COMMENTARY COMMENTARY
Placenta plays a critical role in maternal–fetal resource allocation Thomas Janssona,1
Genes and lifestyle were long believed to be the predominant risk factors for the development of major noncommunicable diseases, such as type 2 diabetes and cardiovascular disease. However, a large body of epidemiological evidence has challenged this paradigm by demonstrating that adverse influences during early development, in particular in utero, increase the risk of developing disease in adult life (1, 2). This concept, known as “fetal programming” or “developmental origins of health and disease,” has a profound impact on public health strategies for the prevention of major illnesses. Associations between an adverse intrauterine environment and subsequent metabolic and cardiovascular health were pioneered by Barker and coworkers, who reported that low birth weight markedly increased the risk of developing type 2 diabetes (3) and cardiovascular disease (4). More recently, it has become clear that altered fetal nutrient availability, rather than changes in birth weight per se, constitutes one of the critical links between a suboptimal intrauterine environment and later disease. Because the availability of nutrients during fetal life is largely governed by placental function, it has been proposed that the placenta determines lifelong health (5, 6). The paper by Sferruzzi-Perri et al. in PNAS (7) uses elegant mouse studies to determine how the maternal and fetal genotypes interact in the regulation of placental growth and function. The placenta has long been regarded as a selective passive filter. However, our understanding of the role of the placenta in fetal nutrition has evolved, and it is now recognized that the placenta adapts by responding to maternal nutritional cues, intrinsic nutrient-sensing signaling pathways, and fetal-demand signals (8–11) (Fig. 1). The complexity of these regulatory pathways is only now beginning to be appreciated. Maternal metabolic hormones, such as adiponectin, insulin, leptin, cortisol, and insulin-like growth factor (IGF)1, are examples of maternal signals impinging on placental function (12). Nutrient-sensing signaling pathways intrinsic to the placenta may include mechanistic target of rapamycin (MTOR), a signaling pathway that regulates placental nutrient transporters in response to a large number of upstream signals, including growth
factors and nutrients (13) (Fig. 1). The Igf2P0 knockout mouse is an elegant model where the growth potential of the placenta can be genetically manipulated independently of the fetus. Investigators using this model have generated compelling evidence implicating placental igf2, a paternally expressed/maternally repressed imprinted gene, in the regulation of placental function (14–17). Furthermore, in response to placental-specific reduction of igf2 expression, placental nutrient transporters have been shown to be up-regulated to increase placental efficiency when a small placenta cannot meet the demands of the normally growing fetus. These data are consistent with the existence of fetal-demand signals matching fetal and placental growth. The nature of these signals originating in the fetus and regulating placental function remains largely unknown. However, based on evidence from mouse models of placenta-specific and global igf2 gene deletions, it has been proposed that IGF2 is a key fetal-demand signal (15). Using genetically modified mice, Sferruzzi-Perri et al. (7) explored the role of maternal and fetal Pik3ca, encoding the p110α subunit of phosphoinositol 3-kinase (PI3K), in regulating maternal metabolism, placental-fetal growth, placental morphology, and placental nutrient transport. As expected, fetuses and placentas heterozygous for Pik3ca were growth-restricted; placentas had smaller labyrinthine zones, fetal capillary volumes, and exchange surface area and changes in placental nutrient transport capacity. Interestingly, dams heterozygous for Pik3ca had increased circulating leptin and insulin levels and decreased plasma triglyceride concentrations compared with wild-type, demonstrating that p110α deficiency influences the maternal endocrine and metabolic profile. The Sferruzzi-Perri et al. paper provides evidence to support the emerging model that maternal genotype and environment have a significant influence on placental growth and function and that the placenta integrates intrinsic and extrinsic signals (Fig. 1). Because genetic inactivation of both Pik3ca alleles is associated with embryonic lethality, Sferruzzi-Perri et al. (7) adopted a breeding strategy where heterozygous or wild-type females were mated with heterozygous or wild-type males, thereby generating wild-type and
a
Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 Author contributions: T.J. wrote the paper. The author declares no conflict of interest. See companion article on page 11255. 1 Email: [email protected].
