AMPK and Placental Progenitor Cells

  • Melissa R. Kaufman
  • Thomas L. BrownEmail author
Part of the Experientia Supplementum book series (EXS, volume 107)


AMPK is important in numerous physiological systems but plays a vital role in embryonic and placental development. The placenta is a unique organ that is the essential lifeline between the mother and baby during pregnancy and gestation. During placental development, oxygen concentrations are very low until cells differentiate to establish the appropriate lineages that take on new functions required for placental and embryonic survival. Balancing the oxygen regulatory environment with the demands for energy and need to maintain metabolism during this process places AMPK at the center of maintaining placental cellular homeostasis as it integrates and responds to numerous complex stimuli. AMPK plays a critical role in sensing metabolic and energy changes. Once activated, it turns on pathways that produce energy and shuts down catabolic processes. AMPK coordinates cell growth, differentiation, and nutrient transport to maintain cell survival. Appropriate regulation of AMPK is essential for normal placental and embryonic development, and its dysregulation may lead to pregnancy-associated disorders such as intrauterine growth restriction, placental insufficiency, or preeclampsia.


Placenta Trophoblast AMPK Pregnancy Stem cells Differentiation 



We would like to thank Dr. David Natale (University of California San Diego) for critical reading of the manuscript and helpful input. This work was supported in part by a grant from the National Institutes of Health NICHD-R01 HD059969 (TLB) and The Wright State University Endowment for Research on Pregnancy Associated Disorders ( (TLB).


