Name: WANG Hongmei

Tel: +86-10-64807316

Email: wanghm@ioz.ac.cn

Education

1999-2002 Ph.D. in Reproductive Physiology, Institute of Zoology, Chinese Academy of Sciences

1995-1998 Master in Cell Proliferation and Regulation Biology, Beijing Normal University

1991-1995 Bachelor degree, Department of Biology, Beijing Normal University

Major Research Interests

We are aimed at investigating the molecular mechanisms involved in placental development, particularly in the area of trophoblast differentiation including invasion and syncytialization of the trophoblast lineage and placentation-related diseases, such as fetal growth restriction (FGR) and preeclampsia. Human placental villous trophoblast cells undergo terminal differentiation and fusion to form the multinucleated syncytiotrophoblast, while the extravillous cytotrophoblast infiltrates the endomyometrium to anchor the placenta. Inadequate/excessive invasion of trophoblast or dysregulation in syncytialization results in early pregnancy loss, FGR or preeclampsia, etc. The main research interest of us is to study the physiological mechanisms of placentation and related complications and diseases, especially the key events including trophoblast invasion/migration and syncytialization, the crosstalk between trophoblast and decidual immune cells, and the function of mesenchymal stem cells in maintaining and rebuilding the ovarian function. For many years, my lab has been working on key factors/pathways involved in embryo implantation and placental trophoblast differentiation, and has gained valuable information of the important functions of the ubiquitin-proteasome pathway, TGF-βsignaling pathway, proprotein convertases and corticosteroid binding globulin (CBG) in embryo implantation, placentation and pregnancy maintenance by combining a well-established platform for placenta research (including various trophoblast cell fusion/invasion/migration models, trophoblast stem cells, live-cell imaging, tissue clearing, in vivo lineage tracing, placenta-specific knockout or knockdown mouse models, high-throughput proteomics, single cell RNA-seq, and cutting-edge molecular and biochemical technologies) and a clinical sample library on pregnancy-related diseases.

Current Research and Future Directions

1. The construction of human and mouse placenta atlas

To understand the placenta better, we need to systematically know how the placenta is developed, that is, how different trophoblast lineages are specified. Human placenta is a very complicated organ. The cell types and the function of the placenta varies with the progression of pregnancy. We isolated human placental cells at different stages of pregnancy, under physiological or pathological (preeclampsia, placenta accrete, etc. conditions and subjected them to the single cell RNA-seq analysis (10X genomics and Smart seq2) to classify different types placental cells, in order to find as many types of placental cells as possible. Then based on the transcriptome of each type of cells, we hope to find the specific markers for each population of cells and isolate these cells and further study their functions. On the other hand, we will study how the trophoblast lineages are specified. With this, we hope to eventually generate the human placenta atlas. We will use similar strategy to try to specify mouse trophoblast lineages.

2. The mechanism and function of human trophoblast primary/secondary syncytialization

Implantation of the blastocyst is a developmental milestone in mammalian embryonic development. During embryo implantation, a trophectoderm-derived multinucleated syncytiotrophoblast connects the fetus and the mother. The formation of this primary syncytiotrophoblast determines the successful implantation. However, this process remains mysterious in despite of its basic and clinical importance. According to the textbook, the primary syncytiotrophoblast is formed by cell fusion. However, the existence of the obvious big nuclei in the syncytiotrophoblast suggests atypical cell fusion or endoreduplication. We are taking advantage of a novel in vitro culture system to cultivate human embryos and studying how the primary syncytiotrophoblast is formed. At the same time, we are also interested in studying the function of the primary syncytiotrophoblast and comparing the difference between primary and secondary syncytialization using trophoblast stem cell differentiation model and primary cultures. Using a similar culture system, monkey embryos are cultured in vitro beyond early gastrulation. We are using the in vitro monkey embryo model (with Zhou Qi lab and Li Lei Lab) to study trophoblast differentiation at early stages of gestation.