11066–11068 | PNAS | October 4, 2016 | vol. 113 | no. 40
www.pnas.org/cgi/doi/10.1073/pnas.1613437113
MATERNAL CAPACITY TO SUPPORT PREGNANCY
Obesity Diabetes Undernutrition Stress High altitude Reduced UPBF
FETAL GOWTH & PROGRAMMING
Adiponectin Insulin Leptin Cortisol IGF1
Placental function Maternal Genotype (PI3K)
Maternal Signals
Fetal oxygen and nutrient availability
MTOR Fetal Genotype
PI3K
(PI3K)
Fetal Demand Signals
Fig. 1. The role of the placenta in maternal–fetal resource allocation. Placental function adapts in response to maternal nutritional cues, nutrient sensing signaling pathways intrinsic to the placenta, and fetal-demand signals. As a result, fetal oxygen and nutrient delivery changes, affecting fetal growth and programming the fetus for disease later in life. The figure highlights the findings of Sferruzzi-Perri et al. (7), demonstrating an important role of maternal and fetal PI3K signaling in regulating maternal-fetal resource allocation. UPBF, utero–placental blood flow. Modified from ref. 20, with permission from Elsevier.
heterozygous Pik3ca mutants in the same litter in either heterozygous or wild-type dams. This approach allowed the investigators to explore the impact of maternal and fetoplacental Pik3ca genotypes independently on placental function and fetal growth. Placental morphology and nutrient transport were the key placental phenotypes under investigation. Sferruzzi-Perri et al. (7) used stereology to study placental morphology, which was found to adapt to fetal Pik3ca genotype. In pups heterozygous for Pik3ca, placentas were lighter, the vascularization was impaired, and fetal capillaries were shorter in the labyrinthine zone, the maternal blood space volume was decreased, the intrahemal barrier was thicker, and the surface area for exchange was reduced. The observed changes in placental vascularization are reminiscent of what has been reported previously for this model (18) and the changes in labyrinthine morphology are similar to what has been observed in the Igf2P0 mouse (19), consistent with the possibility that the effects of IGF2 on labyrinthine trophoblast is predominantly mediated by the PI3K signaling pathway in the mouse placenta. The effects of maternal genotype on placental morphology were complex. At embryonic day (E) 16, labyrinthine volume and fetal capillary length were decreased, whereas at E19 placentas were heavier and the exchange area larger in dams heterozygous for Pik3ca (7). As expected, the smaller pups heterozygous for Pik3ca had lower total transfer of amino acids and glucose than their wild-type littermates, but transport capacity related to estimated placental exchange area was increased, possibly reflecting compensation in response to a fetal-demand signal. In contrast, in dams heterozygous for Pik3ca, placental capacity to transport glucose was decreased, consistent with the possibility that maternal signals limit fetal growth
Jansson
by down-regulation of placental nutrient transport (7). However, despite the altered maternal endocrine and metabolic profile and placental morphology and function in p110α-deficient compared with wild-type dams, fetal growth remained unaffected. These observations led Sferruzzi-Perri et al. to suggest that the placenta acts as a buffer to fine-tune the delivery of maternal resources to the fetus, to balance fetal demand with the maternal ability to supply nutrients (7). The work of Sferruzzi-Perri et al. (7) highlights the critical role of the placenta in integrating an array of maternal, placental, and fetal signals to balance fetal nutrient supply with the ability of the maternal supply line to provide oxygen and nutrients to the growing fetus. Specifically, Sferruzzi-Perri et al. demonstrate that maternal and fetal PI3K signaling plays an important role in modulating placental function and fetal nutrient delivery (Fig. 1). Identification of the molecular mechanisms by which the placenta responds to maternal and fetal signals and influences maternal–fetal resource allocation will help us better understand the underpinnings of important pregnancy complications and the intrauterine origins of many chronic diseases. Moreover, this knowledge is essential when designing novel intervention strategies to alleviate abnormal fetal growth and prevent the development of metabolic and cardiovascular diseases in future generations. However, there is an urgent need to test these novel concepts in nonhuman primates, which is required before safe and effective treatments can be developed for pregnant women.
Acknowledgments The author’s research is supported by National Institute of Child Health and Development Grants R01HD065007, R01HD68370, R01HD078376, R13HD084096, R03HD078313, and P01HD021350; and the Office of the Director Grant R24OD016724.
