MALAT-1

Metastasis associated lung adenocarcinoma transcript-1 (MALAT-1) was firstly identified in lung cancer; it is a lncRNA of over 8 kb [239]. MALAT-1 normally localizes in the nucleus where it forms nuclear aggregates called speckles involved in the regulation of splicing factors availability [240]. MALAT-1 is overexpressed in placental pathologies associated with uncontrolled trophoblast invasion [241], which prompted Chen and coworkers [33] to investigate its expression in PE. Comparing RNA levels in 18 PE placentas with matched controls, MALAT-1 was found significantly downregulated in PE placentas. Overexpression and downregulation of MALAT-1 in JEG-3 regulates cell proliferation and invasion, while inhibiting apoptosis [33]. These findings sugges<sup>t</sup> that MALAT-1 deregulation could lead to poor invasion of the maternal endometrium, a ffecting the spiral arteries' remodeling and placenta development. Li and coworkers [242] have shown that the role of MALAT-1 is not restricted solely to the trophoblast but has a key role in regulating the angiogenesis and vascularization of the maternal decidua and fetal umbilical vasculature. MALAT-1 is expressed by mesenchymal stem cells (MSCs) in the maternal decidua and in the umbilical cord. These cells are pluripotent progenitors which are able of self-renewal and proliferation, di fferentiate to promote tissue regeneration, form de novo vasculature, angiogenesis and regulate immune system responses [243]. Li and coworkers (2017) observed a decreased MALAT-1 expression in MSCs from decidua and umbilical cord of preeclamptic pregnancies and set out to investigate its function in these cells. Similarly, MALAT-1 promotes proliferation and protects from apoptosis in isolated MSCs. Interestingly, coculture of MSCs with trophoblast cell line HTR-8/SVneo clearly showed how MALAT-1 overexpression could promote migration and invasion of the trophoblasts towards the MSCs layer. Coculture of the endothelial cell line HUVECs (Human Umbilical Vein Endothelial Cells) in supernatant obtained from MSCs which either expressed or had downregulated MALAT-1 showed how MALAT-1 promotes tube formation this process being dependent on Vascular Endothelial Growth Factor secretion. Finally, MALAT-1 over-expression increased the levels of the IDO protein, which activated macrophage maturation, proving its role in immune system regulation. These findings combined with the work of Chen and coworkers (2015) beautifully illustrates how MALAT-1 has a symmetric regulatory function in placentation: on the one hand, it promotes trophoblast proliferation, invasive and migratory potential and on the other hand, its expression in MSCs cells helps to attract and promote trophoblast

invasion, stimulates tube formation, promotes angiogenesis and vascularization. Increase in Reactive Oxygen Species caused MALAT-1 and VEGF downregulation in MSCc exposed to oxidative stress in a dose-dependent manner [242]. MALAT-1 downregulation in preeclampsia could therefore have a huge impact on placentation and further development of the placenta over the course of gestation. It is possible that a first triggering event maybe of immunological nature, causes an increase of oxidative stress during implantation which will then alter the expression level of many targets, including MALAT-1; based on the data, this consequent deregulation would have an impact on both trophoblast and MSCs physiology, culminating in preeclampsia.
