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Yan-Ling WANG, Ph. D.

Regulation of placental development, pregnancy adaptation, and the pathogenesis of pregnancy disorders (preeclampsia and recurrent spontaneous abortion) derived from placental defects.


Staffs: Yu-Xia Li, Xuan Shao, Qian Yang, Feiyang Wang, Xin Yu
PhD Candidates: Mingming Fan, Yun Yang, Hongyu Wu, Yuelin Zhu, Qianqian Li, Wenlong Li, Yuan Xie, Shanshan Zhang, Xiao Fang, Yang Hu, Tengqi Shao

· WANG Group website
 

The mammalian pregnancy beginning from the recognition and adhesion of trophoblast cells of blastocyst with endometrium, and further invasion into the latter. The formation of the placenta is one of the critical events in mammalian pregnancy. Owing to the appropriately controlled invasion to uterine stroma and spiral arteries remodeling by placental trophoblasts, the utero-placental circulation can be successfully formed. Failures in the regulatory network of trophoblast functions will lead to serious clinical complications, such as preeclampsia, recurrent miscarriage, and fetal growth restriction, etc. These disorders bring severe burden for maternal and perinatal care, even cause health problems for the affected mothers and children in their short-term and long-term development.

So far, the understanding of human placenta is still a "black box", the regulatory mechanisms underlying placental development and the maternal adaptation to pregnancy remain largely unknown. The prediction, prevention, and treatment of the placenta-associated pregnant diseases are also urgently needed.

Under the guidance of cutting-edge scientific issues and major national needs, Wang Lab is committed to studying the regulation mechanism of placental development and pregnancy maintenance, as well as the pathogenesis of major pregnancy diseases such as gestational hypertension and recurrent spontaneous abortion. It aims to demystify human pregnancy health and lay a solid scientific foundation for the development of prediction and intervention strategies for pregnancy diseases.

Wang Lab has established and maintained several in vitro models, including the culture system for human trophoblast cells differentiating to different pathways, three-dimensional co-culture system of trophoblasts-endothelial cells, trophoblast stem cells, and decidual NK cells, etc. We have successfully established several placenta specific gene manipulation mouse models using strategies of CYP19-Cre, ELF5-Cre or lentivirus/adenovirus-mediated gene delivery. We have discovered that placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply, explained that protein O-GlcNAcylation modification fine-tunes trophoblast cells syncytialization, revealed the immune modulating function of endovascular extravillous trophoblasts (enEVTs) and the fate of vascular smooth muscle cells dedifferentiation in the process of uterine spiral arteries remodeling, systematically elucidated the cellular and molecular regulatory networks of pregnancy adaptation at the maternal-fetal interface. A prospective resource bank of pregnant diseases has been established through collaborating with multi-center clinical units. A batch of molecular markers for early diagnosis of preeclampsia were obtained. The mechanism of dysregulated multicellular interaction and the molecular pathway of maternal pregnancy adaptation at the maternal-fetal interface involved in the occurrence and development of preeclampsia, FGR, recurrent spontaneous abortion, etc were revealed. Nearly 100 research papers have been published in peer-reviewed journals including Cell Stem Cell, PNAS, J Pineal Res, J Biomed Sci, Cell Chem Biol, Genomics Proteomics Bioinformatics, Hypertension, Cell Prolif, etc.



Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply



The mechanisms of the spiral artery remodeling in human placenta



Single-Cell Immune Landscape of Human Recurrent Miscarriage



Quantitative chemoproteomics reveals O-GlcNAcylation of Cystathionine γ-lyase (CSE) represses trophoblast syncytialization

 
Research content and objectives:

Generally, the research in Dr. Wang’s lab is aiming to understand the regulatory mechanisms of placenta development in human beings, and to deepen the understanding on the pathogenesis of severe pregnancy-associated diseases including preeclampsia (PE), recurrent spontaneous abortion (RSA) and fetal growth restriction (FGR). The long-term goal is to reveal the critical checkpoint in placenta development that governs pregnancy outcomes, and to figure out reliable and specific molecular targets for early diagnosis and intervention of the relevant diseases.