PNAS | October 4, 2016 | vol. 113 | no. 40 | 11067
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Gluckman PD, Hanson MA (2004) Living with the past: Evolution, development, and patterns of disease. Science 305(5691):1733–1736. Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359(1):61–73. Hales CN, et al. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303(6809):1019–1022. Barker DJP, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1(8489):1077–1081. Jansson T, Powell TL (2006) IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: Does the placenta function as a nutrient sensor? A review. Placenta 27(SupplA):S91–S97. Lewis RM, Cleal JK, Hanson MA (2012) Review: Placenta, evolution and lifelong health. Placenta 33(Suppl):S28–S32. Sferruzzi-Perri AN, Lopez-Tello ´ J, Fowden AL, Constancia M (2016) Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation. Proc Natl Acad Sci USA 113:11255–11260. Jansson T, Powell TL (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56(3):591–601. Sferruzzi-Perri AN, Vaughan OR, Forhead AJ, Fowden AL (2013) Hormonal and nutritional drivers of intrauterine growth. Curr Opin Clin Nutr Metab Care 16(3): 298–309. Fowden AL, Sferruzzi-Perri AN, Coan PM, Constancia M, Burton GJ (2009) Placental efficiency and adaptation: endocrine regulation. J Physiol 587(Pt 14): 3459–3472. Sferruzzi-Perri AN, Camm EJ (2016) The programming power of the placenta. Front Physiol 7:33. D´ıaz P, Powell TL, Jansson T (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91(4):82. Rosario FJ, Kanai Y, Powell TL, Jansson T (2013) Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J Physiol 591(3):609–625. Constancia ˆ M, et al. (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417(6892):945–948. Constancia ˆ M, et al. (2005) Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci USA 102(52):19219–19224. Sferruzzi-Perri AN, et al. (2011) Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. Endocrinology 152(8):3202–3212. Sibley CP, et al. (2004) Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci USA 101(21):8204–8208. Graupera M, et al. (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453(7195):662–666. Coan PM, et al. (2008) Disproportional effects of Igf2 knockout on placental morphology and diffusional exchange characteristics in the mouse. J Physiol 586(20): 5023–5032. Jansson T, Aye IL, Goberdhan DC (2012) The emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta 33(Suppl 2):e23–e29.
11068 | www.pnas.org/cgi/doi/10.1073/pnas.1613437113
Jansson
Placenta plays a critical role in maternal–fetal resource allocation Thomas Janssona,1
Genes and lifestyle were long believed to be the predominant risk factors for the development of major noncommunicable diseases, such as type 2 diabetes and cardiovascular disease. However, a large body of epidemiological evidence has challenged this paradigm by demonstrating that adverse influences during early development, in particular in utero, increase the risk of developing disease in adult life (1, 2). This concept, known as “fetal programming” or “developmental origins of health and disease,” has a profound impact on public health strategies for the prevention of major illnesses. Associations between an adverse intrauterine environment and subsequent metabolic and cardiovascular health were pioneered by Barker and coworkers, who reported that low birth weight markedly increased the risk of developing type 2 diabetes (3) and cardiovascular disease (4). More recently, it has become clear that altered fetal nutrient availability, rather than changes in birth weight per se, constitutes one of the critical links between a suboptimal intrauterine environment and later disease. Because the availability of nutrients during fetal life is largely governed by placental function, it has been proposed that the placenta determines lifelong health (5, 6). The paper by Sferruzzi-Perri et al. in PNAS (7) uses elegant mouse studies to determine how the maternal and fetal genotypes interact in the regulation of placental growth and function. The placenta has long been regarded as a selective passive filter. However, our understanding of the role of the placenta in fetal nutrition has evolved, and it is now recognized that the placenta adapts