Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Metabolic effects of GDF15 and Activin A on trophoblasts (#465)

Sunhild Hartmann 1 2 3 4 5 6 , Theresa Zucker 6 , Stefan Marc Botha 1 2 3 4 5 6 , Ruth Schmidt-Ullrich 6 , Berthold Huppertz 7 , Christina Stern 8 , Sabrina Geisberger 6 , Dominik N. Müller 5 6 , Martin Gauster 7 , Tu’uhevaha J Kaitu’u-Lino 1 3 , Ralf Dechend 2 4 5 6 9 , Olivia Nonn 2 4 5 6 7
  1. The University of Melbourne, Melbourne, Victoria, Australia
  2. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
  3. Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
  4. Experimental and Clinical Research Center, a cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité - Universitätsmedizin Berlin, Berlin, Germany
  5. DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany
  6. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
  7. Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
  8. Department of Obstetrics and Gynaecology, University Hospital Graz, Graz, Austria
  9. HELIOS Clinic, Department of Cardiology and Nephrology, Berlin, Germany

Aims

Preeclampsia, a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality.

Activin A and GDF15 are two senescence associated secretory phenotype factors. Serum levels of GDF15 and Activin A are elevated in the maternal blood prior to the onset of the disease and highly expressed in placental tissue of women with preeclampsia  [1-3]. Placental trophoblasts are essential for maternal-fetal transport of oxygen and nutrients. In these cells, mitochondrial dysfunction causing senescence has been associated with preeclampsia [4]. Since both GDF15 and Activin A have been associated with mitochondrial function [5, 6], the aim of this work was to investigate their role in metabolism in trophoblast cells.

Methods

Metabolically reprogrammed BeWo cells (placental cell line) and primary trophoblasts were differentiated into multinucleated syncytiotrophoblasts with Forskolin and treated with DMSO to model mononucleated cytotrophoblasts. Subsequently, cells were treated with GDF15 (20ng/ml) and Activin A (20ng/ml), (equivalent concentrations to preeclamptic maternal blood), and the cell metabolic profile was analyzed.

Additionally, the metabolic profile of a human trophoblast organoid single cell dataset [7] was investigated together with the expression of GDF15 and INHBA (Activin A).

Results

Treating both BeWo cells and primary trophoblasts with Activin A and GDF15 led to increased mitochondrial activity, shown by an increase in the ATP level in syncytiotrophoblast (p < 0.0001) and an increase in mitochondrial membrane potential (p = 0.04) in BeWo-cytotrophoblasts. Additionally, the oxygen consumption rate was significantly increased in Activin A treated BeWo cells (p = 0.0377).

In human trophoblast organoids, cytotrophoblasts showed the highest metabolic activity. GDF15 and INHBA(Activin A) were strongly expressed in syncytiotrophoblasts.

Conclusion

Activin A and GDF15 have been shown to influence trophoblast metabolism. Here, the reported increase in metabolic activity aligns with previous results where an increase in metabolic activity in preeclamptic placentas was observed

 

 

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  6. Song, W., et al., Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model. Proceedings of the National Academy of Sciences, 2017. 114(32): p. 8596-8601.
  7. Shannon, M., et al., Single cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment. bioRxiv, 2021: p. 2021.03. 27.437349.