Specific research aims include:

  1. The lineage programming of the placental trophoblast cells.
  2. Mechanisms underlying the establishment of uterine-placental-fetal circulation.
  3. The cellular and molecular basis of the immune adaptation during pregnancy.
  4. The etiology of severe pregnant diseases such as preeclampsia and recurrent miscarriage.

 

Selected publications:

  1. Shao X#, Yang Y#, Liu Y#, Wang Y#, Zhao Y, Yu X, Liu J, Li YX, Wang YL*. Orchestrated feedback regulation between melatonin and sex hormones involving GPER1-PKA-CREB signaling in the placenta. J Pineal Res. 2023 :e12913.
  2. Shao X#, Yu W#, Yang Y#, Wang F, Yu X, Wu H, Ma Y, Cao B*, Wang YL*. The mystery of the life tree: the placenta. Biol Reprod. 2022;107(1):301-316.
  3. Li Y#, Li Z#, Yang M#, Wang F#, Zhang Y#, Li R#, Li Q, Gong Y, Wang B, Fan B, Wang C, Chen L, Li H, Ong J, Teng Z, Jin L*, Wang YL*, Du P*, Jiao J*. Decoding the temporal and regional specification of microglia in the developing human brain. Cell Stem Cell. 2022;29(4):620-634.e6.
  4. Chen J#, Du L#, Wang F#, Shao X#, Wang X, Yu W, Bi S, Chen D, Pan X, Zeng S, Huang L, Liang Y, Li Y, Chen R, Xue F, Li X, Wang S, Zhuang M, Liu M, Lin L, Yan H, He F, Yu L, Jiang Q, Xiong Z, Zhang L, Cao B*, Wang YL*, Chen D*. Cellular and molecular atlas of the placenta from a COVID-19 pregnant woman infected at mid-gestation highlights the defective impacts on fetal health. Cell Prolif. 2022;55(4):e13204.
  5. Yu X#, Wu Hong#, Yang Y, Wang F, Wang YL*, Shao X*. Placental development and Pregnancy-Associated Diseases. Maternal-Fetal Medicine. 2022;4(1):36-51.
  6. Li G#, Wang Y#, Cao G#, Ma Y, Li YX, Zhao Y*, Shao X*, Wang YL*. Hypoxic stress disrupts HGF/Met signaling in human trophoblasts: implications for the pathogenesis of preeclampsia. J Biomed Sci. 2022;29(1):8.
  7. Yang Q#, Ma Y#, Liu Y, Shao X, Jia W, Yu X, Li YX, Yang L, Gu W, Wang H, Wang J*, Wang YL*. MNSFβ regulates placental development by conjugating IGF2BP2 to enhance trophoblast cell invasiveness. Cell Prolif. 2021;54(12):e13145.
  8. Zhen XX#, Yang L#, Gu Y, Yang Q, Gu WW, He YP, Wang YL*, Wang J*. MNSFb Regulates TNFa Production by Interacting with RC3H1 in Human Macrophages, and Dysfunction of MNSFb in Decidual Macrophages Is Associated With Recurrent Pregnancy Loss. Front Immunol. 2021;12:691908.
  9. Xu P#, Ma Y#, Wu H, Wang YL*. Placenta-Derived MicroRNAs in the Pathophysiology of Human Pregnancy. Front Cell Dev Biol. 2021;9:646326.
  10. Ma Y#, Yu X#, Zhang L#, Liu J, Shao X, Li YX, Wang YL*. Uterine decidual niche modulates the progressive dedifferentiation of spiral artery vascular smooth muscle cells during human pregnancy. Biol Reprod. 2021 Mar 11;104(3):624-637.(Editorial Choice; Faculty Opinions)
  11. Shao X#, Cao G#, Chen D#, Liu J, Yu B, Liu M, Li YX, Cao B*, Sadovsky Y*, Wang YL*. Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply. Proc Natl Acad Sci U S A. 2021;118(3):e2017092118.
  12. Wang F#, Jia W#, Fan M#, Shao X#, Li Z, Liu Y, Ma Y, Li YX, Li R*, Tu Q*, Wang YL*. Single-cell immune landscape of human recurrent miscarriage. Genomics Proteomics Bioinformatics. 2021;S1672-0229(21)00003-6. (Editorial Highlight)
