Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques

Sureshchandra, Suhas; Chan, Chi N.; Robino, Jacob J; Parmelee, Lindsay K; Nash, Michael J.; Wesolowski, Stephanie R.; Pietras, Eric M.; Friedman, Jacob E.; Takahashi, Diana; Shen, Weining; Jiang, Xiwen; Hennebold, Jon D.; Goldman, Devorah C.; Packwood, William; Lindner, Jonathan R.; Roberts, Charles T.; Burwitz, Benjamin J.; Messaoudi, Ilhem; Varlamov, Oleg

doi:10.1016/j.stemcr.2022.10.003

Cited by 13 publications

(12 citation statements)

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“…Indeed, monocytes and macrophages are some of the earliest immune cells to develop with the first wave originating from late yolk-sac-derived erythromyeloid progenitors and fetal liver ( Wolf et al, 2019 ). A recent study demonstrated a proinflammatory phenotype within bone marrow macrophages of GD130 fetuses born to dams on WSD ( Sureshchandra et al, 2022 ). The heightened maternal inflammatory milieu associated with obesity/WSD during critical windows of fetal immune ontogeny may skew the maturation of immune cells toward a regulatory state, perhaps a protective adaptation to limit fetal inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, neonates born to obese mothers are at high risk for respiratory infections, sepsis, wheezing, and asthma ( Rastogi et al, 2015 ; Suk et al, 2016 ). Recent studies have reported dampened responses by human UCB monocytes of babies born to mothers with obesity ( Wilson et al, 2015 ; Sureshchandra et al, 2017 ; Anderson et al, 2021 ; de Goede et al, 2017 ) as well as by splenocytes from pups born to obese dams to LPS stimulation ( Sureshchandra, 2021a ). Additional studies indicate increased airway reactivity and aberrant responses to RSV in pups born to dams fed a HFD during gestation ( Griffiths et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…PBMC, ileal lamina propria lymphocytes (LPL), and splenocytes from gestational day (GD) 130 rhesus macaque fetuses born to obese and lean dams (n=3/group) were isolated and cryopreserved from animals described in Sureshchandra et al, 2022 . PBMC were stimulated with 1 µg/mL LPS for 16 hr in a 37 °C incubator with 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

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Maternal obesity blunts antimicrobial responses in fetal monocytes

Sureshchandra

Doratt

Mendza

et al. 2023

eLife

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Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli respectively were significantly dampened. Although upstream signaling events were comparable, translocation of the key transcription factor NF-kB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Maternal obesity blunts antimicrobial responses in fetal monocytes

Sureshchandra

Doratt

Mendza

et al. 2023

eLife

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“…22 A study in Rhesus monkeys showed that a maternal high-fat diet is associated with a decrease in the number of B cells in the offspring's bone marrow without changes in the peripheral blood frequency of these cells. 26 Even though more studies are needed, it seems that cord blood B lymphocytes are less sensitive to changes in maternal nutritional status and obesity than T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Maternal obesity is associated with a higher number of regulatory‐T‐cells in newborns without affecting suppression

Arroyo-Jousse

Borzutzky

Bono

et al. 2023

American J Rep Immunol

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Background Maternal obesity (MO) is associated with a higher risk of immune‐mediated diseases in the offspring and higher leptin levels in cord blood (CB). This study evaluates the number and function of lymphocyte subtypes in CB related to MO and its relationship with leptin concentration and leptin receptor expression. Methods Pregnant women with (n = 32) or without obesity (n = 41) were enrolled at delivery. Cord blood mononuclear cells were separated with Ficoll‐Hypaque. B and CD4+, regulatory and effector T cells were quantified by Flow Cytometry. Cord blood leptin concentration was measured by ELISA, and the leptin receptor (sLepR) on Treg cells was determined by Flow Cytometry. Results MO was associated with higher numbers of CD4+, Treg and effector T cells in the CB of their offspring, without differences in the suppressive function of Tregs. Female offspring had a higher number of these cells and a higher cord leptin concentration. Tregs expressed higher levels of sLepR than effector T cells, without differences between groups. Conclusions MO is associated with changes in the newborn's immune profile, more evident in female newborns with higher leptin concentrations. More studies are needed to identify the mechanisms by which the high levels of cord leptin in the newborn of women with obesity could affect the offspring's immune system.

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“…To test whether T+WSD disrupts the immune milieu that may affect normal egg implantation and other relevant reproductive processes, we conducted immune cell profiling during the mid-luteal phase, the interval during the menstrual cycle when the uterine endometrium is permissive for embryo implantation. Immune cells residing in omental (OM)-WAT, the corpus lutetium (CL), the contralateral ovary not containing the CL (OV), endometrium (ENDO), lymph nodes (LNs), bone marrow (BM; a source of myeloid cells 14,15 ), and peripheral blood mononuclear cells (PBMCs) were characterized by flow cytometry, using NHP-specific antibodies 16,17 (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Western‐style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques

Burwitz,

Yusova,

Robino

et al. 2023

American J Rep Immunol

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ProblemAnovulatory infertility is commonly associated with hyperandrogenemia (elevated testosterone, T), insulin resistance, obesity, and white adipose tissue (WAT) dysfunction associated with adipocyte hypertrophy. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown.Method of studyYoung adult female rhesus macaques were exposed to an obesogenic Western‐style diet (WSD) in the presence of elevated circulating testosterone (T+WSD) or a low‐fat control diet with no exogenous T. Immune cells residing in visceral omental white adipose tissue (OM‐WAT), corpus luteum and the contralateral ovary, endometrium, lymph nodes, bone marrow, and peripheral blood mononuclear cells were characterized by flow cytometry during the luteal phase of the reproductive cycle.ResultsFollowing one year of treatment, T+WSD animals became more insulin‐resistant and exhibited increased body fat and adipocyte hypertrophy compared to controls. T+WSD treatment did not induce macrophage polarization toward a proinflammatory phenotype in the tissues examined. Additionally, T+WSD treatment did not affect TNFα production by bone marrow macrophages in response to toll‐like receptor agonists. While the major lymphoid subsets were not significantly affected by T+WSD treatment, we observed a significant reduction in the frequency of effector memory CD8+ T‐cells (Tem) in OM‐WAT, but not in other tissues. Notably, OM‐WAT Tem frequencies were negatively correlated with insulin resistance as assessed by the Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR).ConclusionThis study shows that short‐term T+WSD treatment induces weight gain, insulin resistance, and adipocyte hypertrophy, but does not have a significant effect on systemic and tissue‐resident proinflammatory markers, suggesting that adipocyte hypertrophy and mild hyperandrogenemia alone are not sufficient to induce a proinflammatory response.

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Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques

Cited by 13 publications

References 76 publications

Maternal obesity blunts antimicrobial responses in fetal monocytes

Maternal obesity blunts antimicrobial responses in fetal monocytes

Maternal obesity is associated with a higher number of regulatory‐T‐cells in newborns without affecting suppression

Western‐style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques

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