  1. Banek CT, Bauer AJ, Needham KM, Dreyer HC, Gilbert JS (2013) AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat. Am J Physiol Heart Circ Physiol 304:H1159–H1165CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bigham AW, Julian CG, Wilson MJ, Vargas E, Browne VA, Shriver MD, Moore LG (2014) Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude. Physiol Genomics 46:687–697CrossRefPubMedPubMedCentralGoogle Scholar
  3. Caniggia I, Winter J, Lye SJ, Post M (2000) Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 21(Suppl A):S25–S30Google Scholar
  4. Carey EAK, Albers RE, Doliboa SR, Hughes M, Wyatt CN, Natale DRC, Brown TL (2014) AMPK knockdown in placental trophoblast cells results in altered morphology and function. Stem Cells Dev 23:2921–2930CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cetin I, Alvino G (2009) Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 30(Suppl A):S77–S82CrossRefPubMedGoogle Scholar
  6. Chaddha V, Viero S, Huppertz B, Kingdom J (2004) Developmental biology of the placenta and the origins of placental insufficiency. Semin Fetal Neonatal Med 9:357–369CrossRefPubMedGoogle Scholar
  7. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461CrossRefPubMedGoogle Scholar
  8. Evans AM, Hardie DG, Galione A, Peers C, Kumar P, Wyatt CN (2006) AMP-activated protein kinase couples mitochondrial inhibition by hypoxia to cell-specific Ca2+ signalling mechanisms in oxygen-sensing cells. Novartis Found Symp 272:234–252CrossRefPubMedGoogle Scholar
  9. Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908CrossRefPubMedPubMedCentralGoogle Scholar
  10. Jansson T, Powell TL (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56:591–601CrossRefPubMedPubMedCentralGoogle Scholar
  11. Kaufman MR, Albers RE, Keoni C, Kulkarni-Datar K, Natale DR, Brown TL (2014) Important aspects of placental-specific gene transfer. Theriogenology 82:1043–1048CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lager S, Powell TL (2012) Regulation of nutrient transport across the placenta. J Pregnancy 2012:179827CrossRefPubMedPubMedCentralGoogle Scholar
  14. Louden ED, Luzzo KM, Jimenez PT, Chi T, Chi M, Moley KH (2014) TallyHO obese female mice experience poor reproductive outcomes and abnormal blastocyst metabolism that is reversed by metformin. Reprod Fertil Dev 27:31–39CrossRefPubMedPubMedCentralGoogle Scholar
  15. Mansouri L, Xie Y, Rappolee DA (2012) Adaptive and pathogenic responses to stress by stem cells during development. Cells 1:1197–1224CrossRefPubMedPubMedCentralGoogle Scholar
  16. Mihaylova MM, Shaw RJ (2011) The AMPK signaling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023CrossRefPubMedPubMedCentralGoogle Scholar
  17. Natale DR, Starovic M, Cross JC (2006) Phenotypic analysis of the mouse placenta. Methods Mol Med 121:275–293PubMedGoogle Scholar
  18. Okada Y, Ueshin Y, Isotani A, Saito-Fujita T, Nakashima H, Kimura K, Mizoguchi A, Oh-Hora M, Mori Y, Ogata M, Oshima RG, Okabe M, Ikawa M (2007) Complementation of placental defects and embryonic lethality by trophoblast-specific lentiviral gene transfer. Nat Biotechnol 25:233–237CrossRefPubMedGoogle Scholar
  19. Rafalski VA, Mancini E, Brunet A (2012) Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J Cell Sci 125:5597–5608CrossRefPubMedPubMedCentralGoogle Scholar
  20. Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M, Fisher SJ (2004) Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest 114:744–745CrossRefPubMedPubMedCentralGoogle Scholar
  21. Selesniemi KL, Reedy MA, Gultice AD, Brown TL (2005a) Identification of committed placental stem cell lines for studies of differentiation. Stem Cells Dev 14:535–547CrossRefPubMedGoogle Scholar
  22. Selesniemi K, Reedy M, Gultice A, Guilbert LJ, Brown TL (2005b) Transforming growth factor-beta induces differentiation of the labyrinthine trophoblast stem cell line SM10. Stem Cells Dev 14:697–711CrossRefPubMedGoogle Scholar
  23. Selesniemi KL, Albers RE, Brown TL (2016) Id2 mediates differentiation of labyrinthine placental progenitor cell line, SM10. Stem Cells Dev. ePubGoogle Scholar
  24. Skeffington KL, Higgins JS, Mahmoud AD, Evans AM, Sferruzzi-Perri AN, Fowden AL, Yung HW, Burton GJ, Giussani DA, Moore LG (2016) Hypoxia, AMPK activation and uterine artery vasoreactivity. J Physiol 594:1357–1369CrossRefPubMedGoogle Scholar
  25. Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078CrossRefPubMedGoogle Scholar
  26. Tangeman L, Wyatt CN, Brown TL (2012) Knockdown of AMP-activated protein kinase alpha 1 and alpha 2 catalytic subunits. J RNAi Gene Silencing 8:470–478PubMedPubMedCentralGoogle Scholar
  27. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Losón OC, Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275–281CrossRefPubMedPubMedCentralGoogle Scholar
  28. Vazquez-Martin A, Vellon L, Quirós PM, Cufí S, Ruiz de Galarreta E, Oliveras-Ferraros C, Martin AG, Martin-Castillo B, López-Otín C, Menendez JA (2012) Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells. Cell Cycle 11:974–989CrossRefPubMedGoogle Scholar
  29. Viollet B, Andreelli F, Jørgensen SB, Perrin C, Flamez D, Mu J, Wojtaszewski JF, Schuit FC, Birnbaum M, Richter E, Burcelin R, Vaulont S (2003) Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models. Biochem Soc Trans Part 1:216–219CrossRefGoogle Scholar
  30. Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, Lantier L, Hebrard S, Devin-Leclerc J, Beauloye C, Foretz M, Andreelli F, Ventura-Clapier R, Bertrand L (2009) AMPK: lessons from transgenic and knockout animals. Front Biosci 14:19–44CrossRefGoogle Scholar
  31. Watson ED, Cross JC (2005) Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20:180–193CrossRefGoogle Scholar
  32. Xie Y, Awonuga A, Liu J, Rings E, Puscheck EE, Rappolee DA (2013) Stress induces AMPK-dependent loss of potency factors Id2 and Cdx2 in early embryos and stem cells. Stem Cells Dev 22:1564–1575CrossRefPubMedPubMedCentralGoogle Scholar
  33. Young NP, Kamireddy A, Van Nostrand JL, Eichner LJ, Shokhirev MN, Dayn Y, Shaw RJ (2016) AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. Genes Dev 30:535–552CrossRefPubMedPubMedCentralGoogle Scholar
  34. Zhong W, Xie Y, Abdallah M, Awonuga AO, Slater JA, Sipahi L, Puscheck EE, Rappolee DA (2010) Cellular stress causes reversible, PRKAA1/2-, and proteasome-dependent ID2 protein loss in trophoblast stem cells. Reproduction 140:921–930CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Neuroscience, Cell Biology and PhysiologyWright State University Boonshoft School of MedicineDaytonUSA

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