  13. Liu J#, Shao X#, Qin W#, Yanling Zhang#, Dang F, Yang Q, Yu X, Li YX, Chen X, Wang C*, Wang YL*. Quantitative chemoproteomics reveals O-GlcNAcylation of Cystathionine γ-lyase (CSE) represses trophoblast syncytialization. Cell Chem Biol. 2021;S2451-9456(21)00050-7. (Cover story)
  14. Xu P#, Li Z#, Wang Y#, Yu X, Shao X, Li YX, Peng C, Zhao Y*, Wang YL*. miR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-β Signaling. Mol Ther Nucleic Acids. 2020;22:542-556.
  15. Ma Y#, Yang Q#, Fan M#, Zhang L, Gu Y, Jia W, Li Z, Wang F, Li YX, Wang J, Li R*, Shao X*, Wang YL*. Placental endovascular extravillous trophoblasts (enEVTs) educate maternal T-cell differentiation along the maternal-placental circulation. Cell Prolif. 2020;53(5):e12802.
  16. Wang H#, Zhao Y#, Luo R, Bian X, Wang Y, Shao X, Li YX, Liu M, Wang YL*. A positive feedback self-regulatory loop between miR-210 and HIF-1αmediated by CPEB2 is involved in trophoblast syncytialization: implication of trophoblast malfunction in preeclampsia. Biol Reprod. 2020;102(3):560–570.
  17. Shao X#, Wang Y#, Liu Y, Guo X, Li D, Huo R, Jia W, Cao G, Li YX, Liu M, Sha J, Zhao Y, Wang YL*. Association of imbalanced sex hormone production with excessive procoagulation factor SerpinF2 in preeclampsia. J Hypertens. 2019;37:197–205
  18. Li G#, Ma L#, Lu H#, Cao G, Shao X, Liu Y, Li YX, Liu M, Yang H, Wang YL*. Transactivation of Met signalling by semaphorin4D in human placenta: implications for the pathogenesis of preeclampsia. J Hypertens. 2018;36(11):2215-2225.
  19. Dai J, Liang K, Zhao S, Jia W, Liu Y, Wu H, Lv J, Cao C, Chen T, Zhuang S, Hou X, Zhou S, Zhang X, Chen X, Huang Y, Xiao R, Wang YL, Luo T, Xiao J, Wang C*. Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis. Proc Natl Acad Sci U S A. 2018;115(26):E5896-E5905.
  20. Qin K, Zhu Y, Qin W, Gao J, Shao X, Wang YL, Zhou W, Wang C*, Chen X*. Quantitative Profiling of Protein O-GlcNAcylation Sites by an Isotope-Tagged Cleavable Linker. ACS Chem Biol. 2018;13:1983-1989.
  21. Ma L#, Li G#, Cao G#, Zhu Y, Du MR, Zhao Y, Wang H, Liu Y, Yang Y, Li YX, Li DJ, Yang H, Wang YL*. dNK cells facilitate the interaction between trophoblastic and endothelial cells via VEGF-C and HGF. Immunol Cell Biol. 2017;95(8):695-704.
  22. Shao X#, Liu Y#, Liu M, Wang Y, Yan L, Wang H, Ma L, Lia YX, Zhao Y*, Wang YL*. Testosterone represses estrogen signaling via upregulating mir-22: mechanism for imbalanced steroid hormone production in preeclampsia. Hypertension. 2017;69:721-730. (Editorial highlight)
  23. Luo R#, Wang Y#, Xu P#, Cao G, Zhao Y, Shao X, Li YX, Chang C, Peng C, Wang YL*. Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A. Sci Rep. 2016;6:19588.
  24. Xu P#, Zhao Y#, Liu M, Wang Y, Wang H, Li YX, Zhu X, Yao Y, Wang H, Qiao J, Ji L*, Wang YL*. Variations of micrornas in human placentas and plasma from preeclamptic pregnancy. Hypertension. 2014;63:1276-1284.
  25. Ji L#, Brkic J#, Liu M#, Fu G, Peng C*, Wang YL*. Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Asp Med. 2013;34:981-1023.