by responding to maternal nutritional cues, intrinsic nutrient-sensing signaling pathways, and fetal-demand signals (8–11) (Fig. 1). The complexity of these regulatory pathways is only now beginning to be appreciated. Maternal metabolic hormones, such as adiponectin, insulin, leptin, cortisol, and insulin-like growth factor (IGF)1, are examples of maternal signals impinging on placental function (12). Nutrient-sensing signaling pathways intrinsic to the placenta may include mechanistic target of rapamycin (MTOR), a signaling pathway that regulates placental nutrient transporters in response to a large number of upstream signals, including growth
factors and nutrients (13) (Fig. 1). The Igf2P0 knockout mouse is an elegant model where the growth potential of the placenta can be genetically manipulated independently of the fetus. Investigators using this model have generated compelling evidence implicating placental igf2, a paternally expressed/maternally repressed imprinted gene, in the regulation of placental function (14–17). Furthermore, in response to placental-specific reduction of igf2 expression, placental nutrient transporters have been shown to be up-regulated to increase placental efficiency when a small placenta cannot meet the demands of the normally growing fetus. These data are consistent with the existence of fetal-demand signals matching fetal and placental growth. The nature of these signals originating in the fetus and regulating placental function remains largely unknown. However, based on evidence from mouse models of placenta-specific and global igf2 gene deletions, it has been proposed that IGF2 is a key fetal-demand signal (15). Using genetically modified mice, Sferruzzi-Perri et al. (7) explored the role of maternal and fetal Pik3ca, encoding the p110α subunit of phosphoinositol 3-kinase (PI3K), in regulating maternal metabolism, placental-fetal growth, placental morphology, and placental nutrient transport. As expected, fetuses and placentas heterozygous for Pik3ca were growth-restricted; placentas had smaller labyrinthine zones, fetal capillary volumes, and exchange surface area and changes in placental nutrient transport capacity. Interestingly, dams heterozygous for Pik3ca had increased circulating leptin and insulin levels and decreased plasma triglyceride concentrations compared with wild-type, demonstrating that p110α deficiency influences the maternal endocrine and metabolic profile. The Sferruzzi-Perri et al. paper provides evidence to support the emerging model that maternal genotype and environment have a significant influence on placental growth and function and that the placenta integrates intrinsic and extrinsic signals (Fig. 1). Because genetic inactivation of both Pik3ca alleles is associated with embryonic lethality, Sferruzzi-Perri et al. (7) adopted a breeding strategy where heterozygous or wild-type females were mated with heterozygous or wild-type males, thereby generating wild-type and
a
Department of Obstetrics & Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 Author contributions: T.J. wrote the paper. The author declares no conflict of interest. See companion article on page 11255. 1 Email: [email protected].
11066–11068 | PNAS | October 4, 2016 | vol. 113 | no. 40
www.pnas.org/cgi/doi/10.1073/pnas.1613437113
MATERNAL CAPACITY TO SUPPORT PREGNANCY
Obesity Diabetes Undernutrition Stress High altitude Reduced UPBF
FETAL GOWTH & PROGRAMMING
Adiponectin Insulin Leptin Cortisol IGF1
Placental function Maternal Genotype (PI3K)
Maternal Signals
Fetal oxygen and nutrient availability
MTOR Fetal Genotype
PI3K
(PI3K)
Fetal Demand Signals
Fig. 1. The role of the placenta in maternal–fetal resource allocation. Placental function adapts in response to maternal nutritional cues, nutrient sensing signaling pathways intrinsic to the placenta, and fetal-demand signals. As a result, fetal oxygen and nutrient delivery changes, affecting fetal growth and programming the fetus for disease later in life. The figure highlights the findings of Sferruzzi-Perri et al. (7), demonstrating an important role of maternal and fetal PI3K signaling in regulating maternal-fetal resource allocation. UPBF, utero–placental blood flow. Modified from ref. 20, with permission from Elsevier.