3. 3D imaging of mouse placenta using a modified tissue clearing method

Understanding the placental vasculature (maternal and fetal blood vessels) is crucial to elucidate the normal and pathological placental functions. The previous evidence on placental vasculature is mostly based on classical tissue sections and histological techniques and they are at 2D level. Analyzing the placental blood vessels at 3D level will provide more accurate global structural changes in the placenta. Work in James C. Cross’s lab provided the first comprehensive description of the anatomy vascular space in the mouse mature placenta by plastic vascular casts. However, owing to the small diameter of the vessels and the plastic viscosity, the fetal side casts were impossible for the placentas before E12.5. The architecture of placental vasculature in the early development is thus missing. We are taking advantage of a modified tissue clearing system combining PACT and CUBIC methods to study the anatomy of the mouse placenta at earlier pregnancy stage with light-sheet fluorescence microscopy, in order to obtain the long missing architecture of the fetal placenta vascular network after chorioallantoic attachment. At the same time, we also cleared the mouse uterus and oviduct (with Duan Lab) to study how the mouse uterine glands are developed and how the sperms cooperate to enter into female oviduct.

4. MSCs transplantation to treat women with pathological or physiological ovarian failures

Pathological ovarian failure (premature ovarian insufficiency [POI]) and physiological ovarian failure (menopausal syndrome) affect not only women’s fertility, but also life quality. In recent years, MSCs have been successfully used to repair the damaged ovarian function in mice, rats, rabbits, etc. We also showed that human umbilical cord MSCs restored ovarian function in mice (chemotherapy-induced POI mouse model and aged mouse model). With an aim to test the clinical efficacy of MSCs in alleviating pathological and physiological ovarian senescence, we have recruited patients with POI and menopausal syndrome, injected MSCs into the patients’ovaries, and examined sex hormone levels (AMH, FSH and E2), ovary volume, antral follicle number, pregnancy rate to assess the curative effect.

Selected Publications (^# equal contribution; ^* corresponding authors)

1. Ma H^#, Zhai J^#, Wan H^#, Jiang X^#, Wang X, Wang L, Xiang Y, He X, Zhao ZA, Zhao B, Zheng P^*, Li L^*, Wang H^*. (2019). In vitro culture of cynomolgus monkey embryos beyond early gastrulation. Science. 366(6467).

2. Hong LM, Yan L, Xin ZM, Hao J, Liu WJ, Wang SY, Liao SJ, Wang H^*, Yang XK^*. (2019). Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage. J Mol Cell Biol. 12(5). (Epub ahead of print)

3. Wang R, Yu RX, Zhu C, Lin HY, Lu XY^*, Wang H^*. (2019). Tubulin detyrosination promotes human trophoblast syncytium formation. J Mol Cell Biol. 11(11):967-978.

4. Ma J, Wu J, Han L, Jiang XX, Yan L, Hao J^*, Wang H^*. (2018). Comparative analysis of mesenchymal stem cells derived from amniotic membrane, umbilical cord, and chorionic plate under serum-free condition. Stem Cell Res Ther. 10(1):19.

5. Liu YW^#, Fan XY^#, Wang R^#, Lu XY^#, Dang YL, Wang HY, Lin HY, Zhu C, Ge H, Cross JC^*, Wang H^*. (2018). Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Research. 28(8):819-832.

6. Wang Y, Wang H^*. (2018). Successful derivation of human trophoblast stem cells. Biol Reprod. 99(2):271-272.

7. Jiang XX, Du MR, Li M, Wang H^*. (2018). Three macrophage subsets are identified in the uterus during early human pregnancy. Cell Mol Immunol.15(12):1027-1037.

8. Chang WL^#, Liu YW^#, Dang YL^#, Jiang XX, Xu HL, Huang X, Wang YL, Wang H, Zhu C, Xue LQ, Lin HY, Meng WX^*, Wang H^*. (2018). Plac8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion and migration. Development. 145(2).