NAME	Hongmei Wang
TITLE	Professor of State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology (IOZ) Chinese Academy of Sciences (CAS)
POSITION TITLE	Assistant director of IOZ Director of State Key Laboratory of Stem Cell and Reproductive Biology, IOZ, CAS Director of Institute of Reproductive Health, Institute for Stem cell and Regeneration, CAS
CONTACT DETAILS	1, Beichen West Rd, Chaoyang District Beijing 100101, P.R. China Telephone: 086-10-64807187 Fax: 86-10-64807316 Email: wanghm@ioz.ac.cn

CURRICULA VITAE-HONGMEI WANG

EDUCATION

PROFESSIONAL HISTORY

RESEARCH SUPPORT

MAJOR RESEARCH INTERESTS

For many years, my lab has been working on key factors/pathways involved in embryonic development and placental trophoblast differentiation, and has gained valuable information of the important functions of the ubiquitin-proteasome pathway, TGF-β signaling pathway, proprotein convertases and corticosteroid binding globulin (CBG) in embryo implantation, placentation and pregnancy maintenance by combining a well-established platform for placenta and embryo 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, in vitro long-term culture system for mice and monkey embryos, 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.

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.

we also focus on investigating the pathological dysfunction and physiological aging of the ovary. The pathogenesis and treatment of ovarian dysfunction, especially premature ovarian insufficiency, are of interest to us. We are also studying the mechanisms that regulate normal ovarian physiological aging to find the secret of senility. In addition, building a complete data model of follicle number with age is an important challenge in understanding ovarian reproductive aging. The aims of these works are to understand the ovarian physiology and to promote the theoretical development and clinical transformation of the treatment of ovarian diseases and fertility recovery in women.

Primate’s embryogenesis at early stages is another subject we are focusing on, especially at the post-implantation stage, ranging from the angiogenesis, embryonic disc formation and early placentation, gastrulation, neurulation and organogenesis. To reveal the most essential but special developmental stage, we set up mouse, monkey and human blastocyst long-term in vitro culture system, which could support mouse and monkey embryos in vitro developing beyond early gastrulation, and support human embryos to embryonic day 14 (ethical limitation).

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 recapitulation of primate gastrulation in vitro

Gastrulation is a developmental process which occurred represented by the differentiation, migration and rearrangement of gastrulating cells, and eventually leads to the formation of three germ layers and the establishment of anterior-posterior（A-P）axis. Therefore, the orderly occurrence of gastrulation sets an important foundation for the body plan and organogenesis. Due to the inaccessibility of post-implantation embryos and the limitation of detective techniques and research ethics, the gastrulation of primate embryos still maintains mysterious. To uncover the mysterious mask of gastrulation, we established an in vitro culture (IVC) system that supports the continuous development of cynomolgus monkey blastocysts beyond early gastrulation and to 20 days post fertilization. The IVC embryos highly recapitulated the key events of in vivo early post-implantation development without the maternal support, which were proved by morphologies detection, specific markers identification and scRNA-seq analysis. This study will provide an important theoretical basis for primate embryonic gastrulation and human early embryonic development and related diseases. We will further optimize the long-term IVC system, and promote mammal (non-human primate and rodent) embryos to more advanced developmental stages.

3) 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.

4) 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.

5) 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.

RECOGNITION IN THE FIELD

SELECTED HONORS AND AWARDS

INTERNATIONAL JOURNAL SERVICES OR MEMBERSHIPS

SEMINARS AND INVITED PRESENTATIONS

CURRENT GROUP MEMBERS

PAST GROUP MEMBERS

PUBLICATIONS (#, equal contribution; *, corresponding authors)

