Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

Gurman Kaur; Caroline B.M. Porter; Orr Ashenberg; Jack Lee; Samantha J. Riesenfeld; Matan Hofree; Maria Aggelakopoulou; Ayshwarya Subramanian; Subita Balaram Kuttikkatte; Kathrine E. Attfield; Christiane A.E. Desel; Jessica L. Davies; Hayley G. Evans; Inbal Avraham-Davidi; Lan T. Nguyen; Danielle A. Dionne; Anna E. Neumann; Lise Torp Jensen; Thomas R. Barber; Elizabeth Soilleux; Mary Carrington; Gil McVean; Orit Rozenblatt-Rosen; Aviv Regev; Lars Fugger

doi:10.1038/s41467-022-32171-w

Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

Gurman Kaur, Caroline B.M. Porter, Orr Ashenberg, Jack Lee, Samantha J. Riesenfeld, Matan Hofree, Maria Aggelakopoulou, Ayshwarya Subramanian, Subita Balaram Kuttikkatte, Kathrine E. Attfield, Christiane A.E. Desel, Jessica L. Davies, Hayley G. Evans, Inbal Avraham-Davidi, Lan T. Nguyen, Danielle A. Dionne, Anna E. Neumann, Lise Torp Jensen, Thomas R. Barber, Elizabeth SoilleuxMary Carrington, Gil McVean, Orit Rozenblatt-Rosen, Aviv Regev^*, Lars Fugger^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

Original language	English
Article number	4398
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32171-w
State	Published - Dec 2022
Externally published	Yes

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Publisher Copyright:
© 2022, The Author(s).

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Kaur, G., Porter, C. B. M., Ashenberg, O., Lee, J., Riesenfeld, S. J., Hofree, M., Aggelakopoulou, M., Subramanian, A., Kuttikkatte, S. B., Attfield, K. E., Desel, C. A. E., Davies, J. L., Evans, H. G., Avraham-Davidi, I., Nguyen, L. T., Dionne, D. A., Neumann, A. E., Jensen, L. T., Barber, T. R., ... Fugger, L. (2022). Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade. Nature Communications, 13(1), Article 4398. https://doi.org/10.1038/s41467-022-32171-w

@article{884f60871eea4fe591edbdf82e3f523c,

title = "Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade",

abstract = "Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.",

author = "Gurman Kaur and Porter, {Caroline B.M.} and Orr Ashenberg and Jack Lee and Riesenfeld, {Samantha J.} and Matan Hofree and Maria Aggelakopoulou and Ayshwarya Subramanian and Kuttikkatte, {Subita Balaram} and Attfield, {Kathrine E.} and Desel, {Christiane A.E.} and Davies, {Jessica L.} and Evans, {Hayley G.} and Inbal Avraham-Davidi and Nguyen, {Lan T.} and Dionne, {Danielle A.} and Neumann, {Anna E.} and Jensen, {Lise Torp} and Barber, {Thomas R.} and Elizabeth Soilleux and Mary Carrington and Gil McVean and Orit Rozenblatt-Rosen and Aviv Regev and Lars Fugger",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32171-w",

language = "אנגלית",

volume = "13",

journal = "Nature Communications",

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Kaur, G, Porter, CBM, Ashenberg, O, Lee, J, Riesenfeld, SJ, Hofree, M, Aggelakopoulou, M, Subramanian, A, Kuttikkatte, SB, Attfield, KE, Desel, CAE, Davies, JL, Evans, HG, Avraham-Davidi, I, Nguyen, LT, Dionne, DA, Neumann, AE, Jensen, LT, Barber, TR, Soilleux, E, Carrington, M, McVean, G, Rozenblatt-Rosen, O, Regev, A & Fugger, L 2022, 'Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade', Nature Communications, vol. 13, no. 1, 4398. https://doi.org/10.1038/s41467-022-32171-w

TY - JOUR

T1 - Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

AU - Kaur, Gurman

AU - Porter, Caroline B.M.

AU - Ashenberg, Orr

AU - Lee, Jack

AU - Riesenfeld, Samantha J.

AU - Hofree, Matan

AU - Aggelakopoulou, Maria

AU - Subramanian, Ayshwarya

AU - Kuttikkatte, Subita Balaram

AU - Attfield, Kathrine E.

AU - Desel, Christiane A.E.

AU - Davies, Jessica L.

AU - Evans, Hayley G.

AU - Avraham-Davidi, Inbal

AU - Nguyen, Lan T.

AU - Dionne, Danielle A.

AU - Neumann, Anna E.

AU - Jensen, Lise Torp

AU - Barber, Thomas R.

AU - Soilleux, Elizabeth

AU - Carrington, Mary

AU - McVean, Gil

AU - Rozenblatt-Rosen, Orit

AU - Regev, Aviv

AU - Fugger, Lars

PY - 2022/12

Y1 - 2022/12

N2 - Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

AB - Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

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U2 - 10.1038/s41467-022-32171-w

DO - 10.1038/s41467-022-32171-w

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C2 - 35906236

AN - SCOPUS:85135171777

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4398

ER -

Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

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