<i>In vivo, ex vivo</i>, and<i>in vitro</i>models of placental serine metabolism

The placenta is responsible for the transport of nutrients and waste across the maternal-fetal interface, sustaining fetal growth and development during gestation. The non-essential amino acid serine is crucial to protein synthesis and fetal growth, and it is a primary endogenous methyl donor to one carbon metabolism. The conversion of serine to glycine by serine hydroxymethyl transferase (SHMT) provides methyl groups critical to purine synthesis and placental DNA methylation. Serine has been shown to have an unusual transport mechanism in epitheliochorial placentas (commonly found in hoofed mammals) [1], however research on this transport mechanism in the hemochorial placenta structure shared by humans and rodents is inconclusive and sometimes contradictory. We have previously measured limited transplacental transport of stable-isotope labeled serine in vivo in late-gestation mice (18.5 days post-conception). We hypothesize that, similar to in an epitheliochorial placenta, serine is not directly transported across the hemochorial maternal-fetal interface. Instead, serine is converted to glycine (releasing a methyl group) in the placenta, then glycine may be transported across the placenta into fetal circulation where it can be metabolized back into serine and other fetal products. In parallel, we have developed fetal mouse tissue and placenta explant studies, an ex vivo murine placental perfusion model and cultured trophoblast cells from a choriocarcinoma (BeWo cells). Using stable-isotope labeled L-serine in both tissue culture experiments and explant studies, we have found that there is (1) considerable cellular serine uptake and conversion of serine into glycine and (2) excretion of glycine by these cells. Inhibition of SHMT using SHIN1 (5µM) halts serine conversion and glycine excretion, demonstrating cellular dependence on SHMT for serine-glycine conversion. We have also found that conversion of serine into glycine occurs in fetal liver tissue explants. Finally, we have developed and are currently optimizing an ex vivo murine placental perfusion system based on Goeden and Bonnin [2]. Cannulation through both the umbilical artery and vein as well as the uterine artery of late-gestation murine placentas has allowed us to perfuse stable-isotope labelled serine through placental tissue in order to directly assess its transport in a whole organ setting. Understanding serine metabolism in these contexts may provide novel insights into placental metabolism and amino acid transport, with relevance to fetal metabolic health and disease. 1. Moores, R. R., Rietberg, C. C., Battaglia, F. C., Fennessey, P. V., &amp; Meschia, G. (1993). Metabolism and transport of maternal serine by the ovine placenta: Glycine production and absence of serine transport into the fetus. Pediatric Research, 33(6), 590–594. 2. Goeden, N., &amp; Bonnin, A. (2013). Ex vivo perfusion of mid-to-late-gestation mouse placenta for maternal-fetal interaction studies during pregnancy. Nature Protocols, 8(1), 66–74. Funding provided by Williams College. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.