Poster Presentation ESA-SRB-APEG-NZSE 2022

Mucin 15 (MUC15) a cell surface associated protein is increased in preeclampsia (#400)

Anna Nguyen 1 2 , Lucy Bartho 1 2 , Stephen Tong 1 2 , Ping Cannon 1 2 , Manju Kandel 1 2 , Tuong-Vi Nguyen 1 2 , Natalie J Hannan 1 2 , Tu'uhevaha J Kaitu'u-Lino 1 2
  1. The Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
  2. Mercy Perinatal, Mercy Hospital for Women, Melbourne, Victoria, Australia

Mucins are a family of proteins involved in the physical protection of epithelium. A particular subtype, MUC15 is highly expressed in placental trophoblast cells. This study aimed to characterise MUC15 in preeclampsia, a disease associated with placental oxidative stress, and investigate its role in isolated (cyto)trophoblast (placental) stem cells.

MUC15 was measured in placentas of patients with early-onset (delivering <34 weeks’ gestation) preeclampsia. MUC15 protein was significantly increased (p=0.0003, n=32 vs n=20 controls) whilst mRNA was unaltered (n=61 vs n=18 controls). Circulating MUC15 protein was significantly increased in the serum of patients with preeclampsia (p=0.0156, n=32 vs n=22 controls).

Given that mucins are localised to epithelium, human trophoblast stem cells (hTSCs) (1) were differentiated into the placental epithelial cell layer, syncytiotrophoblast for 96 hours. Downregulation of cytotrophoblast markers (CDH2, TEAD4) and upregulation of syncytial markers (GATA3, SDC1) confirmed syncytialisation. MUC15 mRNA (p=0.0049) and protein secretion (p=0.0059) significantly increased after 48 hours and 96 hours, respectively as cells syncytialised. To investigate the mechanisms of MUC15 secretion, syncytialised hTSCs were treated with brefeldin A and batimastat. Brefeldin A inhibits protein transport from the endoplasmic reticulum to the golgi complex whilst batimastat inhibits matrix metalloproteinases (MMPs), reducing cleavage of some extracellular matrix proteins. Interestingly, treatment with brefeldin A had no effect while batimastat reduced secretion of MUC15 (p=0.0436) from syncytialised hTSCs.

Finally, to assess if oxidative stress alters MUC15 expression, syncytialised hTSCs were exposed to hypoxia (1% O2) and inflammatory cytokines (TNFα, IL-6). MUC15 mRNA and protein expression remained unchanged. However, preliminary data suggests that knockdown of MUC15 elevates heme-oxygenase-1, a cytoprotective enzyme.  

In conclusion, MUC15 protein is increased in early-onset preeclampsia. It is cleaved by MMPs but not induced by hypoxia or inflammation. Increased MUC15 may be a protective mechanism associated with placental dysfunction. Further research will aid in confirming this.  

  1. Okae H, Toh H, Sato T, Hiura H, Takahashi S, Shirane K, et al. Derivation of Human Trophoblast Stem Cells. Cell Stem Cell. 2018;22(1):50-63.e6.