1. Zhao Y^#, Ma J^#, Yi P^#, Wu J^#, Zhao F, Tu W, Liu W, Li T, Deng Y, Hao J*, Wang H*, Yan L*. Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice. Stem Cell Research & Therapy. 2020 Nov 4，11(1)，466. IF2019：5.116
2. Yan L^#, Wu Y^#, Li L^#, Wu J^#, Zhao F, Gao Z, Liu W, Li T, Fan Y*, Hao J*, Liu J*, Wang H*. Clinical analysis of human umbilical cord mesenchymal stem cell allotransplantation in patients with premature ovarian insufficiency. Cell Proliferat. 2020, 53(12), e12938. IF2019：5.753
3. Xiao Z^#, Yan L^#, Liang X*, Wang H*. Progress in deciphering trophoblast cell differentiation during human placentation. Current Opinion in Cell Biology. 2020, 18(67), 86-91. IF2019:8.240. (invited review)
4. Lim H, Alvarez Y, Gasnier M, Wang Y, Tetlak P, Bissiere S, Wang H, Biro M, Plachta N*. Keratins are asymmetrically inherited cell fate determinants in the mammalian embryo. Nature, 2020, 585(7825):404-409.
5. Xiao Z^#, Yan L^#, Liang X*, Wang H*. Progress in deciphering trophoblast cell differentiation during human placentation. Curr Opin Cell Biol, 2020, 18;67:86-91.
6. Cui D^#, Liu Y^#, Jiang X^#, Ding C, Poon L*, Wang H* , Yang H*. Single-cell RNA Expression Profiling of ACE2 and TMPRSS2 in the Human Trophectoderm and Placenta. Ultrasound Obstet Gynecol, 2020, Accepted.
7. Jiang X, Wang H*. Macrophage subsets at the maternal-fetal interface. Cell Mol Immunol, 2020, 17(8):889-891.
8. Gao H^#, Liu C^#, Wu B^#, Wu B^#, Cui H, Zhao Y, Duan Y, Gao F*, Gu Q*, Wang H*, Li W*. Effects of Different Biomaterials and Cellular Status on Testicular Cell Self-Organization. Adv Biosyst, 2020, 4(7).
9. 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*. In vitro culture of cynomolgus monkey embryos beyond early gastrulation. Science, 2019, 366(6467).
10. Hong LM, Yan L, Xin ZM, Hao J, Liu WJ, Wang SY, Liao SJ, Wang H*, Yang XK*. Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage. J Mol Cell Biol, 2019, 12(5):372-385.
11. Wang R, Yu RX, Zhu C, Lin HY, Lu XY*, Wang H*. Tubulin detyrosination promotes human trophoblast syncytium formation. J Mol Cell Biol. 2019, 11(11), 967-978.
12. Ma J, Wu J, Han L, Jiang XX, Yan L, Hao J*, Wang H*. Comparative analysis of mesenchymal stem cells derived from amniotic membrane, umbilical cord, and chorionic plate under serum-free condition. Stem Cell Res Ther, 2018, 10(1), 19.
13. Liu YW^#, Fan XY^#, Wang R^#, Lu XY^#, Dang YL, Wang HY, Lin HY, Zhu C, Ge H, Cross JC*, Wang H*. Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Research, 2018, 28(8), 819-832.
14. Wang Y, Wang H*. Successful derivation of human trophoblast stem cells. Biol Reprod. 2018, 99(2), 271-272.
15. Jiang XX, Du MR, Li M, Wang H*. Three macrophage subsets are identified in the uterus during early human pregnancy. Cell Mol Immunol, 2018, 15(12), 1027-1037.
16. 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*. Plac8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion and migration. Development, 2018, 145(2).
17. Lu XY^#, Wang R^#, Zhu C, Wang H, Lin HY, Gu Y, Cross JC*, Wang H*. Fine-Tuned and Cell-Cycle-Restricted Expression of Fusogenic Protein Syncytin-2 Maintains Functional Placental Syncytia. Cell Reports, 2017, 21(5), 1150-1159.
18. Yan L^#, Li Y^#, Shi Z^#, Lu X^#, Ma J, Hu B, Jiao J*, Wang H*. The zinc finger E-box-binding homeobox 1 (Zeb1) promotes the conversion of mouse fibroblasts into functional neurons. J Biol Chem, 2017, 292(31), 12959-12970.
