Introduction:

A recent study by Sureshchandra et al. shows that maternal obesity may influence the development of fetal bone marrow and immune system. Many studies have established an association between pre-pregnancy obesity and increased risk of infection and inflammatory responses. However, few have studied the effects of maternal obesity on fetal hematopoesis, especially in ‘models that resemble human development’.

Hematopoesis is the process involved in the formation of blood, which starts during embryonic development and continues throughout life to replenish blood. Hematopoesis involves the migration of hematopoetic stem and progenitor cells (HSPCs) between different hematopoetic sites including the bone marrow, liver, and spleen. HSPCs are a rare population of precursor cells that have the capacity to renew itself and differentiate into multiple different lineages of cells [1].

Following the emergence of HSPCs during the first trimester, the fetal liver (FL) becomes the main site for HSPC expansion. During the second and third trimesters, HSPCs migrate from the FL to the fetal bone marrow (FBM), where immune cells important for anti-microbial defense, including macrophages and B lymphocytes, are produced [2]. Therefore, the maternal environment may affect the immunity of the offspring by altering the products of HSPC in the FBM and the FL. However, the underlying mechanism remains largely unknown.

Hence, Sureshchandra et al. conducted an experimental study on female rhesus monkeys, whose hematpoetic and immune systems are similar to humans, to investigate these molecular mechanisms in mothers following a Western-style diet (WSD).

Methods:

To investigate the underlying mechanism by which a maternal high fat-diet affects fetal development, the researchers randomized 13 female monkeys into either a control diet (fiber-balanced monkey chow) or a high fat diet (Purina 5LOP, which is 36% fat, 18% protein, and 46% carbohydrates). After five and half years of treatment, the monkeys underwent timed mating breeding. Nine control and four WSD fetuses were eventually examined in this study [1].

To deteremine hematopoetic development in the fetuses, the researchers isolated cells from the fetal bone marrow and fetal liver. Through flow cytometry, a lab test that analyzes characteristics of particles, they were able to analyze HSCs and the fetal liver immune cells, by detecting the marker CD34-. They also conducted RNA sequencing to determine the transcriptional landscape of FBM HSPCs and identify the overlapping transcriptomes from the control and WSD-exposed fetuses.

Results:

The impact of maternal WSD on fetal development

The authors found that mothers consuming the high-fat diet had significantly higher percentages of body fat and body weight compared to the controls. However, the fetal weights were not significantly affected by maternal WSD. Fetal retroperitoneal or abdomen fat pad weight and maternal and umbilical artery glucose levels were increased significantly in the WSD group compared to the control. The BM of fetal femurs from the WSD group was shown to be densely populated with fat cells, termed adipocytes, while the femurs of the controls rarely contained adipocytes. These differences were also observed in the fetal breastbone, the sterna, which serves as an alternative hematopoesis site. The total number of macrophages and HSPCs per sternal section was significantly higher in the WSD fetuses compared to controls, which suggests that maternal WSD induces FBM adiposity in fetal bones.

Maternal WSD induces a proinflammatory phenotype in fetal HSPCs and macrophages
Analyzing differentially expressed genes within HSCs, revealed that maternal WSD upregulates proinflammatory genes and signaling pathways. Specifically, maternal WSD resulted in a heightened proinflammatory response by the fetal bone marrow macrophages.

Furthermore, the flow cytometry analysis of immune cells revealed that maternal WSD attenuates B cell development in fetal bone, as suggested by the reduced B cell content.

Maternal WSD attenuates B cell development in fetal bones

Flow cytometry analysis showed that the number of B cells in the FBM was significantly decreased in maternal WSD. However, the number of T immune cells, which are released from the thymus, were relatively similar between the WSD and control groups. The analysis of differentially expressed genes in fetal HSCs reveal that genes required for pre-B cell differentiation were downregulated in maternal WSD, as well as genes required for fetal hematopoesis.

Maternal WSD alters the engraftment ability of FBM HSPCs under regenerative stress
To test whether maternal WSD alters HSPC function, the researcher transplanted 120,000 FBM CD34+ HSPCs into nonlethally irradiated immunodeficient mice. The levels of CD34+ cells in the BM were found to be significantly lower in the mice engrafted with HSPCs from the WSD group compared to those engrafted with the control HSPCs after 13 days of engraftment.

Discussion:

In this study, it was found that exposure to WSD triggers premature FBM adipogenesis, the process of fat production. Based on previous studies, the pattern of FBM adipogenesis induced by a maternal WSD seems to resemble age and obesity related replacement of the hematopoetic marrow with adipogentic marrow in adults. Earlier research has described BM adipocytes as negative regulators of hematopoesis under regenerative stress in mice.

The results have also shown that maternal WSD elicits an inflammatory gene profile in FBM HSPCs and a latent hyperinflammatory phenotype in FBM macrophages, which suggests that a maternal WSD regulates fetal immune system development by reprogramming fetal HSPC function in neonates. Given the negative impacts of maternal WSD on hematpoetic function, the researcher speculate that excess BM adiposity in utero has negative effects on aspects of hematopoesis. However, it is possible that other components of the FBM niche, like stromal cells, are affected by maternal WSD. Hence, more research is needed to understand the cross talk between an adipocyte-rich microenvironement and HSPCs on the development and function of the immune system. The study also shows that the maternal WSD also resulted in the reduction of FBM B cell numbers, which is consistent with previous studies. All which suggest that diet-induced expansion of BM adipose tissue is also associated with an increase in a proinflammatory environment in the FBM.

The study, however, has several limitations. It is underpowered with a small sample size. The small number of fetuses in the WSD group limited the ability to detect weaker defects of maternal WSD on fetal outcomes. It also limited the ability to examine sex differences in fetal hematopoiesis.Further studies are also needed to test whether maternal obesity disrupts offspring responses to infection and inflammation.

Despite these limitations, this study sets the stage for understanding the association between maternal obesity, prenatal diet and nutrition, and immune related diseases in children.

References:

1. Jagannathan-Bogdan, M., & Zon, L. I. (2013). Hematopoiesis. Development (Cambridge, England), 140(12), 2463–2467. https://doi.org/10.1242/dev.083147
2. Sureshchandra et al. (2022). Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques: Stem Cell Reports. . Retrieved November 19, 2022, from https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(22)00499-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2213671122004994%3Fshowall%3Dtrue#