112 (Supplement 4) e229–e235. (https://doi.org/10.1016/j.fertnstert.2019.08.096)

    • PubMed
    • Search Google Scholar
    • Export Citation