19. Hai T^#, Cao C^#, Shang H^#, Guo W^#, Mu Y^#, Yang S, Zhang Y, Zheng Q, Zhang T, Wang X, Liu Y, Kong Q, Li K, Wang D, Qi M, Hong Q, Zhang R, Wang X, Jia Q, Wang X, Qin G, Li Y, Luo A, Jin W, Yao J, Huang J, Zhang H, Li M, Xie X, Zheng X, Guo K, Wang Q, Zhang S, Li L, Xie F, Zhang Y, Weng X, Yin Z, Hu K, Cong Y, Zheng P, Zou H, Xin L, Xia J, Ruan J, Li H, Zhao W, Yuan J, Liu Z, Gu W, Li M, Wang Y, Wang H*, Yang S*, Liu Z*, Wei H*, Zhao J*, Zhou Q*, Meng A*. Pilot study of large-scale production of mutant pigs by ENU mutagenesis. Elife, 2017, (6), e26248.
20. Zhang Y^#, Wang Q^#, Wang H*, Duan EK*. Uterine Fluid in Pregnancy: A Biological and Clinical Outlook. Trends Mol Med, 2017, 23(7), 604–614.
21. 王红梅*，杜美蓉*.人类胎盘滋养层细胞的分化与妊娠相关疾病. 生命科学, 2017, 29(1), 15-20.
22. Liu D^#, Mo G^#, Tao Y, Wang H*, Liu XJ*. Putrescine supplementation during in vitro maturation of aged mouse oocytes improves the quality of blastocysts. Reprod Fertil Dev, 2017, 29(7), 1392-1400.
23. Zheng R^#, Li Y^#, Sun H^#, Lu X, Sun BF, Wang R, Cui L, Zhu C, Lin HY*, Wang H. Deep RNA sequencing analysis of syncytialization-related genes during BeWo cell fusion. Reproduction, 2017, 153 (1), 35-48.
24. Lu X^#, He Y^#, Zhu C, Wang H, Chen S*, Lin HY*. Twist1 is involved in trophoblast syncytialization by regulating GCM1. Placenta, 2016, 39, 45-54.
25. Lu X^#, Wang Y^#, Yan L, Wang L, Li W, Wang H*. Variations in mesenchymal-epithelial transition-related transcription factors during reprogramming of somatic cells from different germ layers into iPSCs. J Genet Genomics, 2016, 43(10), 609-612.
26. Cui L^#, Wang H^#, Lu X, Wang R, Zheng R, Li Y, Yang X, Jia WT, Zhao Y, Wang Y, Wang H, Wang YL, Zhu C, Lin HY*, Wang H*. Effects of individually silenced N-glycosylation sites and non-synonymous single-nucleotide polymorphisms on the fusogenic function of human syncytin-2. Cell Adh Migr, 2016, 10(1-2), 39-55.
27. Wang X^#, Cao C^#, Huang J^#, Yao J, Hai T, Zheng Q, Wang X, Zhang H, Qin G, ChengJ, Wang Y, Yuan Z, Zhou Q, Wang H*, Zhao J*. One-step generation of triplegene-targeted pigs using CRISPR/Cas9 system. Sci Rep, 2016, 6,1-7.
28. Nie M^#, Yu S^#, Peng S, Fang Y, Wang H*, Yang X*. miR-23a and miR-27a Promote Human Granulosa Cell Apoptosis by Targeting SMAD5. Biol Reprod, 2015, 93(4), 98, 1-10.
29. Zhang Q^#, Yu S^#, Huang X^#, Tan Y, Zhu C, Wang Y, Wang H, Lin H, Fu J*, Wang H*. New insights into the function of Cullin 3 in trophoblast invasion and migration. Reproduction, 2015 , 150(2), 139-149.
30. Lei JH^#, Yang XK^#, Peng S^#, Li Y, Underhill C, Zhu C, Lin HY*, Wang H*, Hammond GL*. Impact of corticosteroid-binding globulin deficiency on pregnancy and neonatal sex. J Clin Endocrinol Metab, 2015, 100(5), 1819-27.
31. Chang W^#, Yang Q^#, Zhang H^#, Lin HY, Zhou Z, Lu X,, Zhu C, Xue LQ*, Wang H*. Role of placenta-specific protein 1 in trophoblast invasion and migration. Reproduction, 2014, 148(4), 343-352.
32. Zhou Z^#, Wang R^#, Yang X, Lu XY, Zhang Q, Wang YL, Wang H, Zhu C, Lin HY*, Wang H*. The cAMP-responsive element binding protein (CREB) transcription factor regulates furin expression during human trophoblast syncytialization. Placenta, 2014, 35(11), 907-18.