heterozygous Pik3ca mutants in the same litter in either heterozygous or wild-type dams. This approach allowed the investigators to explore the impact of maternal and fetoplacental Pik3ca genotypes independently on placental function and fetal growth. Placental morphology and nutrient transport were the key placental phenotypes under investigation. Sferruzzi-Perri et al. (7) used stereology to study placental morphology, which was found to adapt to fetal Pik3ca genotype. In pups heterozygous for Pik3ca, placentas were lighter, the vascularization was impaired, and fetal capillaries were shorter in the labyrinthine zone, the maternal blood space volume was decreased, the intrahemal barrier was thicker, and the surface area for exchange was reduced. The observed changes in placental vascularization are reminiscent of what has been reported previously for this model (18) and the changes in labyrinthine morphology are similar to what has been observed in the Igf2P0 mouse (19), consistent with the possibility that the effects of IGF2 on labyrinthine trophoblast is predominantly mediated by the PI3K signaling pathway in the mouse placenta. The effects of maternal genotype on placental morphology were complex. At embryonic day (E) 16, labyrinthine volume and fetal capillary length were decreased, whereas at E19 placentas were heavier and the exchange area larger in dams heterozygous for Pik3ca (7). As expected, the smaller pups heterozygous for Pik3ca had lower total transfer of amino acids and glucose than their wild-type littermates, but transport capacity related to estimated placental exchange area was increased, possibly reflecting compensation in response to a fetal-demand signal. In contrast, in dams heterozygous for Pik3ca, placental capacity to transport glucose was decreased, consistent with the possibility that maternal signals limit fetal growth
Jansson
by down-regulation of placental nutrient transport (7). However, despite the altered maternal endocrine and metabolic profile and placental morphology and function in p110α-deficient compared with wild-type dams, fetal growth remained unaffected. These observations led Sferruzzi-Perri et al. to suggest that the placenta acts as a buffer to fine-tune the delivery of maternal resources to the fetus, to balance fetal demand with the maternal ability to supply nutrients (7). The work of Sferruzzi-Perri et al. (7) highlights the critical role of the placenta in integrating an array of maternal, placental, and fetal signals to balance fetal nutrient supply with the ability of the maternal supply line to provide oxygen and nutrients to the growing fetus. Specifically, Sferruzzi-Perri et al. demonstrate that maternal and fetal PI3K signaling plays an important role in modulating placental function and fetal nutrient delivery (Fig. 1). Identification of the molecular mechanisms by which the placenta responds to maternal and fetal signals and influences maternal–fetal resource allocation will help us better understand the underpinnings of important pregnancy complications and the intrauterine origins of many chronic diseases. Moreover, this knowledge is essential when designing novel intervention strategies to alleviate abnormal fetal growth and prevent the development of metabolic and cardiovascular diseases in future generations. However, there is an urgent need to test these novel concepts in nonhuman primates, which is required before safe and effective treatments can be developed for pregnant women.
Acknowledgments The author’s research is supported by National Institute of Child Health and Development Grants R01HD065007, R01HD68370, R01HD078376, R13HD084096, R03HD078313, and P01HD021350; and the Office of the Director Grant R24OD016724.
PNAS | October 4, 2016 | vol. 113 | no. 40 | 11067
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Gluckman PD, Hanson MA (2004) Living with the past: Evolution, development, and patterns of disease. Science 305(5691):1733–1736. Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359(1):61–73. Hales CN, et al. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303(6809):1019–1022. Barker DJP, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1(8489):1077–1081. Jansson T, Powell TL (2006) IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: Does the placenta function as a nutrient sensor? A review. Placenta 27(SupplA):S91–S97. Lewis RM, Cleal JK, Hanson MA (2012) Review: Placenta, evolution and lifelong health. Placenta 33(Suppl):S28–S32. Sferruzzi-Perri AN, Lopez-Tello ´ J, Fowden AL, Constancia M (2016) Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation. Proc Natl Acad Sci USA 113:11255–11260. Jansson T, Powell TL (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56(3):591–601. Sferruzzi-Perri AN, Vaughan OR, Forhead AJ, Fowden AL (2013) Hormonal and nutritional drivers of intrauterine growth. Curr Opin Clin Nutr Metab Care 16(3): 298–309. Fowden AL, Sferruzzi-Perri AN, Coan PM, Constancia M, Burton GJ (2009) Placental efficiency and adaptation: endocrine regulation. J Physiol 587(Pt 14): 3459–3472. Sferruzzi-Perri AN, Camm EJ (2016) The programming power of the placenta. Front Physiol 7:33. D´ıaz P, Powell TL, Jansson T (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91(4):82. Rosario FJ, Kanai Y, Powell TL, Jansson T (2013) Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J Physiol 591(3):609–625. Constancia ˆ M, et al. (2002) Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417(6892):945–948. Constancia ˆ M, et al. (2005) Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci USA 102(52):19219–19224. Sferruzzi-Perri AN, et al. (2011) Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. Endocrinology 152(8):3202–3212. Sibley CP, et al. (2004) Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci USA 101(21):8204–8208. Graupera M, et al. (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453(7195):662–666. Coan PM, et al. (2008) Disproportional effects of Igf2 knockout on placental morphology and diffusional exchange characteristics in the mouse. J Physiol 586(20): 5023–5032. Jansson T, Aye IL, Goberdhan DC (2012) The emerging role of mTORC1 signaling in placental nutrient-sensing. Placenta 33(Suppl 2):e23–e29.
11068 | www.pnas.org/cgi/doi/10.1073/pnas.1613437113
Jansson