33. Wang R^#, Dang YL^#, Zheng R, Li Y, Li WW, Lu XY, Wang LJ, Zhu C, Lin HY*, Wang H*. Live cell imaging of in vitro human trophoblast syncytialization. Biol Reprod, 2014, 90(6), 117,1-10 (cover story).
34. Li W, Liu D, Chang W, Lu XY, Wang YL, Wang H, Zhu C, Lin HY, Zhang Y, Zhou J*, Wang H*. Role of IGF2BP3 in trophoblast cell invasion and migration. Cell Death Dis, 2014, 5, e1025.
35. Aguilar PS^#, Baylies MK^#, Fleissner A^#, Helming L^#, Inoue N^#, Podbilewicz B*, Wang H^#, Wong M^#. Genetic basis of cell–cell fusion mechanisms. Trends Genet, 2013, 29, 427-437 (invited review).
36. Zhou Z, Zhang Q, Lu XY, Wang R, Wang H, Wang YL, Zhu C, Lin HY*, Wang H*. The proprotein convertases furin is required for trophoblast syncytialization. Cell Death Dis, 2013, 4, e593.
37. Zhang Q, Chen Q, Lu XY, Zhou Z, Zhang H, Lin HY, Duan E, Zhu C, Tan Y*, Wang H*. CUL1 promotes trophoblast cell invasion at the maternal-fetal interface. Cell Death Dis, 2013, 4, e502.
38. Yang X, Wang Q, Gao Z, Zhou Z, Peng S, Chang WL, Lin HY, Zhang W*, Wang H*. Proprotein convertases furin regulates apoptosis and proliferation of granulosa cells in the rat ovary. PLoS ONE, 2013, 8, e50479.
39. Lin HY*, Underhill C, Lei JH, Helander-Claesson A, Lee HY, Gardill BR, Muller YA, Wang H*, Hammond GL*. High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects. J Clin Endocrinol Metab, 2012, 97, E678-E686.
40. Zhao KQ, Lin HY*, Zhu C, Yang X, Wang H*. Maternal Smad3 deficiency compromises decidualization in mice. J Cell Biochem, 2012, 113, 3266-3275.
41. Wu L, Zhou HH, Lin HY, Qi JG, Zhu C, Gao ZY*, Wang H*. Circulating microRNAs are elevated in plasma from severe pre-eclamptic pregnancies. Reproduction, 2012, 143, 389-397.
42. Yang XK, Zhou Y, Peng S, Wu L, Lin HY, Wang SY*, Wang H*. Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis. Reproduction, 2012, 144, 235-244.
43. Lin P, Fu J, Zhao B, Lin F, Zou H, Liu L, Zhu C, Wang H*, Yu X*. Fbxw8 is involved in the proliferation of human choriocarcinoma JEG-3 cells. Mol Biol Rep, 2011, 38, 1741–1747.
44. Fu J, Lv X, Lin HY, Wu L, Wang R, Zhou Z, Zhang B, Wang YL, Tsang BK, Zhu C, Wang H*. Ubiquitin ligase cullin 7 induces epithelial-mesenchymal transition in human choriocarcinoma cells. J Biol Chem, 2010, 285, 10870-10879.
45. Zhang B, Zhou Z, Lin HY, Lv X, Fu J, Lin P, Zhu C, Wang H*. Protein phosphatase 1A (PPM1A) is involved in human cytotrophoblast cell invasion and migration. Histochem Cell Biol, 2009, 132, 169-179.
46. Zhou Z, Shen T, Zhang BH, Lv XY, Lin HY, Zhu C, Xue LQ*, Wang H*. The proprotein convertases furin in human trophoblast: Possible role in promoting trophoblast cell migration and invasion. Placenta, 2009, 30, 929-938.
47. Fu JJ, Lin P, Lv XY, Yan XJ, Wang HX, Zhu C, Tsang BK, Yu XG*, Wang H*. Low molecular mass polypeptide-2 in human trophoblast: over-expression in hydatidiform moles and possible role in trophoblast cell invasion. Placenta, 2009, 30, 305-312.
48. Wang H*, Tsang BK*. Nodal signalling and apoptosis. Reproduction, 2007, 133, 847-853.
49. Zhang X, Zhu C, Lin HY, Yang Q, Ou Q, Li Y, Chen Z, Racey P, Zhang S*, Wang H*. Wild fulvous fruit bats (Rousettusleschenaulti) exhibit human-like menstrual cycle. Biol Reprod, 2007, 77, 358-364.
50. Wang H*, Jiang JY, Zhu C, Peng C, Tsang BK*. Role and regulation of nodal/activin receptor-like kinase 7 signaling pathway in the control of ovarian follicular atresia. Mol Endocrinol, 2006, 20, 2469-2482.